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WO1993013779A2 - Utilisation de diphosphoglucose d'uridine en tant qu'antidote electif dans le traitement therapeutique de cancers - Google Patents

Utilisation de diphosphoglucose d'uridine en tant qu'antidote electif dans le traitement therapeutique de cancers Download PDF

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Publication number
WO1993013779A2
WO1993013779A2 PCT/US1991/007613 US9107613W WO9313779A2 WO 1993013779 A2 WO1993013779 A2 WO 1993013779A2 US 9107613 W US9107613 W US 9107613W WO 9313779 A2 WO9313779 A2 WO 9313779A2
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WO
WIPO (PCT)
Prior art keywords
tumor
udpg
administration
effective amount
administered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1991/007613
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English (en)
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WO1993013779A3 (fr
Inventor
Robert L. Stolfi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics SpA
Original Assignee
Boehringer Mannheim Italia SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Mannheim Italia SpA filed Critical Boehringer Mannheim Italia SpA
Priority to AU41001/93A priority Critical patent/AU4100193A/en
Priority to PCT/US1991/007613 priority patent/WO1993013779A2/fr
Priority to EP93910550A priority patent/EP0617625A1/fr
Priority to JP5510416A priority patent/JPH07501810A/ja
Publication of WO1993013779A2 publication Critical patent/WO1993013779A2/fr
Publication of WO1993013779A3 publication Critical patent/WO1993013779A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the oral an intravenous administration of Uridine Diphosphoglucos (UDPG) as a rescue agent in cancer therapy after th administration of pyrimidine inhibitors or antipyrimidin compounds known as anti-tumor compounds and relate compounds exhibiting similar activity with or without th administration of 5-benzylacyclouridine.
  • UDPG Uridine Diphosphoglucos
  • 5-FU metabolite 5-fluoro-2 '-deoxyuridine-5'-phosphate
  • F-dUMP metabolite 5-fluoro-2 '-deoxyuridine-5'-phosphate
  • This nucleotide has an unusually grea affinity for the enzyme thymidylate synthetase resultin in a decreased DNA synthesis.
  • a second mechanism o action of 5-FU may involve the incorporation of 5-fluoro- uridine-5'-triphosphate into RNA leading to impaire processing of nuclear RNA. (Groeningen et al, "Reversal of 5-fluorouracil Induced Myelosuppression by Prolonged Administration of High-Dose Uridine", Reports.
  • 5-fluoro-2'- deoxyuridine-5'-triphosphate (FdUTP) is incorporated in DNA.
  • 5-FU and other related antipyrimidine chemicals used alone or in combination with other anticancer agents are toxic to cancer cells and normal healthy cells. Accordingly, the dose of antipyrimidine compounds administered to patients undergoing cancer therapy is limited by the toxic effects exhibited by such compounds.
  • the therapeutic index of such compounds in general, is low. The low therapeutic index and-the toxicity associated with such drugs has provided motivation for increasing the anti-tumor activity of the antipyrimidine drugs and decreasing toxic effects to host tissue.
  • uridine increases the pool of uridine available to both healthy and diseased cells and thus accelerates the clearance of the anti-cancer agent from these cells as the uridine competes with the anti-cancer agent.
  • the normal cells are reported to clear the anti-tumor agent quicker than the cancer cells by selectively taking up uridine.
  • uridine administration has been shown to provide rescue, resulting in an increased therapeutic effect, after the administration of antipyrimidine anti-cancer agents.
  • antipyrimidine chemotherapy may be only one of a number of treatments being simultaneously administered to the patient, and, therefore, any loss of fluid level caused by severe diarrhea may be fatal to the patient. Accordingly, the oral administered dose of uridine is limited by its toxicity and the limited dose may not provide successful rescue.
  • BAU 5-benzylacyclouridine
  • uridine rescue is known to enhance the rescue effect by preventing the premature catabolism of uridine.
  • BAU prevents the breakdown of uridine by phosphorylase and the subsequent rapid body clearance of uridine, and thus slows the rate of uridine catabolism (Martin et al Id.).
  • the administration of BAU fails to cure or eliminate all of the problems associated with administering i.v. uridine to patients.
  • the present invention relates to the oral administration of UDPG, which provides uridine plasma concentrations necessary to produce a rescue effect, and which appears to prevent diarrhea associated with the oral administration of rescue effective amounts of uridine.
  • UDPG can be administered without surgical intervention and without the risks associated with oral administration of uridine.
  • UDPG can be administered without surgical intervention and without the risks associated with oral administration of uridine.
  • the therapeutic effect of the antipyrimidine anti-cancer agent is increased and/or the toxicity of the pyrimidine anti-cancer agent to healthy cells is simultaneously lowered.
  • the present invention relates to a method of rescuing the healthy cells of a cancer patient being treated with antipyrimidine anti-tumor compounds. Rescue is accomplished by administering rescue effective amounts of UDPG to the patient after the administration of the anti-tumor agent.
  • the invention also relates to orally administering rescue effective amounts of UDPG to cancer patients.
  • the invention also relates to UDPG rescue in association with BAU administration after the administration of antipyrimidine anticancer drugs or after the administration of antipyrimidine anticancer drugs in combination with other anticancer drugs.
  • the invention also relates to a pharmaceutical kit composed of at least anticancer effective amounts of an antipyrimidine or pyrimidine inhibitor and rescue effective amounts of UDPG.
  • Fig. 1 is a plot showing the toxicity of 5- fluorouracil. Toxicity in the plot is measured as a function of the percent of body weight change over time. The plot shows the change in body weight of mice after the administration of 5-fluorouracil.
  • Fig. 2 is a schematic diagram of the kit of the present invention.
  • the present invention relates to the use of UDPG as an agent for the rescue of healthy cells after the administration of an effective dose of an antipyrimidine anti-cancer drug used in the chemotherapy of a cancer patient.
  • the present invention uses UDPG as a source of uridine, which is preferentially taken up by healthy cells and, therefore, functions as a rescue agent in antipyrimidine anticancer chemotherapy.
  • the types of tumors to be treated by the method of the invention include tumors of the gastrointestinal tract (esophagus, stomach, colon, rectum) , breast, prostate, ovaries, liver, head and neck and pancreas.
  • 5-FU and other related antipyrimidine compounds are administered to human cancer patients according to different schedules, as is well known to those with ordinary skill in the art. For example, in one schedule an antipyrimidine compound is only administered during the first five days of a monthly schedule. In a second schedule the antipyrimidine compound is administered once a week. In a third schedule, the antipyrimidine compound is given by a continuous infusion every hour of the day for months.
  • a representative schedule of clinical administration includes administering weekly i.v. injections of a bolus of 5-FU on an outpatient basis.
  • a typical starting dose is about 500 mg/m 2 .
  • Every four weeks the 5-FU dose is increased by 20% until dose-limiting toxicity occurs, which can be indicated by weight loss, or destruction of bone marrow cells and the loss of white blood cells.
  • Table 1 shows the toxic dose of weekly 5-FU administrations and severity of myelosuppression. Table 1
  • Comparative Example 1 Establishing Toxic Levels of 5-FU
  • a first group of ten CD8FI female mice having an average tumor weight of 120 mg was treated by i.v. with saline once a week for three weeks; a second group of ten CD8FI female mice having an average tumor weight of 120 mg was treated by i.v. with a single bolus of 100 mg/kg of 5- fluorouracil once a week for three weeks; and a third group of ten female CD8FI female mice having an average tumor weight of 120 mg was treated by i.v. with a single bolus of 150 mg/kg of 5-fluorouracil once a week for three weeks. Observations were recorded 6 days after the last injection. The results are reported in Table 2 on the following page:
  • Table 2 shows that a therapeutic effect is obtained with the weekly maximum tolerated dose (MTD) for mice of 100 mg/kg of 5-fluorouracil.
  • MTD weekly maximum tolerated dose
  • Fig. 1 establishes that 5-FU administered by i.v. in doses of 130 mg/kg/wk to mice is a toxic dose. Toxicity is determined by a change in body weight. Ten CD8FI female mice with breast tumors were treated with weekly doses of 5-fluorouracil in amounts of 130 mg/kg for three weeks. The percent of body weight change of the mice is shown and plotted over a period of approximately 12 days after administration of the last dose. The mice receiving 130 mg/kg of 5-FU suffered a weight loss of approximately 25% and a mortality of 30% . These results establish toxicity of fluorouracil in mice at 130 mg/kg/wk.
  • Example 1 - Rescue Levels of UDPG The experiment of the third group of mice of Comparative Example 1 (5FU 150 ) , as reported in Table 2, was repeated except that after each injection of 5-FU, UDPG was administered orally by gavage in concentrations of 1500 mg/kg 2 hours after each weekly dose of 5- fluorouracil. Two and one-half hours later, after the first administration of UDPG, additional oral administrations of UDPG were made in concentrations of 2000 mg/kg every 8 hours 5 times. Ten mice were also treated orally by gavage with UDPG at concentrations of 1950 mg/kg 2 hours after each weekly administration of 5- fluorouracil. Subsequently, UDPG was orally administered 2 1/2 hours later at concentrations of 2600 mg/kg every 8 hours 5 times. The results are shown in Table 3.
  • Comparative Example 4 It is known that BAU administered in vivo allows uridine to accumulate in the body, as BAU has been shown to prevent the breakdown of uridine by phosphorylase and the subsequent rapid body clearance of uridine. Accordingly, since it has been determined by the present results that UDPG provides a source of uridine, it is one extension of the present invention to include the administration of BAU when using UDPG as a rescue agent. BAU can be administered simultaneously, before or after the addition of UDPG.
  • BAU was administered orally by gavage at concentrations of
  • Example 2 - Rescue Levels of Oral UDPG with Oral BAU
  • the experiment of Group 4 of Example 1 was repeate except that BAU was administered orally by gavage at dosage of 250 mg/kg 2 hours after the administration of 5 FU, along with the first administration of UDPG. BAU wa then administered orally by gavage 4 1/2 hours after th administration of 5-fluorouracil and then every 8 hour four times. The results are reported in Table 6.
  • toxicity is shown to be reduced and a safe therapeutic effect is established that is greater than that achieved by FU alone at its MTD of 100 mg/kg.
  • Table 8 shows plasma levels of uridine in human patients receiving a first i.v. dose of UDPG of 2 grams over a sixty minute period and thereafter a second i.v. 2 gram dose over a twenty minute period. As is seen plasma concentrations of uridine increase with administration of
  • Table 9 shows the uridine plasma levels in human patients receiving an i.v. dose of UDPG of 4 grams over a thirty minute period. Again plasma levels of uridine increase with administration and fall after administration. Table 10 UDPG 6 g over 60 minutes
  • Table 10 shows the uridine plasma levels in human patients receiving an i.v. dose of UDPG of 6 grams over a sixty minute period. The results obtained are similar to the results as reported above in Tables 8 and 9.
  • UDPG In administering UDPG by the parenteral route no fever and no phlebitis occurred at the site of peripheral injection (antecubital vein) . As shown in the examples above, UDPG is effective in providing rescue after the administration of antipyrimidine anti-cancer agents or related compounds.
  • 5-fluorouracil is administered in amounts of at least 600 mg/m 2 /wk in human patients as evidenced from Table 1 above.
  • a proposed range for the administration of UDPG via i.v. is approximately 1-6 g/m 2 /h over an interval of 1-3 hours with 2 - 3 hour intervals of rest up to 72 hours after the administration of 5-FU, i.e., in amounts of between 24 g/m 2 /wk and 216 g/m 2 /wk .
  • the administration begins approximately 1-4 hours after the administration of 5-FU. If UDPG is to be administered orally then 2-8 g/m 2 of UDPG may be administered every 4 - 6 hours for 3 days starting 1 - 3 hours after the administration of 5-FU.
  • UDPG has been taken orally in 4 gm doses.without side effects and without toxicity. Based on this test it is expected that much higher amounts, for example 20 to even as high as 40 gm every 6 hours may be given per administration over a 72 hour period.
  • BAU may be administered orally at the rate of 0.5 - 2g/m 2 every 4 - 6 hours for 3 days starting 1/2 - 2 hours after 5-FU administration, i.e., between 6 g/m 2 /wk and 36 g/m 2 /wk.
  • Based on animal data BAU is non-toxic. Accordingly, it appears that the amounts of BAU which can be administered are not limited by toxic effects and, therefore, increased amounts of BAU may be administered. Accordingly the proposed ratio of 5- fluorouracil/UDPG/BAU is 1 : 40 to 800 : 5 to 200 preferably 1 : 40 to 360 : 10 to 60.
  • kits 10 may include an effective dose of the pyrimidine inhibitor such as 5-fluorouracil in dosage ampule 11. Pyrimidine inhibitors are always administered parenterally and, therefore, the kit may also include a syringe 13.
  • the kit will also contain an effective dose of the rescue agent UDPG.
  • UDPG as discussed above, is basically an antidote for the pyrimidine inhibitor and may be administered orally or parenteral. Accordingly, UDPG will be packaged separately from the pyrimidine inhibitor and may be packaged in a dosage ampule 15 for parenteral administration, or in a sachet for oral administration.
  • the kit may also contain an effective unit dose of the uridine phosphorylase inhibitor BAU.
  • BAU is administered orally and, therefore, BAU may be packaged in the kit separately from the other ingredients in the form of a dosage ampule 17 or sachet.
  • antipyrimidine therapy may be only one of many anti-cancer therapies being given to a cancer patient. Regardless of the number of therapies, so long as an antipyrimidine anti-tumor agent is administered, rescue with UDPG can be accomplished.
  • doses of the antipyrimidine anticancer agent as reported herein may have to be reduced to avoid drug mortality. Therefore, Figs. 1 and 2 and the examples of the application are only used for illustration and direction. The invention is limited only in scope by the appended claims.

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Abstract

Procédé permettant de sauver les cellules saines d'un patient atteint d'un cancer qui est traité avec des composés antitumoraux d'antipyrimidine, ou avec des composés apparentés. On sauve ces cellules en administrant du diphosphoglucose d'uridine (UDPG) après avoir administré le composé antitumoral d'antipyrimidine associé préférablement à l'administration de 5-benzylacyclouridine (BAU).
PCT/US1991/007613 1991-12-16 1991-12-16 Utilisation de diphosphoglucose d'uridine en tant qu'antidote electif dans le traitement therapeutique de cancers Ceased WO1993013779A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU41001/93A AU4100193A (en) 1991-12-16 1991-12-16 Use of udpg as cancer therapy rescue agent
PCT/US1991/007613 WO1993013779A2 (fr) 1991-12-16 1991-12-16 Utilisation de diphosphoglucose d'uridine en tant qu'antidote electif dans le traitement therapeutique de cancers
EP93910550A EP0617625A1 (fr) 1991-12-16 1991-12-16 Utilisation de diphosphoglucose d'uridine en tant qu'antidote electif dans le traitement therapeutique de cancers
JP5510416A JPH07501810A (ja) 1991-12-16 1991-12-16 癌治療のレスキュー剤としてのｕｄｐｇの利用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1991/007613 WO1993013779A2 (fr) 1991-12-16 1991-12-16 Utilisation de diphosphoglucose d'uridine en tant qu'antidote electif dans le traitement therapeutique de cancers

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WO1993013779A2 true WO1993013779A2 (fr) 1993-07-22
WO1993013779A3 WO1993013779A3 (fr) 1993-08-19

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EP (1) EP0617625A1 (fr)
JP (1) JPH07501810A (fr)
AU (1) AU4100193A (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1465616A4 (fr) * 2001-12-13 2005-04-06 Magral Ltd Traitement des effets secondaires de la statine faisant appel a des derives d'uridine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62501704A (ja) * 1984-12-20 1987-07-09 メモリアル　ホスピタル　フオ−　キヤンサ−　アンド　アライド　デイジ−ジイズ Ｕｄｐｇによる腫瘍の治療用組成物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1465616A4 (fr) * 2001-12-13 2005-04-06 Magral Ltd Traitement des effets secondaires de la statine faisant appel a des derives d'uridine
US8293755B2 (en) 2001-12-13 2012-10-23 Magral Pty Ltd. Treatment of statin side effects using uridine derivatives

Also Published As

Publication number Publication date
JPH07501810A (ja) 1995-02-23
EP0617625A1 (fr) 1994-10-05
AU4100193A (en) 1993-08-03
WO1993013779A3 (fr) 1993-08-19

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