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WO1999038992A9 - Synergie entre une therapie genique utilisant la thymidine kinase et les inhibiteurs de la topo-isomerase i et la topo-isomerase ii - Google Patents

Synergie entre une therapie genique utilisant la thymidine kinase et les inhibiteurs de la topo-isomerase i et la topo-isomerase ii

Info

Publication number
WO1999038992A9
WO1999038992A9 PCT/US1999/002302 US9902302W WO9938992A9 WO 1999038992 A9 WO1999038992 A9 WO 1999038992A9 US 9902302 W US9902302 W US 9902302W WO 9938992 A9 WO9938992 A9 WO 9938992A9
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
cells
gene therapy
adv
gcv
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/US1999/002302
Other languages
English (en)
Other versions
WO1999038992A1 (fr
Inventor
Dirk G Kieback
Xiao-Wen Tong
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.)
Baylor College of Medicine
Original Assignee
Baylor College of Medicine
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 Baylor College of Medicine filed Critical Baylor College of Medicine
Priority to AU26562/99A priority Critical patent/AU2656299A/en
Publication of WO1999038992A1 publication Critical patent/WO1999038992A1/fr
Publication of WO1999038992A9 publication Critical patent/WO1999038992A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention is in the field of cancer therapeutics. This invention is
  • the invention is directed further to the combination use of thymidine kinase
  • Ovarian cancer is the most lethal female malignancy and has so far been treated
  • the standard therapy for ovarian cancer often includes radical debulking surgery and platinum-based combination chemotherapy.
  • ovarian cancer have been used to treat ovarian cancer include cyclophosphamide, taxol, cisplatin,
  • topoisomerase I There are two forms of topoisomerase, topoisomerase I and topoisomerase II.
  • Topoisomerase II is selectively inhibited by the compound Vepesid® (VP-16) which currently is supplied in an intravenous preparation and an oral dosage form.
  • VP-16 Vepesid®
  • Topoisomerase I is an enzyme critical for cell growth and proliferation. It catalyzes
  • Hycamtin is one example of a topoisomerase inhibitor. Hycamtin exerts its cytotoxic effect, not by inhibiting the enzyme, but by stabilizing the covalent DNA-enzyme complex thus blocking DNA repair. Potmesil, M. era/., Cancer Research 54: 1431 -1439 (1994); Hsiang,
  • topoisomerase I fragmentation of DNA causes cell death.
  • Cells selected for resistance to hycamtin and defective in topo.somerase I are hypersensitive to ionizing radiation. Mattern, M.R. etal, Cancer Research 51 :5813-5816 (1991 ). Increased expression of topoisomerase I has
  • topoisomerase I topoisomerase I
  • Adenovirus mediated thymidine kinase (ADV-TK) gene therapy of ovarian cancer has been
  • ADV Adenovirus
  • RSV Rous Sarcoma Virus
  • TK herpes simplex thymidine kinase
  • GCV ganciclovir
  • adenovirus mediated thymidine kinase gene therapy of ovarian cancer viral particles carrying the thymidine kinase gene are used to infect the
  • a prodrug is administered to the patient which is metabolized to
  • the antiviral agent GCV is the original part of this treatment concept.
  • the drug is
  • intravenous GCV have been performed at the 10mg/kg/day dose level.
  • Acyclovir is a synthetic purine nucleoside analog. It has in vitro inhibitory
  • HSV Herpes simplex virus
  • HSV-1 and HSV-2 Herpes simplex virus types 1 and 2
  • varicella zoster Herpes simplex virus
  • Epstein-Barr Herpes simplex virus
  • cytomegalovirus Herpes simplex virus
  • pyrimidine nucleosides can be considered to be a consequence of selective activation by
  • ACV shares the same mechanism of selective cell killing in
  • ADV/TK positive cells as GCV (Elion, G.B. etal, Proc. Natl. acad. Sci. USA 74:5716-5720
  • ACV-triphosphate can be incorporated into growing chains of DNA and terminate the DNA chain resulting in cell death (Cheng, Y.C. etal, J. Biol. Chem.258:12460-12464 (1983); Culver, K.W. etal, Science 256: 1550-1552
  • the present invention combines surgical tumor reduction with gene therapy to
  • the present invention includes the
  • adenovirus mediated thymidine kinase gene therapy which in itself is a
  • the uniqueness of the present invention consists of the
  • ovarian cancer cells but is also present, for example, in bladder cancer cells. Additionally, the invention will function with any cell line that is capable of
  • the synergistic effect is not a tumor specific effect, but rather,
  • chemotherapeutic agents are enhanced in their treatment potential by combination with
  • One aspect of the present invention utilizes gene therapy as an integral part of
  • adenovirus mediated thymidine kinase gene therapy and topoisomerase inhibitors is novel, and improves treatment of ovarian and other cancers.
  • topoisomerase inhibitors such as Topotecan and Vepesid® (VP-16) are used follwoing
  • the ADV-TK therapy also enhances the effect of subsequent chemotherapy, even though
  • An object of the invention is a method of arresting or slowing uncontrolled cellular
  • division comprising the steps of: surgical reduction of the uncontrolled cells if possible; introducing an adenoviral vector into said cells wherein said vector is comprised of a DNA sequence encoding ADV-TK operatively linked to a promoter and wherein sai ⁇ cells
  • a further object of the invention is a method which uses a retrovirus or a liposome
  • the delivery system to deliver the viral thymidine kinase suicide gene to the target cells.
  • Another object of the invention is a method in which the promoter is a Rous Sarcoma Virus - Long Terminal Repeat, cytomegalovirus promoter, murine leukemia virus LTR, simian virus 40 early and late, or a herpes simplex virus.
  • the promoter is a Rous Sarcoma Virus - Long Terminal Repeat, cytomegalovirus promoter, murine leukemia virus LTR, simian virus 40 early and late, or a herpes simplex virus.
  • a further object of the invention is a method of treating uncontrolled cell division
  • a further object of the invention is a method of treating ovarian cancer.
  • objects of the invention include the treatment of endometrial cancer, cervical caner,
  • pancreatic cancer breast cancer, colon cancer, stomach cancer, liver cancer, bladder
  • cancer prostate cancer, peritoneal cancer, lung cancer, kidney cancer, tube cancer, or
  • An additional object of the invention is a combination therapy in which there is
  • chemotherapeutic administration of a topoisomerase inhibitor such as Vepesid® (VP-16), topotecan, irinotecan, or hycamtin.
  • VP-16 Vepesid®
  • irinotecan irinotecan
  • hycamtin a topoisomerase inhibitor
  • a prodrug such as ganciclovir, acyclovir, pamciclovir, valacyclovir,
  • famcirclovir or FIAU where that prodrug is converted to a toxic compound by cells expressing ADV-TK or other TK forms.
  • Another object of the invention utilizes any suitable enzyme-prodrug combination
  • Still another object of the invention is a method wherein the ADV-TK, or other TK-
  • based suicide gene therapy is administered before the topoisomerase inhibitor chemotherapy is administered.
  • FIG 1 shows a comparison of acyclovir (ACV) and ganciclovir (GCV) toxicity
  • Figure 2 shows a comparison of cell killing efficiency of adenovirus mediated
  • ganciclovir in OV-CA-2774 cells low percent ADV/RSV-TK positive cells.
  • Figure 4 shows a comparison of bystander effects of adenovirus mediated
  • ganciclovir in OV-CA-2774 cells high percent ADV/RSV-TK positive cells.
  • Figure 5 shows the survival of treated mice as a percentage survival rate vs.
  • Figure 6 shows the interaction between adenoviral vector alone and chemotherapy.
  • the percent of surviving cells is on the Y-axis, and multiplicity of infection (MOI) is plotted
  • Figure 7 shows the cell killing efficacy in ovarian cancer cells (OV-CA-2774) pre-
  • Figure 8 shows the interaction between adenovirus mediated thymidine kinase
  • C5 represents the serum concentration in
  • Figure 9 shows the interaction between adenovirus mediated thymidine kinase
  • C6 represents the serum concentration in
  • Figure 10 shows the interaction between adenovirus mediated thymidine kinase
  • Figure 11 shows the time dependent synergistic effect between adenovirus
  • D 0 represents the concomitant
  • D 1 represents chemotherapy with hycamtin performed 24 hours after gene therapy.
  • D 2 represents chemotherapy with hycamtin
  • D 3 represents chemotherapy with hycamtin
  • Figure 12 shows the interaction between adenovirus mediated thymidine kinase
  • C4 represents the serum concentration in patients 2 hours after i.v. infusion of 100mg/m 2 over 3 hours.
  • FIAU is 1-(2-deoxy-2-fluoro- ⁇ -D-arabinofuranosyl)-5-iodouracil.
  • prodrug refers to any non-toxic chemical that can be converted to a toxic
  • the prodrug is converted to the toxic product by the gene product of the therapeutic nucleic acid sequence in the vector of the present
  • promoter refers to a recognition site on a DNA strand to
  • the promoter is usually a DNA fragment of about 100 to 200 bp in the 5' flanking DNA upstream of the cap site or the transcriptional initiation
  • the promoter forms an initiation complex with RNA polymerase to initiate and drive transcriptional activity.
  • vector refers to some means by which DNA fragments
  • vectors can be introduced into a host organism or host tissue.
  • vectors There are various types of vectors
  • adenoviruses such as adenoviruses, retroviruses, and liposomes.
  • the present invention provides a method of arresting or slowing uncontrolled
  • cellular division comprising the steps of: surgical reduction of the uncontrolled cells if
  • the present invention may incorporate the use of retroviruses or liposomes as
  • promoters may be used to drive the vector useful in the method of the
  • Rous Sarcoma Virus - Long Terminal Repeat cytomegalovirus promoter
  • murine leukemia virus LTR murine leukemia virus LTR
  • simian virus 40 early and late herpes simplex
  • the present invention may be used to treat a variety of conditions in which it is
  • the invention is designed to treat endometrial cancer, cervical caner, pancreatic cancer, breast cancer, colon cancer, stomach cancer, liver cancer,
  • bladder cancer prostate cancer, peritoneal cancer, lung cancer, kidney cancer, tube
  • gallbladder cancer or gallbladder cancer.
  • Any topoisomerase inhibitor is suitable for use in the invention.
  • Any topoisomerase inhibitor is suitable for use in the invention.
  • any topoisomerase inhibitor is suitable for use in the invention.
  • the topoisomerase inhibitor is one of VP-16 (Vepesid®), topotecan, irinotecan, or hycamtin.
  • the present invention uses any prodrug that is converted to a toxic form by ADV-
  • the prodrug is ganciclovir, acyclovir,
  • pamciclovir pamciclovir, valacyclovir, famcirclovir, or FIAU.
  • the present invention can utilize any combination of
  • gene therapy can be used as a chemotherapy-sensitizer for treating ovarian cancer.
  • OV-CA-1225 OV-CA-1225
  • SKOV-3 purchased from ATCC
  • HGDMEM Dulbecco's Modified Eagle Medium with high glucose, Gibco#56-439-110)
  • ADV/RSV-TK thymidine kinase gene
  • ADV/CMV-TK ADV/CMV-TK
  • the viral titer is based on biological infection (plaque
  • ADV/RSV-TK and ADV/CMV-TK were compared in the gene therapy
  • the drugs chosen were cisplatin, carboplatin, doxorubicin, taxol,
  • a MTT based assay was used to evaluate cytotoxicity as described in the art. (See e.g., Carmichael, J. et al, Cancer Research 47:936-942 (1987) and Denizot, F. et al, J.
  • OV-CA-2774 cells 500 cells were considered optimal to ensure logarithmic growth at the
  • OV-CA-2774 and OV-CA-1225 1000, 500, 250, 125, 61 , 30, 15, 7.5, 3.6, 1.8, 0.9 and 0
  • FCS fetal calf serum
  • CA-2774 or 2000 cells (OV-CA-1225 or SKOV 3) in a volume of 100 ⁇ l were plated out in flat-bottomed 96-well microtiter trays for six hours at 37°C and 5% CO 2 in a humidified
  • GCV or ACV dose-dependent cell killing efficacy was also seen in other groups of cells transduced at higher MOIs. 98% cell death was achieved by using GCV or ACV at a
  • ADV/RSV-TK positive plus ADV/RSV-TK negative cells were exposed to different doses
  • SKOV3 in a volume of 10O ⁇ l containing varying mixing ratios of transduced and untreated cells were seeded in 96-well tissue culture plates and incubated for another 12 hours (0,
  • GCV or ACV 100 ⁇ g/ml
  • the human epithelial ovarian cancer cell line OV-CA-2774 was selected because
  • OV-CA-2774 cells are especially suited for the testing of novel gene therapy approaches
  • the ovarian cancer animal model was established in 6-8 weeks old female athymic CD-1 nu/nu mice after intraperitoneal injection of 1 x 10 8 OV-CA-2774 cells.
  • the tumor was established in 6-8 weeks old female athymic CD-1 nu/nu mice after intraperitoneal injection of 1 x 10 8 OV-CA-2774 cells.
  • mice were needed per treatment group. 75 female CD-1 nu/nu mice were
  • IU were injected intraperitoneally followed by administration of GCV (1 Omg/kg) at a
  • mice inoculated with tumor were treated
  • mice treated with ACV were still alive without evidence of disease 150
  • ADV/RSV-TK in combination with ACV administration can achieve at least the same
  • ADV-mediated gene therapy followed by the administration of ACV is superior to GCV
  • liver toxicity is a major concern of intraperitoneal ADV-mediated gene therapy in combination with high dose GCV. No liver toxicity was observed in the animal model of
  • ADV/RSV-TK gene therapy concept may improve the margin of treatment safety in patients whose renal and/or bone marrow function may have been impaired by previous
  • chemotherapeutic agents tested The sensitivity to chemotherapy was mildly enhanced in the cells transduced with higher doses of virus (up to 61 MOI for OV-CA-2774 and OV- CA-1225, up to 1000 for SKOV3). This effect is probably explained by viral toxicity alone.
  • ovarian cancer cell lines showed a decreased sensitivity towards chemotherapy when
  • ADV-TK-pretreatment or simultaneous application enhanced the chemotherapeutic
  • ADV-TK gene therapy combined with GCV administration causes an accumulation of the phosphorylated product of GCV in tumor cells, which can be incorporated into
  • Hycamtin is an advantageous choice when selecting chemotherapeutic agents to be administered in
  • Randomization was chosen as a means to eliminate potential confounding influences on the data by animal age, cell passage number, viral storage time and
  • control group was comparable to each other with a statistical power of 80%.
  • Group I 6.67 x 10 8 ADV/RSV-TK + ganciclovir
  • Group V topotecan alone (using 1/10 of the corresponding dose
  • Group VI 6.67 x 10 8 ADV/RSV-TK + ganciclovir (1 Omg/kg, bid for six
  • Each mouse is injected with 1 x 10 8 tumor cells of OV-CA-2774 in a volume of
  • mice were treated each week for up to six months. Another five months were
  • Randomization was chosen as a means to eliminate potential confounding
  • mice were needed per treatment group. 102 female CD-1 nu/nu
  • mice (Charles River Laboratories, Wilmington, MA) age 6-10 weeks were divided into 9
  • Group 1 6.67 x 10 8 ADV/RSV-TK + ganciclovir (1 Omg/kg, bid for six days); Group
  • Group IV VP-16 alone (using the corresponding dose used in human); Group
  • mice untreated mice as control group. Each mouse is injected with 1 x 10 8 tumor cells of OV-CA-2774 in a volume of 2ml Hanks buffer intraperitoneally. At that dosage all mice
  • mice inoculated with tumor were treated each week.
  • mice were treated each week for up to six months. Another five months were

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé dans lequel la thérapie génique utilisant la thymidine kinase véhiculée par l'adénovirus augmente la sensibilité des cellules cancéreuses de l'ovaire à la chimiothérapie par inhibiteurs de topo-isomérases. Cette combinaison présente des propriétés synergiques et est plus efficace lorsque le traitement par thérapie génique est administré en premier, suivi par une chimiothérapie par inhibiteurs de topo-isomérases.
PCT/US1999/002302 1998-02-03 1999-02-03 Synergie entre une therapie genique utilisant la thymidine kinase et les inhibiteurs de la topo-isomerase i et la topo-isomerase ii Ceased WO1999038992A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26562/99A AU2656299A (en) 1998-02-03 1999-02-03 Synergism between thymidine kinase gene therapy and topoisomerase i and topoisomerase ii inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7356198P 1998-02-03 1998-02-03
US60/073,561 1998-02-03

Publications (2)

Publication Number Publication Date
WO1999038992A1 WO1999038992A1 (fr) 1999-08-05
WO1999038992A9 true WO1999038992A9 (fr) 1999-10-21

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Country Status (2)

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AU (1) AU2656299A (fr)
WO (1) WO1999038992A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19947668A1 (de) * 1999-10-04 2001-04-19 Univ Eberhard Karls Tumorspezifischer Vektor für die Gentherapie
ATE392210T1 (de) * 1999-10-07 2008-05-15 Aguilar Cordova Carlos Estuard Methoden zur behandlung von festen tumoren und metastasen mit gentherapie

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5604090A (en) * 1994-06-06 1997-02-18 Fred Hutchinson Cancer Research Center Method for increasing transduction of cells by adeno-associated virus vectors

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AU2656299A (en) 1999-08-16
WO1999038992A1 (fr) 1999-08-05

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