MXPA00008843A

MXPA00008843A - Improved radiation therapy methods

Info

Publication number: MXPA00008843A
Application number: MXPA/A/2000/008843A
Authority: MX
Inventors: Kathleen E Rodgers; Gere Dizerega
Original assignee: Gere Dizerega; Kathleen E Rodgers; University Of Southern California
Priority date: 1998-03-10
Filing date: 2000-09-08
Publication date: 2001-07-09

Abstract

The present invention provides methods and kits for mitigating radiation induced tissue damage, improving the effectiveness of radiation therapy, to support bone marrow transplantation, and promoting megakaryocyte production and mobilization and platelet production, each method comprising the administration of an effective amount of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII), AII analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists.

Description

IMPROVED METHODS OF RADIATION THERAPY BACKGROUND OF THE INVENTION Radiation therapy is currently one of the most useful methods for the treatment of cancerous tumors. However, radiation therapy damages normal tissue surrounding the tumor (U.S. Patent No. 5,599,712, incorporated herein by reference in its entirety). This damage may include fibrosis, transformation of the extracellular matrix, vascular damage, abnormal angiogenesis, pneumonia, atherogenesis, osteonecrosis, mucositis, immunosuppression and functional weakness (U.S. Patent No. 5,616,561, incorporated herein by reference in its entirety). As a result of these side effects induced by radiation, techniques have been developed to minimize the radiation induced damage to the surrounding normal tissues by limiting the radiation to the lowest effective level for the treatment of cancer. Since there is a direct relationship between the amount of radiation and the effectiveness of the treatment, this method compromises the overall efficacy of the treatment. For some cancer patients, haematopoietic toxicity often limits the opportunity to raise the radiation dose (Watanabe et al., British J. Haematol, 94: 619-627 (1996)). High or repeated dose cycles of radiation therapy may be responsible for the severe reduction of pluripotent cells leading to significant long-term hematopoietic sequelae and bone marrow depletion (Masse et al., Blood 91: 441-449 ( 1998) This reduction of pluripotent cells leads to the reduction of the complete range of hematopoietic lineage-specific cells, including megakaryocytes, platelets, monocytes, neutrophils and lymphocytes and the complications resulting from such reduction, for example, in patients suffering from Reduced platelet count (thrombocytopenia) the inability to form clots is the most immediate and serious consequence, a potentially fatal complication of many cancer therapies, such patients with cancer are usually treated for this problem with platelet transfusions. of platelet transfusions are those that They undergo transplantation of the bone marrow or patients with aplastic anemia. The platelets for these procedures are obtained by plaquetoferesis from normal donors. Like most blood products, platelets for transfusion have a relatively short life span and also expose patients to considerable risk of exposure to dangerous viruses, such as acquired immunodeficiency virus (HIV). The administration of hematopoietic growth factors can reduce the short-term side effects induced by radiation, but has been freeze-dried to cause long-term haematopoietic damage (Masse et al., 1998; Watanabe et al., 1996). Several studies have suggested that the co-administration of negative hematopoietic regulators can minimize the myelotoxicity induced by radiation therapy by reducing a number of progenitor cells that penetrate the cell cycle. (Watanabe et al., 1996; Dunlop et al., Blood 79: 2221-2225 (1992); Paukovits et al., Blood 81: 1755-1761; Bodgen et al., Annals NY Acad. Sci. 628: 126- 139 (1191); Deeg et al., Ann .. Hematol 74: 117-122 (1997); Masse et al., 1998). This treatment is based on the premise that hematopoietic stem cells are relatively protected from radiation-related toxicity when inactive, particularly when the malignant cells are proliferating (DEG et al., (1997)). The bone marrow contains pluripotent progenitor cells that are capable of reconstructing the complete heamtopoietic system. Bone marrow transplantation has been used to treat several intractable hematopoietic diseases including leukemia and severe aplastic anemia. (Patent of U.S.A. No. 5, 186,931, incorporated herein by reference in its entirety). Typically, a patient with a bone marrow transplant undergoes irradiation to reduce the leukocyte count to zero, followed by transplantation of the bone marrow cells that function for the production of a sufficient number of normal leukocytes. However, several complications such as death, infectious diseases, graft against host disease, radiation nephritis, and interstitial pneumonia frequently occur during the period of time between transplantation and return to normal levels of white blood cells after transplantation. As a result of these frequent side effects, currently unsatisfactory methods are available to support bone marrow transplantation that are capable of increasing the survival of patients with bone marrow transplantation and also accelerate the reconstitution of the patient's hematopoietic system. Chronic radiation injuries, such as radiation nephropathy, have been observed as unavoidable, progressive and intractable (Moulder et al., Bone Marrow Transplantation 19: 729-731 (1997)). The intractable and progressive nature of late tissue damage follows the assumption that the injury is due to delayed mitotic cell death resulting from a genetic lesion that occurs and is irrevocably fixed in place at the time of irradiation (Moulder et al. al., 1997). From this point of view, the only way to reduce the likelihood of damage is by limiting the radiation dose or protecting the organs of risk. However, recent results indicate that late tissue injury induced by the onset of radiation it involves dynamic and complex interactions between vascular and parenchymal cells within an organ (Moulder et al., 1997). This model of chronic radiation damage suggests that this surgical intervention after exposure to radiation would be effective. Therefore, despite advances in the field of radiation therapy, prior art methods have proven to be of limited utility in minimizing radiation-induced tissue damage and improving the effectiveness of therapy. by radiation to tumors and bone marrow transplantation. Therefore, there is a need for improved therapeutic methods to mitigate tissue damage induced by radiation and to improve the effectiveness of radiation therapy. In addition, the ability to stimulate the formation of endogenous platelets in thrombocytopenic patients with a concomitant reduction in their dependence on platelet transfusion would be of great benefit. Apart from that, the ability to correct or prevent thrombocytopenia in patients undergoing radiation therapy or cancer chemotherapy would make said treatments safer and possibly allow increases in the intensity of the therapy thereby producing greater anti-cancer effects.

SUMMARY OF THE INVENTION In one aspect, the present invention provides methods and equipment to mitigate tissue damage induced by radiation, improving the effectiveness of radiation therapy to support bone marrow transplantation and promote the production of megakaryocytes and mobilization and the production of platelets, each method comprises the administration of angiotensinogen, angiotensin I (Al), Al analogs, Al fragments and analogs thereof, angiotensin II (All), All analogs, All fragments or analogs thereof or All receptor agonists. AT2 of type 2 to a patient in need of it. In another aspect of the present invention, there is provided an improved cell culture medium and equipment for the production of megakaryocytes and platelets wherein the improvement comprises the addition to the cell culture medium of an effective amount of angiotensinogen, Al, Al analogs, fragments Al and analogs thereof, All, All analogs, All or analogue fragments thereof or All AT2 type 2 receptor agonists. These aspects and other aspects of the invention become apparent in the light of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the effect of the All treatment two days before the exposure in post-irradiation mouse mortality, where: A = Survival percentage B = Treatment group a = day 12 b = day 15 c = day 22 Figure 2 is a graph showing the effect of the All treatment on the day of exposure on mouse post-irradiation mortality. Figure 3 is a graph showing the effect of the All treatment two days following the exposure in post-irradiation mouse mortality. Figure 4 is a graph showing the effect of the All treatment two days before exposure to a certain number of white blood cells after irradiation, where: C = Cells / ml (x106) D = days after irradiation a = day 12 b = day 15 d = day 5 e = day 8 Figure 5 is a graph showing the effect of the All treatment on the day of exposure in a certain number of white blood cells after irradiation. Figure 6 is a graph showing the effect of the All treatment two days following exposure to a certain number of white blood cells after irradiation. Figure 7 is a graph showing the effect of the All treatment two days before exposure in a certain number of megakaryocytes after irradiation.

Figure 8 is a graph showing the effect of All treatment on the day of exposure in a certain number of megakaryocytes after irradiation.

Figure 9 is a graph showing the effect of treatment two days after exposure in a megakaryocyte percentage after irradiation, where: E = Percentage D = Days after irradiation Figure 10 is a graph showing the effect of the Treatment All two days before exposure to a certain number of monocytes after irradiation. Figure 11 is a graph showing the effect of the All treatment on the day of exposure in a certain number of monocytes after irradiation.

Figure 12 is a graph showing the effect of the All treatment two days following exposure to a certain number of monocytes after irradiation. Figure 13 is a graph showing the effect of All treatment two days before exposure in a certain number of neutrophils after irradiation, where: F = Number / ml (x106) D = Days after irradiation Figure 14 is a graph showing the effect of treatment on the day of exposure on a certain number of neutrophils after irradiation.

Figure 15 is a graph showing the effect of the All treatment two days following exposure to a certain number of neutrophils after irradiation. Figure 16 is a graph showing the effect of All treatment two days before exposure in a certain number of lymphocytes after irradiation. Figure 17 is a graph showing the effect of the All treatment on the day of exposure in a certain number of lymphocytes after irradiation, Figure 18 is a graph showing the effect of the All treatment two days after exposure in a certain number of lymphocytes after irradiation. Figure 19 is a graph showing the effect of treatment with analogs and All fragments on a certain number of white blood cells after irradiation, where: G = GB / ml (x106) B = Treatment group f = day 7 g = day 14 h = day 21 Figure 20 is a graph showing the effect of treatment with analogs and All fragments on a certain number of platelets after irradiation, where: H = Platelets / ml (x108) B = Control Group f = day 7 g = day 14 h = day 21 Figure 21 is a graph showing the effect of All in a surviving mouse receiving a bone marrow transplant after lethal irradiation, where: A =% Survival I = Donor: Target Group Figure 22 is a graph showing the effect of treatment with analogs and All fragments on a certain number of white blood cells after irradiation. Figure 23 is a graph showing the effect of All on a certain number of white blood cells in the blood of mice receiving a bone marrow transplant after lethal irradiation, where: G = GB / ml (x106) J = Donor: Target source Figure 24 is a graph showing the effect of All in a certain number of white blood cells in the blood of mice receiving bone marrow transplantation after lethal irradiation.

BRIEF DESCRIPTION OF THE PREFERRED MODALITIES All references to patents and patent applications are incorporated herein in their entirety as a reference.

The present invention meets the needs of improved therapeutic methods to mitigate tissue damage induced by radiation, to improve the effectiveness of radiation therapy, to support bone marrow transplantation and to promote the production of megakaryocytes and the mobilization and production of platelets. As defined herein, the phrase "mitigation of tissue damage" refers not only to the reduction of damage, but also to recovery of tissue from damage. As used herein, "tissue" refers to any type of tissue and also includes hematopoietic progenitor and pluripotent cells, white blood cells and platelets. As defined herein, the term "mobilization of megakaryocytes" refers to the movement of a megakaryocyte precursor cell of the bone marrow in the periphery. As defined herein, the phrase "improved platelet production" or "improved megakaryocyte production" means that the number of platelets or megakaryocytes is significantly elevated above the normal range of platelets or megakaryocytes in the particular mammal involved. Elevation of platelet or megakaryocyte counts can occur in a time-dependent manner and can be cyclical, increasing and subsequently constant or decreasing or constant, etc. Unless indicated otherwise, the term "active agents" as used herein refers to the group of compounds comprising angiotensinogen, angiotensin I (Al), Al analogs, Al fragments and analogs thereof, angiotensin II. (All), All analogs, All or analogue fragments thereof and All AT2 receptor agonists of type 2. Within this application, unless otherwise stated, the techniques used can be found in any of several well-known references. such as: Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991, Academic Press, San. Diego CA), "Guide to Protein Purification" in Methods in Enzymology (MP Deutscher, ed. (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis, et al., 1990. Academic Press, San Diego, CA), Culture of Animal Cells: A Manual of Basic Technique, 2nd. Ed. (R. Freshney, 1987. Liss, Inc. New York.NY), Gene Transfer and Expression Protocols, pp. 109-128, ed. E.J. Murray, The Humana Press Inc., Clifton, NJ), and the Ambion Catalog 1998 (Ambion, Austin, TX). The Patent of E.U.A. No. 5,015,629 to DiZerega (the entire disclosure of which was incorporated herein by reference) discloses a method for increasing the healing rate of tissue from a wound, comprising the application to said tissue of angiotensin II (All) in a amount that is sufficient for said increase. The application of All to the wound tissue significantly increases the healing rate of the wound, leading to a faster re-epitelialization and repair of the tissue. The term "All" refers to an octapeptide present in humans and other species having the sequence Asp-Arg-Val-Tyr-lle-His-Pro-Phe [SEQ ID NO: 1]. The biological formation of angiotensin is initiated by the action of renin in the angiotensinogen of the plasma substrate. The substance formed is a decapeptide called angiotensin I (Al) that is converted to All through the conversion of the enzyme angiotensinase that removes the C-terminal residues His-Leu from Al (Asp-Arg-Val-Tyr-lle-His-Pro -Phe-His-Leu [SEQ ID NO: 37]). All is a known precursor agent and is commercially available. There has also been described the use of the fragments and analogs All, AT2 agonists, as well as there and analogues there and fragments in the healing of the wound.

(U.S. Patent No. 5,629,292; U.S. Patent No. 5,716,935; 96/39164; all references are incorporated in their entirety in this document).

Studies have shown that All increases mitogenesis and chemotaxis in cultured cells that are involved in wound repair and also increases their release of extracellular growth factors and matrices (diZerega, U.S. Patent No. 5,015,629; Dzau et al. al., J. Mol. Cell, Cardiol.21: S7 (Supp III) 1989, Berk et al., Hypertension 13: 305-14 (1989), Kawahara et al., BBRC 150: 52-9 (1988); Naftilan, et al., J. Clin Invest. 83: 1419-23 (1989); Taubman et al., J. Biol. Chem 264: 526-530 (1989); Nakahara, et al., BBRC 184: 811 -8 (1992), Stouffer and Owens, Ciro, Res. 70: 820 (1992), Wolf, et al., Am. J. Pathol., 140: 95-107 (1992), Bell and Madri, Am. Pathol., 137: 7-12 (1990) .In addition, the All proved to be angiogenic in the rabbit corneal eye and chicken chorioallantoic membrane models (Fernandez, et al., J. Lab. Clin. Med. 105: 141 ( 1985), LeNoble, et al., Eur. J. Pharmacol., 195: 305-6 (1991). Therefore, the All can accelerate the repair ration of the wound through increased neovascularization, release of growth factor, reepithelialization and / or extracellular matrix production.

All has also been applied in cell growth and differentiation (Meffert et al., Mol. And Cellul. Endocrin. 122: 59 (1996)). Two main classes of All, ATi and AT2 receptors have been identified (Meffert, 1996). The effects of the promotion of All growth have been attributed to mediation by the I receptor AT1, even though some evidence suggests that the AT2 receptor can be involved in mediating the effects of cellular differentiation of All (Bedecs et al., Biochem J. 325: 449 (1997)). The effects of the All receptor and the All receptor antagonists have been examined in two experimental models of vascular damage and repair that follow that both the All receptor subtypes (AT1 and AT2) play a role in wound healing (Janiak et al. , Hypertension 20: 737-45 (1992), Prescott, et al., Am. J. Pathol., 139: 1291-1296 (1991); Kauffman et al., Life Sci. 49: 223-228 (1991); , et al., Peptides 13: 783-786 (1992), Kimura, et al., BBRC 187: 1083-1090 (1992) Many studies have focused on AII (1-7) (residues All 1-7) or other All fragments to evaluate their activity The All (1-7) produces some, but not the full range of effects produced by the All. Pfeilschifter, et al., Eur. J. Pharmacol. 225: 57-62 (1992), Jaiswal, et al., Hypertension 19 (Supp.ll): ll-49-ll-55 (1992), Edwards and Stack, J. Pharmacol.Exper. Ther. 266: 506-510 (1993); Jaiswal, et al., J. Pharmacol., Exper. Ther 265: 664-673 (1991); Jaiswal, et al., Hypertension 17: 1 1 15-1 120 ( 1991); Portsi, et a., Br. J. Pharmacol. 1 1 1: 652-654 (1994). While a single pilot study has suggested that All in induced hypertension may be effective in combination with radiation therapy in the treatment of patients with lung cancer (Kato et al., Radiation Medicine 1 1: 86-90 (1993) ), many studies have shown that antagonists of the angiotensin converting enzyme (ACE), which mediates the production of All, are effective in reducing radiation nephropathy, nephropathy in bone marrow transplantation and acute radiation damage (Moulder). et al., Int. J. Radiation Onc. Biol .. Phys. 27: 93-99 (1993), Moulder et al., Bone Marow Transp. 19: 729-735 (1997); Moulder et al., Radiation Res. 146: 106-1 10 (1996); Cohen et al., J. Lab. Clin. Med. 129: 536-547 (1997); Moulder et al., Radiation Res. 136: 404-407 (1993); Yoon et al., Int. J. Radial Oncol. Biol. Phys. 30: 873-878 (1994), Ward et al., Radiation Res. 135: 81-87 (1993); Cohen et al., Lab. Invest. 75: 349-360 (1996); Cohen et al., J. Lab. Clin. Med. 124: 371-380 (1994); Gerarci et al., Radiation Res. 143: 58-68 (1995)). The effect of ACE inhibitors has been demonstrated, in at least one case, to be directly caused by the reduction of AT1 receptor activation by All (Moulder et al., Radiation Res. 146: 106-110 (1996)). These results have led to the suggestion that, in the case of radiation nephropathy, the most effective treatment is the use of ACE inhibitors (Moulder et al., Bone Marrow Transplantation 19: 729-735 (1997)). Furthermore, it has recently been shown that angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, All, All analogs, All fragments or analogues thereof or receptor agonists All AT2 of type 2 are potent stimulators of hematopoietic stem cell proliferation (U.S. Patent Application Serial No. 09 / 012,400 incorporated herein by reference in its entirety). Therefore, it would be expected that the use of these compounds could cause long-term hematopoietic damage if used in conjunction with radiation therapy (Masse et al., 1998; Watanabe et al., 1996). In accordance with the foregoing, it would be unexpected that the use of angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogs thereof, All, All analogues, All fragments or analogues of the The same or All AT2 type 2 receptor agonists would be effective in reducing damage to human tissue induced by radiation or treatment in patients in need of radiation therapy. None of these studies teaches or suggests the use of angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogs thereof, angiotensin II (All), All analogs, All fragments or analogs thereof or All AT2 receptor agonists. of type 2 to stimulate the production and mobilization of megakaryocytes or to stimulate the production of platelets. A peptide agonist selective for the AT2 receptor (All has 100 times higher affinity for AT2 than for AT1) is p-aminophenylalanine6-AII ["p-NH2-Phe) 6-AII"], Asp-Arg-Val- Tyr-lle-Xaa-Pro-Phe [SEQ ID NO. 36] where Xaa is p-NH2-Phe (Speth and Kim, BBRC 169: 997-1006 (1990) .This peptide gave comparable binding characteristics to the AT2 antagonists in the experimental models tested (Catalioto, et al., Eur. J. Pharmacol 256: 93-97 (1994), Bryson, et al., Eur. J. Pharmacol. 225: 119-127 (1992) Active Al, Al analogs, Al fragments and analogues of the same, All analogs, All fragments and analogues thereof of particular interest according to the present invention are characterized in that they comprise a sequence consisting of at least three contiguous amino acids of the groups R ^ R8 in the sequence of the formula general I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups , RA is appropriately selected from Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB and is appropriately selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Lie, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr, excluding sequences that include R4 as a terminal group Tyr. Compounds falling within the category of the AT2 agonists useful in the practice of the invention include the All analogs set forth above subject to the restriction that R6 is p-NH2-Phe. In addition to the peptide agents, various nopeptide agents (e.g., peptidomimetics) that have the activity requirement of the AT2 agonist are further contemplated for use in accordance with the present invention. Particularly preferred combinations for RA and RB are Asp-Arg, Asp-Lys, Glu-Arg and Glu-Lys. Particularly preferred embodiments of this class include the following: All, There or AII (2-8), Arg-Val-Tyr-lle-His-Pro-Phe [SEQ ID NO: 2j; AII (3-8), also known as desl-AIII or AIV, Val-Tyr-lle-Hls-Pro-Phe [SEQ ID NO: 3]; AII (1-7), Asp-Arg-Val-Tyr-lle-His-Pro [SEQ ID NO: 4]; AII (2-7). Arg- Val-Tyr-lle-His-Pro [SEQ ID NO: 5]; At 1 (3-7), Val-Tyr-lle-His-Pro [SEQ ID NO: 6]; AII (5-8), lle-His-Pro-Phe [SEQ ID NO: 7]; AII (1-6), Asp-Arg-Val-Tyr-lle-His [SEC ID NO: 8]; AII (1-5), Asp-Arg-Val-Tyr-lle [SEQ ID NO: 9]; AII (1-4), Asp-Arg-Val-Tyr [SEC ID NO: 10] and AII (1-3), Asp-Arg-Val [SEQ ID NO: 11]. Other preferred embodiments include: Arg-norLeu-Tyr-lle-His-Pro-Phe [SEQ ID NO: 12] and Arg-Val-Tyr-norLeu- His-Pro-Phe [SEQ ID NO: 13]. Another preferred embodiment comprised within the scope of the invention is a peptide having the sequence Asp-Arg-Pro-Tyr-lle-His-Pro-Phe [SEQ ID NO: 31]. At 1 (6-8), His-Pro-Phe [SEQ ID NO: 14] and A1 (4-8), Tyr-lle-His-Pro-Phe [SEQ ID NO: 15], were also tested and It was found that they are not effective. A class of particularly preferred compounds according to the present invention consists of those with the following general structure: R1 -Arg-R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, lie, Leu and norLeu and R5 is Phe, lie or is absent. A particularly preferred embodiment of this class is selected from the group consisting of SEQ ID NO: 1; SEQ ID NO: 4; SEQ ID NO: 18; SEQ ID NO: 26; SEQ ID NO: 31; SEQ ID NO: 32; SEQ ID NO: 34 and SEQ ID NO: 38. Another class of compounds of particular interest according to the present invention are those of the general formula II R2-R3-R4-R5-R6-R7-R8 wherein R2 is selected from the group consisting of H, Arg, Lys, Ala , Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Me, Gly, Pro, Aib, Acpc and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr. A particularly preferred sub-class of the compounds of the general formula II has the formula R2-R3-Tyr-R5-His-Pro-Phe [SEQ ID NO: 16] wherein R2, R3 and R5 are as previously defined. Particularly preferred is angiotensin III of the formula Arg-Val-Tyr-lle-His-Pro-Phe [SEQ ID NO: 2]. Other preferred compounds include peptides having the structures Arg-Val-Tyr-Gly-His-Pro-Phe [SEQ ID NO: 17] and Arg-Val-Tyr-Ala-His-Pro-Phe [SEQ ID NO: 18] . The AII fragment (4-8) was ineffective in the repeated tests; this is believed due to the tyrosine exposed in the N-terminus. In the above formulas, the standard three-letter abbreviations for amino acid residues are used. In the absence of an indication to the contrary, the L form of the amino acid is tried. Other waste is abbreviated as follows: TABLE 1 Abbreviation for Amino Acids It has been suggested that the All and its analogues adopt a gamma or beta turn (Regoli, et al., Pharmacological Reviews 26:69 (1974).) In general, it is believed that the neutral side chains in position R3, R5 and R7 can be involved in maintaining the appropriate distance between the active groups in positions R4, R6 and R8 basically responsible for binding to receptors and / or intrinsic activity.The hydrophobic side chains in positions R3, R5 and R8 can also play an important role in the complete conformation of the peptide and / or contribute to the formation of a hypothetical hydrophobic cavity The appropriate side chains in the amino acid in the R2 position can contribute to the affinity of the compounds for target receptors and / or play an important role in the conformation of the peptide For this reason, Arg and Lys are particularly preferred as R. For purposes of the present invention, it is considered that R3 can be involved in the formation of linear and non-linear hydrogen bonds with R5 (in the gamma model) or R6 (in the beta rotation model). R3 would also participate in the first turn in an antiparallel beta structure (which has also been proposed as a possible structure). In contrast to other positions in general formula I, it appears that the beta and gamma branches are equally effective in this position. In addition, a single hydrogen bond may be sufficient to maintain a relatively stable conformation. Accordingly, R3 can be appropriately selected from Val, Ala, Leu, norLeu, Lie, Gly, Pro, Aib, Acpc and Tyr. In another preferred embodiment, R3 is Lys. With respect to R4, conformational analyzes have suggested that the side chain in this position (as well as in R3 and R5) contributes to a hydrophobic cluster that is believed to be essential for receptor occupancy and stimulation. Therefore, R4 is preferably selected from Tyr, Thr, Tyr (P03) 2, homoSer and azaTyr. In this position, Tyr is particularly preferred to form a hydrogen bond with the receptor site capable of accepting a hydrogen from the phenolic hydroxyl (Regoli, et al. (1974), supra). In a further preferred embodiment, R4 is Ala.

In the R5 position, an amino acid with an aliphatic or alicyclic β chain is particularly desirable. Therefore, while Gly is appropriate in the R5 position, it is preferred that the amino acid in this position be selected from lie, Ala, Leu, norLeu, Gly and Val. In Al, Al analogs, Al fragments and analogues thereof, All, analogs There, fragments and analogues of fragments of particular interest according to the present invention, R6 is His, Arg or 6-NH2-Phe. The unique properties of the imidazole ring of histidine (eg, ionization at physiological pH, the ability to act as a donor or proton acceptor, aromatic character) are considered to contribute to its particular utility as R6. For example, conformational models suggest that His can participate in hydrogen bond formation (in the beta model) or in the second antiparallel structure spin by influencing the orientation of R7. Similarly, it is considered that R7 should be Pro to provide the most desirable orientation of R8. In the R8 position, a hydrophobic ring and a terminal anionic carboxyl are particularly useful in binding the analogs of interest to the receptors; therefore, Tyr and especially Phe are preferred for purposes of the present invention. Analogs of particular interest include the following: TABLE 2 Angiotensin Analogs The polypeptides of the present invention can be synthesized by methods such as those described in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. ed., Pierce Chemical Co., Rockford, Ill. (1984) and J. Meienhofer, Hormonal Proteins and Peptides, Vol. 2, Academic Press, New York, (1973) for solid phase synthesis and E. Schroder and K. Lubke, The Peptides, Vol. 1, Academic Press, New York (1965) for the synthesis of the solution. The descriptions of the above treaties are incorporated herein by reference. In general, these methods involve the sequential addition of protected amino acids to a chain of growth peptides (U.S. Patent No. 5,693,616, incorporated herein by reference in its entirety). Normally, the amino or carboxyl group of the first amino acid and any reactive side chain group are protected. This protected amino acid is subsequently bound to an inert solid support or used in solution and the next amino acid in the sequence, also appropriately protected, is added under conditions treatable for the formation of the amide bond. After all the desired amino acids have been linked in the proper sequence, the protecting groups and any solid support are removed to produce the natural polypeptide. The polypeptide is desalted and purified, preferably chromatographically to produce the final product. In one aspect, the present invention provides methods and equipment for mitigating tissue damage due to radiation exposure comprising the administration of angiotensinogen, angiotensin I (Al), Al analogs, Al fragments and analogs thereof, angiotensin II ( All), All analogs, All or analogue fragments thereof or AT2 receptor agonists of type 2 (the "active agents"). In another aspect, the present invention provides improved methods and equipment for treating a patient afflicted with a neoplastic disease state that is being treated with ionizing or non-ionizing radiation, the improvement comprises a conjunctive therapy wherein an effective radioprotective amount of the active agents. In another aspect, the present invention provides improved methods and equipment for treating a patient in need of radiation therapy, the improvement comprising administration of the active agents together with radiation therapy. The invention is suitable for use with any type of exposure to ionizing radiation such as therapeutic or accidental X-rays, gamma rays or exposure to beta particles. Examples of exposure to ionizing radiation appropriate for treatment with the methods and equipment of the present invention include, but are not limited to, clinical radiation therapy, medical diagnoses using radioactive indicators, exposure to sources of ionizing radiation of natural occurrence such as uranium and radon, wartime exposure and accidental exposures including occupational exposure in nuclear power facilities and research and medical institutions. Examples of exposure to non-ionizing radiation suitable for treatment with the methods and equipment of the present invention include, but are not limited to, ultraviolet light, X-rays, microwaves, radio frequency waves and electromagnetic radiation.

Virtually any tissue susceptible to tissue damage induced by radiation can obtain protection through the use of the active agents of the invention. For example, breast tissue is an excellent candidate to receive the benefit of the object of the invention. Radiation-induced tissue damage can be a fatal side effect of overexposure to radiation therapy. Typically, the common fibrotic reaction in normal breast tissue around a cancerous tumor being treated with radiation therapy undermines the cosmetic benefits of radiation therapy in a surgical treatment. This disadvantage would lead many patients to choose a less effective and more dangerous treatment after radiation therapy. The present invention is also particularly suitable for those patients in need of high or repeated doses of radiation therapy. For some patients with cancer, hematopoietic toxicity often limits the opportunity to raise radiation doses (Watanabe et al., British J. Haematol, 94: 619-627 (1996)). High or repeated dose cycles of radiation therapy may be responsible for the severe reduction of pluripotent cells leading to important long-term hematopoietic sequelae and bone marrow depletion. The methods of the present invention provide improved mortality and counting of red blood cells when used in conjunction with radiation therapy. Skin exposure is particularly common in accidental exposure to radiation. This is an excellent candidate for inventive therapy, especially as the compounds of the invention can be administered topically. Other tissues that are susceptible to radiation-induced damage following exposure to non-ionizing or therapeutic or accidental ionizing radiation include but are not limited to: liver, lung, gastrointestinal tract, kidneys, testes, salivary glands, mucosa, and brain. In another aspect, the present invention provides improved methods and equipment to support bone marrow transplantation comprising administering the active agents to a patient in need thereof.

These compounds can be administered in combination with auxiliary agents including, but not limited to, interleukin (IL) -3, IL-1, II-4, 11-5, granule-colony stimulation factor (G-CSF), stimulation of the granulocyte-macrophage colony (GM-CSF), macrophage colony stimulation factor (M-CSF), anticancer agents, antiviral agents and antibiotics. In a further aspect, the present invention provides equipment for mitigating tissue damage induced by radiation and improving the effectiveness of radiation therapy, wherein the equipment comprises an effective amount of the active agents of the invention to mitigate tissue damage. induced by radiation or improve the effectiveness of radiation therapy and instructions for using the effective amount of the active agent as a therapeutic. In a preferred embodiment, the kit further comprises a pharmaceutically acceptable carrier, such as those adjuvants described above. In another preferred embodiment, the kit further comprises a means for releasing the active agent in a patient. Such devices include, but are not limited to injections, micellar or matrix solutions, dressings, wound preparations, aerosols, lipid foams, transdermal patches, topical administration agents, polyethylene glycol polymers, carboxymethyl cellulose preparations, crystalloid preparations (e.g. , saline solution, Ringer's lactate solution, stabilized phosphate saline solution, etc.), viscoelastic, polyethylene glycols and polypropylene glycols. The means for the release may contain the effective amount of angiotensinogen, Al, Al analogs, Al fragments and analogs thereof., All, All analogs or analogs thereof or All AT2 receptor agonists of type 2 or can be separated from the compounds, which are subsequently applied to the means for release at the time of use. The methods and equipment of the present invention, by mitigating tissue damage induced by radiation and improving the effectiveness of radiation therapy and bone marrow transplantation, significantly improves the utility of currently available treatments for damage to tissue induced by radiation and for clinical radiation therapy. In a further aspect of the present invention, a method is described for increasing the production and mobilization of megakaryocytes and the production of platelets by exposure to the active agents of the inventions. In one embodiment, megakaryocytes are isolated from the bone marrow as described in the U.S. Patent. No. 5,178,856 incorporated herein by reference in its entirety. Briefly, the marrow is removed from the femur of a subject with Iscove's modified Dulbecco's medium (IMDM) supplemented with Nutridoma-SP (Boehringer Mannheim, Indianapolis, Ind.), A complement of serum-free medium. For culture studies, a single cell suspension was developed by repetitive ejection through progressively smaller needles. For flow cytometric controls, a single-cell suspension was made by gentle filtration through a 100-micron nylon mesh. Preferably, the adherent cells were removed to enrich the number of megakaryocytes or their progenitor cells. Up to 2 x 106 cells / ml were placed in a growth medium at 37 ° C in a humidified atmosphere in the presence of, preferably, between about 0.1 ng / ml and about 10 mg / ml of the active agents. The cells expanded for a period of between 2 and 21 days and the cell proliferation was determined several times during this period of time. Subsequent changes of the medium were made as needed. In a preferred embodiment, the production and mobilization of megakaryocytes and the production of platelets were determined by extension of the ploidization by flow cytometry as described in the U.S. Patent. No. 5,155.21 1, incorporated herein by reference in its entirety. Briefly, the appearance of granules and the wide surface area connected to the open canalicular membrane system as well as a substantial decrease in the nucleus: cytoplasm volume distribution, indicates that the megakaryocyte population has completed the polyploidization process but has not yet generated a important portion of its final complement of platelet-specific cytoplasmic components. In another embodiment, subjects were irradiated as mentioned above and the active agent was first injected subcutaneously, at the time of and after irradiation. Blood samples were taken several times after administration of the active agent to monitor the number of white blood cells, megakaryocytes and platelets. In a preferred embodiment, subjects were treated with total body irradiation and the active agent was administered subcutaneously (10 μg / kg / day or 100 μg / kg / day) several times before and after irradiation. The number of white blood cells, megakaryocytes and platelets was preferably determined by counting with a hemacytometer followed by differential morphological analysis.

In another embodiment of this aspect of the invention, hematopoietic precursor cells were isolated from the peripheral blood of bone marrow or umbilical cord blood and cultured under appropriate growth conditions, in the presence of the active agents. megakaryocytes was determined several times during culture by differential morphological analysis. In a preferred embodiment, the hematopoietic precursor cells were isolated from the bone marrow aspirated from the posterior iliac crest (Caplan and Haynesworth, U.S. Patent No. 5,486,359). CD34 + hematopoietic precursor cells were isolated from the aspirate by adding a biotinylated monoclonal antibody specific for CD34 (available from Becton Dickinson, Sunnyvale, CA, USA) for a streptavidin affinity column (Ceprate SC, CellPro, Bothell, WA, USA) and passing the aspirated through the column, following proper washing of the column and agitation, in accordance with standard techniques in the art. The isolated cells were suspended in the culture medium and incubated in the presence of, preferably, between about 0.1 ng / ml and about 10 mg / ml of the active agents of the invention. The cells expanded for a period of between 8 and 21 days and the production of megakaryocytes was determined via phase microscopy to detect the increased size and polyploidization several times during this period of time. In a further embodiment of the present invention, a method of increasing the production and mobilization of megakaryocytes and the production of platelets by exposure to active agents, either in the presence or absence of other growth factors and cytokines, is described. Examples of said growth factors and cytokines include, but are not limited to thrombopoietin, lymphokines, interleukins -1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, stimulation factor of the colony of granulosites, granulation / macrophage colony stimulation factor, macrophage colony stimulation factor, tumor necrosis factor, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, beta factor transformation growth and factor of the pluripotent cells. In a preferred embodiment, megakaryocytes and / or platelets that have been cultured in the presence of active agents are used for autologous transplantation to reconstitute an exhausted hematopoietic system. Before transplantation, the cells are rinsed to remove all traces of fluid from the culture, resuspended in an appropriate medium and subsequently granulated and rinsed several times. After final rinsing, the cells were resuspended at between OJ x 106 and 50 x 106 cells per ml in an appropriate medium and reinfused in a subject through intravenous infusions. Following transplantation, peripheral blood samples from the subject were evaluated for the number of platelets and the megakaryocyte ploid increased by flow cytometry and cell sorting techniques. (Talmadge, et al., Supra). In another aspect of the present invention the active agents are used to increase the production and mobilization of megakaryocytes and the production of platelets in vivo. For use in increasing the production and mobilization of megakaryocytes and the production of platelets, the active agents can be administered by any appropriate route, including oral, parental, by inhalation spray, rectally or topically in unit dose formulations containing carriers, adjuvants and conventional pharmaceutically acceptable vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion or intraperitoneally. The active agents of the invention can be manufactured in a solid form (including granules), powders or suppositories) or in a liquid form (for example, solutions, suspensions or emulsions). The compounds of the invention can be applied in a variety of solutions. Appropriate solutions for use in accordance with the invention are sterile, dissolve sufficient amounts of the peptide and are not harmful to the proposed application. In this regard, the compounds of the present invention are very stable but are hydrolyzed by strong acids and bases. The compounds of the present invention are soluble in organic solvents and in aqueous solutions at a pH of 5-8. The active agents can be subjected to conventional pharmaceutical operations such as sterilization and / or they can contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, regulators, etc. For administration, the active agents ordinarily are combined with one or more of the appropriate adjuvants for the indicated route of administration. The compounds can be mixed with lactose, sucrose, starch powder, cellulose esters or alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of sulfuric and phosphoric acids, acacia, gelatin, sodium alginate. , polyvinylpyrrolidine and / or polyvinyl alcohol and are tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention can be dissolved in saline, water, polyethylene glycol, propylene glycol, colloidal solutions of carboxymethyl cellulose, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum and / or several stabilizers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include a retarding material such as glyceryl monostearate or glyceryl distearate alone or with a wax or other materials well known in the art. Formulations suitable for topical administration include liquid or semi-liquid preparations for penetration through the skin (eg, liniments, lotions, ointments, creams or pastes) and appropriate drops for administration to the eye, ear or nose. The dose regimen for mitigating radiation induced tissue damage and improving the effectiveness of radiation therapy with active agents is based on a variety of factors, including the type of damage, age, weight, sex , the medical condition of the individual, the severity of the condition, the route of administration and the particular compound used. Therefore, the dosage regimen can vary widely, but can be determined routinely by a physician using standard methods. The dose levels in the order of between 0.1 ng / kg and 10 mg / kg per body weight of the active agents are useful for all the methods of use described herein.

The treatment regimen will also vary depending on the disease being treated, based on a variety of factors, including the type of injury, age, weight, sex, individual's medical condition, the severity of the condition, the route of administration and the particular compound employed. For example, active agents are administered to an oncological patient for more than 30 days before a radiation therapy method and for more than 60 days post-exposure to radiation. The therapy is administered 1 to 6 times per day in the doses described above. In all of these embodiments, the compounds of the invention may be administered prior to, concurrent with or subsequent to exposure to radiation. In a preferred embodiment, the active agent is administered subcutaneously. An appropriate subcutaneous dose of the active ingredient of the active agent is preferably between about 0.1 ng / kg and about 10 mg / kg administered twice a day for a sufficient time to mitigate tissue damage induced by radiation, to provide a radioprotective effect for the radiation therapy for a patient affected with a neoplastic disease, to effectively treat a patient in need of radiation therapy, to support bone marrow transplantation and to promote the production and mobilization of megakaryocytes and the production of platelets. In a preferred embodiment, the concentration of the active agent is between about 100 ng / kg per body weight and about 10.0 mg / kg per body weight. In a more preferred embodiment, the concentration of the active agent is between about 10 μg / kg per body weight and about 10.0 mg / kg per body weight. This dose regimen maximizes the therapeutic benefits of the subject of the invention while minimizing the amount of the agonist or peptide needed. Such an application minimizes costs as well as possible deleterious side effects. For subcutaneous administration, the active ingredient may comprise from 0.0001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w / w, but preferably not more than 5% w / w and more preferably from 0.1% to 1% of the formulation. In another preferred embodiment of the present invention, the culture agent is administered topically. The appropriate topical dose and the concentration of the active ingredient in the formulation are as described for subcutaneous administration. In a preferred embodiment of all aspects of the invention, the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO.16, SEQ ID NO: 17, SEQ ID NO.18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO.31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36 and SEQ ID NO: 37.

In a preferred embodiment of the above aspects of the invention, the administration of the active agent is localized in the affected area by radiation damaging the tissue. In another aspect of the present invention, an improved cell culture medium is provided for the production of platelets and megakaryocytes, wherein the improvement comprises adding to the cell culture medium an effective amount of between about 0.1 ng and 10 mg / ml of the active agents of the invention. Any cell culture medium that supports the production of platelets and megakaryocytes can be used with the present invention. Said cell culture medium includes, but is not limited to Eagle Basal Medium, Dulbecco Modified Eagle Medium, Iscove Modified Dulbecco's Medium, McCoy's Medium, Minimum Essential Medium, F-10 Nutrient Mixtures, Opti-MEM® Reduced Serum Medium, RPMI Medium, and Macrophage-SFM Medium or combinations thereof. The improved cell culture medium can be provided in a concentrated or non-concentrated form (for example: 10X) and can be provided as a liquid, a powder or a lyophilisate. The cell culture can be chemically defined or it can contain a serum supplement. The culture medium is commercially available from many sources, such as GIBCO BRL (Gaithersburg, MD) and Sigma (St. Louis, MO). In a further aspect, the present invention provides equipment for the production of platelets and megakaryocytes, wherein the equipment comprises an effective amount for the production of platelets and megakaryocytes of the active agents of the invention and instructions for their use as a supplement to the medium of cell culture. In a preferred embodiment, the kit comprises a cell growth culture medium. Any cell culture medium that can support the production of platelets and megakaryocytes can be used with the present invention. Examples of said cell culture media are described above. The cell culture medium can be provided in a concentrated or non-concentrated form (for example: 10X) and can be provided as a liquid, a powder or a lyophilisate. The culture medium can be defined chemically or it can contain a serum supplement. In a further preferred embodiment, the kit further comprises a sterile container which may comprise a sealed container, such as a cell culture flask, an expansion pack or a centrifuge tube or an unsealed container, such as a cell culture dish or chemical microconcentration dish (Nunc; Naperville, IL). In another preferred embodiment, the kit further comprises an antibiotic supplement for inclusion in the reconstituted cell growth medium. Examples of appropriate antibiotic supplements include, but are not limited to, actimonicin D, Fungizone®, kanamycin, neomycin, nystatin, penicillin, streptomycin or combinations thereof (GIBCO). The present invention can be better understood with reference to the accompanying examples which are for illustrative purposes only and should not limit the scope of the invention, as defined by the appended claims.

Example 1. Effect of All on mortality and recovery of white blood cells in rats after irradiation Female C57B1 / 6 mice (Jackson Labs, Bar Harbor, Maine) were irradiated with total body irradiation 600 cGy. Subcutaneous injection with All (10 μg / kg / day or 100 μg / kg / day) or saline (placebo) was started two days before (-day 2), on the day of (day 0) or 2 days after ( + day 2) of the irradiation and continued until the animals succumbed to irradiation or were necropsied. Several times after irradiation, the mice were anesthetized with Metofan (Pittman-Moore Animal Health, NZ) and bled via the retro-orbital sinus. The red blood cells were used with 0.3% acetic acid and the number of white blood cells was determined by counting with a hemacytometer. The data in Figures 1-3 show that administration of All starting two days before irradiation did not protect against mortality resulting from irradiation (Figure 1), but that the administration of All on the day of irradiation (Figure 1) 2) or two days after irradiation (Figure 3) substantially increased survival. In addition, the administration of All in all tested periods always increased the number of circulating white blood cells (Figures 4-6). Additional experiments demonstrated that the administration of All increased the number of megakaryocytes (Figures 7-9), monocytes (Figures 10-12), neutrophils (Figures 13-15) and lymphocytes (Figures 16-18). These data demonstrate that the in vivo administration of All can improve hematopoietic recovery after irradiation.

Example 2. Effect of All, Analogs / All Fragments in GB and Platelet Numbers After Irradiation Animals were irradiated and treated as in Example 1, however, treatment was started on day 0 only with a subcutaneous injection of 10 μg / kg or 100 μg / kg daily until the study was completed. Analogs and fragments of All (see Table 3) were determined for their effect on the recovery of GB and the number of platelets after irradiation. The data are shown in Figures 20 and 21 and show that the peptides increase the production of both of these blood elements.

Table 3: Designation of Analogs / Fragments Name Abbreviation Sequence SEC ID NO GSD 28 lle8-AII DRVYIHPI SEQ ID NO: 38 GSD 24B Pro3-AII DRPYIHPF SEQ ID NO: 31 GSD 22A Ala4-AIII RVYAHPF SEQ ID NO: 18 All (1-7) DRVYIHP SEC ID NO: 4 All DRVYIHPF SEC ID NO: 1 Example 3. Effect of All on the survival of mice receiving bone marrow transplantation after lethal irradiation. C57B1 / 6 donor mice (females, 6-8 weeks) were irradiated with total body irradiation 600 cGy. Starting on the day of irradiation, the mice received either saline (0.1 ml) or 20 μg / ml angiotensin II (0.1 ml, 100 μg / kg) subcutaneously for fourteen days. At the end of this period, the bone marrow was collected from the femur by flowering and the number of viable nucleated cells was determined by counting under a light microscope in a hemac.tometer in the presence of trypan blue. These bone cell donor cells were subsequently injected intravenously into the recipient mice (C57B1 / 6 females, 6-8 weeks old) that had been lethally irradiated (total body irradiation 900 cGy) in two concentrations 1 x 106 or 1 x 105 cells per mouse. After injection, the recipient mice received saline or 100 μg / kg All subcutaneously until death or termination. This study design in its entirety is as follows: Donor Recipient Number of cells Saline solution Saline solution 1 x 106 Saline solution Saline solution 1 x 105 Saline solution All 1 x 106 Saline solution All 1 x 105 All Saline solution 1 x 106 All Saline solution 1 x 105 All All 1 x 106 All All 1 x 105 The survival of the mice and the number of white blood cells circulating was measured as a function of post-transplant time of the bone marrow. The data are presented in Figures 22-24 and demonstrate that All treatment increased both survival and the number of white blood cells in mice receiving bone marrow transplantation after irradiation. The greatest benefit was conferred by treating the white blood cells and the recipient mice with All.

The methand equipment of the present invention, by mitigating radiation induced tissue damage and improving the effectiveness of radiation therapy, significantly improve the usefulness of currently available treatments for tissue damage induced by radiation and for Clinical radiation therapy, as well as for bone marrow transplantation, by increasing the range of survival of patients and accelerating the reconstitution of the hematopoietic system of patients. Similarly, by providing a method for the production of platelets and megakaryocytes, the present invention will greatly enhance the clinical treatments of cancer and bone marrow transplantation and other conditions that lead to decreased production and mobilization of megakaryocytes and the production of platelets. The method of the present invention also decreases the utility potential of megakaryocytes as vehicles for gene therapy in haematopoietic disorders by providing a more efficient means to rapidly expand the transfected megakaryocytes. It is understood that the invention is not limited to the details or exact operation or to the exact compounds, compositions, meth procedures or modalities shown and described, as obvious and equivalent modifications that will be apparent to those skilled in the art and the invention is so both limited only by the full scope of the claims that accompany it.

Claims

1. A method for mitigating tissue damage due to radiation exposure comprising administering an effective amount for mitigation of tissue damage of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg. , Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, lie, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal group Tyr.

2. The method according to claim, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11. SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

3. An improved method of radiation therapy for a patient suffering from a neoplastic disease state, the improvement comprises administration in conjunctive therapy of an effective radioprotective amount of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, in where X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Lie, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, norLeu, Val and Giy; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr, excluding sequences that include R4 as a terminal group Tyr.

4. The method according to claim 3, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

5. An improved method of treating a patient in need of radiation therapy, wherein the improvement comprises administering to said patient an effective amount of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg. , Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Lie, .Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr, excluding sequences that include R4 as a terminal group Tyr.

6. The method according to claim 5, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO.10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO.13, SEC ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO 20, SEQ ID NO: 21. SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38

7. The method according to claims 1, 3 or 5, wherein the active agent is SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31. SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

8. A kit for treating a patient suffering from a neoplastic disease state, comprising: (a) an effective radioprotective amount of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R 1 -R 8 in al sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn , Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Lie, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding the sequences that include R4 as a terminal group Tyr and (b) instructions for using the effective radioprotective amount of the active agent to treat a patient with a neoplastic disease.

9. The kit according to claim 8, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEC ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO : 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32 , SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

10. The equipment according to claim 8, further comprises a means for the release of the active agent.

1 1. A device for treating a patient in need of radiation therapy, comprising: (a) an effective amount to treat a patient in need of radiation therapy of at least one active agent comprising a sequence consisting of at least one three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA- RB-, where X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Lie, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal group Tyr and (b) instructions for using the effective amount of the active agent to treat a patient in need of radiation therapy.

12. The kit according to claim 1, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO.10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13 . SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO.19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

13. The equipment according to claim 11, further comprises a means for the release of the active agent.

14. The kit according to claim 8 or 11, wherein the active agent is SEQ ID: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31, SEQ ID NO. : 32, SEQ ID NO: 34 and SEQ ID NO: 38.

15. An improved method of bone marrow transplantation, the improvement comprising the administration of an effective amount of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn, Ser (Ac) , Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr, excluding sequences that include R4 as a terminal group Tyr.

16. The method according to claim 15, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO.10, SEQ ID NO: 1 1. SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO 20, SEQ ID NO: 21. SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38

17. The method according to claim 15, wherein the active agent is SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO 26, SEQ ID NO: 31, SEQ ID NO: 32 , SEQ ID NO: 34 and SEQ ID NO: 38.

18. A bone marrow transplant team comprising: (a) An amount effective to support the bone marrow transplantation of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr, excluding sequences that include R4 as a terminal group Tyr. (b) instructions for using the effective amount of the active agent to support bone marrow transplantation.

19. The kit according to claim 18, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO.10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13. SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO 20, SEQ ID No. 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

20. The equipment according to claim 18, wherein the active agent is SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO 26, SEQ ID NO: 31, SEQ ID NO: 32 , SEQ ID NO: 34 and SEQ ID NO: 38.

21. The equipment according to claim 18, further comprising a means for the release of the active agent.

22. A method for increasing the production and mobilization of megakaryocytes and the production of platelets in a mammal, comprising administering to the mammal an amount effective for the production and mobilization of megakaryocytes and the production of platelets from at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R -R5-R6-R7-R8 in which R1 and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr, excluding sequences that include R4 as a terminal group Tyr.

23. The method according to claim 22, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEC ID N0: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO. : 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32 , SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

24. The method according to claim 22, wherein the active agent is SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31, SEQ ID NO: 32 , SEQ ID NO: 34 and SEQ ID NO: 38.

25. An improved cell culture medium for the production of platelets and megakaryocytes, wherein the improvement comprises the addition to the cell culture medium of an effective amount to accelerate the production of platelets and megakaryocytes of at least one active agent comprising a sequence consisting of of at least three contiguous amino acids of the groups R -R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of formula X -RA-RB-, where X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Lie, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal group Tyr.

26. The improved cell culture medium according to claim 20, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEC ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12. SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19. SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO.29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

27. The improved cell culture medium according to claim 20, wherein the active agent is SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31, SEC ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

28. A kit for the production of platelets and megakaryocytes, comprising: (a) an amount effective to increase the production of platelets and megakaryocytes of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the R1- groups R8 in the sequence of the general formula I R1-R -R3-R4-R5-R6-R7-R8 in which R and R2 together form a group of formula X-RA-RB-, wherein X is H or one of the three peptide groups, RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (P03) 2, Thr, Ser, homoSer, Ala and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal group Tyr. (b) instructions for using the effective amount of the active agent as a supplement of the cell culture medium.

29. The equipment according to claim 28, further comprising a cell growth medium.

30. The equipment according to claim 28, further comprising a sterile container.

31. The kit according to claim 28, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEC ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO : 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32 , SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38.

32. The kit according to claim 28, wherein the active agent is SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31, SEQ ID NO: 32 , SEQ ID NO: 34 and SEQ ID NO: 38.

33. A method for mitigating tissue damage due to radiation exposure comprising the administration of an effective amount for mitigation of tissue damage of at least one active agent comprising a sequence of the following general formula: R1 -Arg- R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, He, Leu and norLeu and R5 is Phe, He or is absent.

34. The method according to claim 33, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

35. An improved method of radiation therapy for a patient suffering from a neoplastic disease state, the improvement comprises administration in conjunctive therapy of an effective radioprotective amount of at least one active agent comprising a sequence of the following general formula: R1-Arg-R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, Lie, Leu and NorLeu and R5 is Phe, He or is absent.

36. The method according to claim 35, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

37. An improved method of treating a patient in need of radiation therapy, wherein the improvement comprises administering to said patient an effective amount to treat a patient in need of radiation therapy of at least one active agent comprising a sequence of the following general formula: R1 -Arg-R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, lie, Leu and norLeu and R5 is Phe, lie or is absent.

38. The method according to claim 37, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18. SEQ ID NO: 26, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

39. A kit for treating a patient suffering from a neoplastic disease state, comprising: (a) an effective radioprotective amount of at least one active agent comprising a sequence of the following general formula: R1-Arg-R2-R3-R4 -His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2, R4 is selected from the group consisting of Ala, lie, Leu and norLeu and R5 is Phe, He or is absent and (b) instructions for using the radioprotective amount effective of the active agent to treat a patient with a neoplastic disease.

40. The kit according to claim 39, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

41. The equipment according to claim 39, further comprises a means for the release of the active agent.

42. A device for treating a patient in need of radiation therapy, comprising: (a) an effective amount to treat a patient in need of radiation therapy of at least one active agent comprising a sequence of the following general formula: R1 -Arg-R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, Lie, Leu and NorLeu and R5 is Phe, He or is absent. (b) instructions for using the effective amount of the active agent to treat a patient in need of radiation therapy.

43. The kit according to claim 42, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

44. The equipment according to claim 42, further comprising a means for the release of the active agent.

45. An improved method of bone marrow transplantation, the improvement comprises a sequence of the following general formula: R1 -Arg-R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, He, Leu and norLeu and R5 is Phe, lie or is absent.

46. The method according to claim 45, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

47. A bone marrow transplant team, comprising: (a) an effective amount to support the bone marrow transplantation of at least one active agent comprising a sequence of the following general formula: R1 -Arg-R2-R3-R4 -His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, He, Leu and norLeu and R5 is Phe, lie or is absent. (b) instructions for using the effective amount of the active agent to support bone marrow transplantation.

48. The equipment according to claim 47, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEC ID NO: 18, SEQ ID NO: 26, SEQ ID NO.31, SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

49. The equipment according to claim 47, further comprising a means for the release of the active agent.

50. A method for increasing the production and mobilization of megakaryocytes and the production of platelets in a mammal, comprising administering to the mammal an amount effective for the production and mobilization of megakaryocytes and the production of platelets of at least one active agent that it comprises a sequence of the following general formula: R1 -Arg-R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, He, Leu and norLeu and R5 is Phe, lie or is absent.

51. The method according to claim 50, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

52. An improved cell culture medium for the production of platelets and megakaryocytes, wherein the improvement comprises the addition to the cell culture medium of an effective amount to accelerate the production of platelets and megakaryocytes of at least one active agent comprising a sequence of the following general formula: R1 -Arg-R2-R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, Lie, Leu and NorLeu and R5 is Phe, He or is absent.

53. The cell culture medium according to claim 52, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.

54. A device for the production of platelets and megakaryocytes, comprising: (a) an amount effective to increase the production of platelets and megakaryocytes, of at least one active agent comprising a sequence of the following general formula: R1 -Arg-R2- R3-R4-His-Pro-R5 wherein R1 is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro; R3 is selected from the group consisting of Tyr and Tyr (P03) 2; R4 is selected from the group consisting of Ala, He, Leu and norLeu and R5 is Phe, He or is absent and (b) instructions for using the effective amount of the active agent as a supplement of the cell culture medium.

55. The equipment according to claim 54, further comprising the cell growth medium.

56. The equipment according to claim 54, further comprising a sterile container.

57. The kit according to claim 54, wherein the active agent is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34 and SEQ ID NO: 38.