Combination of adenovirus-mediated thymidine kinase gene therapy with cytotoxic chemotherapy in bladder cancer in vitro.
We evaluated efficacy, toxicity and potential synergism of adenoviral-mediated thymidine kinase (tk)- ganciclovir (GCV) gene therapy in combination with 4 cytotoxic chemotherapeutic agents (doxorubicin, cisplatin, mitomycin C, and methotrexate) in 3 human bladder cancer cell lines. Cell lines were exposed to (1) 10 different concentrations of adenovirus expressing tk plus GCV; (2) 8 different concentrations of either doxorubicin, methotrexate, mitomycin C or cisplatin; or (3) combination treatment consisting of either low-, medium- or high-dose tk-GCV gene therapy plus 8 different concentrations of a single chemotherapeutic agent. Cell survival was determined using a MTT-based cell proliferation-assay. For most combinations, adding chemotherapy to tk-GCV gene therapy did not result in any therapeutic benefit. In some scenarios, we observed modest improvement with combinations of high-dose tk-GCV gene therapy and high-dose standard chemotherapy over tk-GCV monotherapy. Low concentrations of methotrexate enhanced the antitumor effects of low- and medium-dose tk-GCV gene therapy. Low level negative interference between tk-GCV gene therapy and chemotherapy occurred in some combinations but was overall negligible. In general, adding chemotherapy to tk-GCV gene therapy did not demonstrate significant therapeutic benefit in vitro. High doses of chemotherapeutic agents should be used in combination with tk-GCV gene therapy in order to take advantage of the occasional instance where modest improvement occurred with combination therapy. Additional studies exploring the role of methotrexate in enhancing the tk-GCV system are required. Investigation of other, potentially more synergistic chemotherapeutic agents in combination with tk-GCV is warranted.
Freund
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Scott Department of Urology, Baylor College of Medicine, and The Methodist Hospital, 6560 Fannin, Suite 2100, Houston, TX 77030, USA.
Tong
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XW
Rowley
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Engehausen
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D
Frolov
A
A
Kieback
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DG
Lerner
Seth P
SP
D000260:Adenoviruses, Human / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000821:virology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; D017361:Viral Nonstructural Proteins; D016685:Mitomycin; D004317:Doxorubicin; D013937:Thymidine Kinase; D015774:Ganciclovir; D002945:Cisplatin; D008727:Methotrexate