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WO1999038992A1 - 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 Download PDF

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Publication number
WO1999038992A1
WO1999038992A1 PCT/US1999/002302 US9902302W WO9938992A1 WO 1999038992 A1 WO1999038992 A1 WO 1999038992A1 US 9902302 W US9902302 W US 9902302W WO 9938992 A1 WO9938992 A1 WO 9938992A1
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Prior art keywords
cancer
cells
gene therapy
adv
gcv
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PCT/US1999/002302
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WO1999038992A9 (fr
Inventor
Dirk G. Kieback
Xiao-Wen Tong
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Baylor College of Medicine
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Baylor College of Medicine
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Priority to AU26562/99A priority Critical patent/AU2656299A/en
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Publication of WO1999038992A9 publication Critical patent/WO1999038992A9/fr
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    • 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 directed towards a cancer treatment combining gene therapy and chemotherapy after surgery. The invention is directed further to the combination use of thymidine kinase suicide gene therapy and topoisomerase I and/or II inhibitor chemotherapy after surgical
  • Ovarian cancer is the most lethal female malignancy and has so far been treated with surgery followed by chemotherapy.
  • the standard therapy for ovarian cancer often
  • chemotherapeutic agents that have been used to treat ovarian cancer include cyclophosphamide, taxol, cisplatin, carboplatin, and adriamycin.
  • chemotherapeutic substances used is cyclophosphamide, taxol, cisplatin, carboplatin, and adriamycin.
  • topoisomerase II 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 the cutting and mending of a single DNA strand and is required for DNA replication, DNA repair, and gene expression. Boothman, D.A. etal., Cancer Research 49:605-612 (1989).
  • 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. etal., Cancer Research 54: 1431 -1439 (1994); Hsiang, Y.H. et al., J. Biol. Chem. 260:14873-14878 (1985). When DNA replicates in the presence of the stabilized complex, double-strand DNA breaks occur, and the resulting fragmentation of DNA causes cell death. Id. Cells selected for resistance to hycamtin and
  • topoisomerase I defective in topoisomerase I are hypersensitive to ionizing radiation. Mattern, M.R. etal., Cancer Research 51 :5813-5816 (1991). Increased expression of topoisomerase I has been found in cisplatin-resistant cell lines. Kotoh, S. et al., Cancer Research 54:3248-3252 (1994); Pratesi, G. et al., Br. J. Cancer 71:525-528 (1995). Radio-sensitizing properties of hycamtin with supra-additive cytotoxicity have been
  • 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 tumor cells. Thereafter, a prodrug is administered to the patient which is metabolized to a highly toxic compound inside the infected tumor cells, which die as a result of this treatment.
  • this treatment is not one hundred percent effective and
  • 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
  • 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.
  • 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
  • the invention will function with any cell line that is capable of being targeted by ADV-TK.
  • the synergistic effect is not a tumor specific effect, but rather,
  • Topoisomerase inhibiting 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
  • ovarian cancer treatment in combination with topoisomerase inhibitors.
  • the specific synergistic effect between adenovirus mediated thymidine kinase gene therapy and topoisomerase inhibitors is novel, and improves treatment of ovarian and other cancers. There is never an antagonistic effect between chemotherapy and gene therapy when the gene therapy was followed by chemotherapy.
  • a synergistic effect is observed with topoisomerase inhibitors such as Topotecan and Vepesid® (VP-16) are used follwoing gene therapy.
  • Topotecan and Vepesid® VP-16
  • chemotherapeutic agent is administered first. A complete recovery of susceptibility to gene therapy is observed when the chemotherapeutic agent is removed.
  • the invention involves the specific interaction between thymidine kinase gene therapy and topoisomerase I and topoisomerase II inhibitors. Topotecan demonstrates this synergistic effect, even when the topotecan was added 72 hours after gene therapy was administered.
  • the ADV-TK therapy also enhances the effect of subsequent chemotherapy, even though up-front chemotherapy was disadvantageous.
  • 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
  • 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
  • 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),
  • Another object of the invention is a combination therapy in which there is
  • a prodrug such as ganciclovir, acyclovir, pamciclovir, valacyclovir,
  • 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-
  • FIG 1 shows a comparison of acyclovir (ACV) and ganciclovir (GCV) toxicity
  • Figure 2 shows a comparison of cell killing efficiency of adenovirus mediated
  • MOI represents multiplicities of infection.
  • Figure 3 shows a comparison of bystander effects 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
  • 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
  • FIAU is 1-(2-deoxy-2-fluoro- ⁇ -D-arabinofuranosyl)-5-iodouracii.
  • prodrug refers to any non-toxic chemical that can be converted to a toxic
  • the prodrug is converted to the toxic product by
  • 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
  • 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
  • a preferred embodiment encompasses the treatment of cancer.
  • the invention is designed to treat endometriai 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 gallbladder cancer.
  • 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- TK.
  • the prodrug is ganciclovir, acyclovir, pamciclovir, valacyclovir, famcirclovir, or FIAU.
  • the present invention can utilize any expressible enzyme and prodrug combination other that TK as long as that combination
  • the ADV-TK suicide gene therapy is administered before the topoisomerase inhibitor is administered.
  • 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,
  • 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
  • GCV or ACV in doses of up to 200 ⁇ g/ml did not inhibit cell growth in either cell line compared to untreated cells (Fig. 1 ).
  • No obvious toxicity and morphological changes were observed under 200 ⁇ g/ml of GCV concentration.
  • a slight inhibitory effect of GCV and ACV on OV-CA-2774 and OV-CA-1225 cell growth was observed at a concentration of 400 ⁇ g/ml without significant morphological changes. The difference of inhibitory effect caused by ACV and GCV was not significant (P>0.05).
  • No obvious toxicity and morphological changes were observed up to 400 ⁇ g/ml of either GCV or ACV concentration in SKOV3.
  • GCV or ACV administered at different doses was significantly different (P ⁇ 0.01 ).
  • This 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 concentration of 10 ⁇ g/ml in the cells transduced at an MOI of 15 while 100% cell death was observed when cells exposed to ACV at a concentration of 25 ⁇ g/ml or 50 ⁇ g/ml.
  • ADV/RSV-TK positive plus ADV/RSV-TK negative cells were exposed to different doses of GCV.
  • Cells were transduced in serum-free medium with ADV/RSV-TK at an MOI by which only 50% of the cells could be transduced (MOI of 7.5 for OV-CA-2774, MOI of 3.6 for OV-CA-1225 and MOI of 150 for SKOV3) and incubated for 2 hours at 37°C and 5%
  • 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
  • a prospective randomized treatment plan was designed to evaluate the therapeutic efficiency and toxicity of ADV/RSV-TK mediated gene therapy followed by administration of ACV vs GCV. Randomization was chosen as a means to eliminate potential confounding influences on the data by animal age, cell passage number, viral storage time and investigator. Survival was chosen as the study endpoint. Each individual treatment and control group was to be comparable to each other with a statistical power of 80%. A 1.5 fold increase in survival time was considered the lower limit of statistical discrimination.
  • mice were needed per treatment group.
  • 75 female CD-1 nu/nu mice were divided into 3 groups.
  • Three days after tumor inoculation 500 ⁇ l PBS containing 6.67x10 8 IU were injected intraperitoneally followed by administration of GCV (1 Omg/kg) at a concentration of 1 mg/ml (i.p., bid , plus Hanks one time a day) or ACV (33.3mg/kg or 66.6mg/kg i.p., tid) for six consecutive days. 6.67x10° IU were chosen because at this
  • mice treated with ACV 100mg/kg/day
  • 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
  • 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
  • MOIs multiplicities of infection
  • cells were incubated with ADV/RSV-TK or ADV/CMV-TK at varying MOIs at which
  • 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-
  • cytotoxicity was at least equal, if not higher compared with gene therapy or chemotherapy alone.
  • ovarian cancer cell lines showed a decreased sensitivity towards chemotherapy when
  • ADV-TK-pretreatment or simultaneous application enhanced the chemotherapeutic
  • hycamtin or VP-16 used is considered sufficient to effectively inhibit even initially elevated
  • ADV-TK gene therapy combined with GCV administration causes an accumulation
  • Hycamtin is an
  • Randomization was chosen as a means to eliminate potential confounding
  • 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 develop ovarian cancer. Three days after tumor inoculation 200 ⁇ l PBS containing 6.67
  • x 10 8 infectious viral particles were injected intraperitoneally or PBS alone followed by administration of GCV (1 Omg/kg, bid) at a concentration of 1 mg/ml for six consecutive days
  • mice inoculated with tumor were treated each week. Cytological examination of the ascites and histological examination of heart, lung, diaphragm, liver, spleen, kidney, bowel, uterus, ovary and omentum were performed
  • mice were treated each week for up to six months. Another five months were required for observing the treatment effects. Daily recordings of animal weight and body temperature and tissue analysis of dead mice were made.

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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)

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

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US7356198P 1998-02-03 1998-02-03
US60/073,561 1998-02-03

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

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003528813A (ja) * 1999-10-07 2003-09-30 アグイラ−コルドバ，カルロス，エストアルド 遺伝子治療による固体腫瘍及び転移の治療方法
US6936595B2 (en) * 1999-10-04 2005-08-30 Heart Biosystems, Gmbh Tumour-specific vector for gene therapy

Citations (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

Patent Citations (2)

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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
US5834182A (en) * 1994-06-06 1998-11-10 Fred Hutchinson Cancer Research Center Method for increasing transduction of cells by adeno-associated virus vectors

Non-Patent Citations (5)

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Title
HALBERT et al., "Transduction by Adeno-Associated Virus Vectors in the Rabbit Airway: Efficiency, Persistence and Readministration", JOURNAL OF VIROLOGY, August 1997, Vol. 71, No. 8, pages 5932-5941. *
KOEBERL et al., "Persistent Expression of Human Clotting Factor IX from Mouse Live After Intravenous Injection of Adeno-Associated Virus Vectors", PROC. NATL. ACAD. SCI. USA, February 1997, Vol. 94, pages 1426-1431. *
RUSSELL et al., "DNA Synthesis and Topoisomerase Inhibitors Increase Transduction by Adeno-Associated Virus Vectors", PROC. NATL. ACAD. SCI. USA, June 1995, Vol. 92, pages 5719-5723. *
TONG et al., "Adenovirus Mediated Gene Therapy in Ovarian Cancer", ANTICANCER RESEARCH, September 1997, Vol. 17, No. 6A, page 3993, Abstract 18. *
WILDNER et al., "Therapy of Colon Cancer with Oncolytic Adenovirus is Enhanced by the Addition of Herpes Simplex Virus-Thymidine Kinase", CANCER RESEARCH, 15 January 1999, Vol. 59, pages 410-413. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6936595B2 (en) * 1999-10-04 2005-08-30 Heart Biosystems, Gmbh Tumour-specific vector for gene therapy
US7351697B2 (en) 1999-10-04 2008-04-01 Kuepper Jan-Heinerr Tumor-specific vector for gene therapy
JP2003528813A (ja) * 1999-10-07 2003-09-30 アグイラ−コルドバ，カルロス，エストアルド 遺伝子治療による固体腫瘍及び転移の治療方法
JP2012001566A (ja) * 1999-10-07 2012-01-05 Carlos Estuard Aguilar-Cordova 遺伝子治療による固体腫瘍及び転移の治療方法

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WO1999038992A9 (fr) 1999-10-21

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