Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma.
OBJECTIVE
Oncolytic replication competent herpes simplex virus type-1 (HSV) mutants have the ability to replicate in and kill malignant cells. We have previously reported the ability of replication competent HSV to control bladder cancer growth in an orthotopic murine model. We hypothesized that the combination of a chemotherapeutic agent used for intravesical treatment, namely mitomycin C (MMC) (Bristol-Myers Squibb Oncology, Princeton, New Jersey), and oncolytic HSV would exert a synergistic effect for the treatment of human transitional cell carcinoma.


METHODS
We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICP0 and ICP4, and selectively infects cancer cells, to treat the transitional cell carcinoma lines KU19-19 and SKUB. Cell survival was determined by lactate dehydrogenase assay for each agent as well as for drug-viral combinations from days 1 to 5. The isobologram method and the combination index method of Chou-Talalay were used to assess the synergistic effect.


RESULTS
NV1066 enhanced MMC mediated cytotoxicity at all combinations tested for KU19-19 and SKUB. The combination of the 2 agents demonstrated a synergistic effect and allowed dose reduction by 12 and 10.4 times (NV1066), and by 3 and 156 times (MMC) for the treatment of KU19-19 and SKUB, respectively, while achieving an estimated 90% cell kill.


CONCLUSIONS
These data provide the cellular basis for the clinical investigation of combined MMC and oncolytic HSV therapy for the treatment of bladder cancer.
Mullerad
Michael
M
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Bochner
Bernard H
BH
Adusumilli
Prasad S
PS
Bhargava
Amit
A
Kikuchi
Eiji
E
Hui-Ni
Chen
C
Kattan
Michael W
MW
Chou
Ting-Chao
TC
Fong
Yuman
Y
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D016685:Mitomycin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014779:Virus Replication
D000903:Antibiotics, Antineoplastic; D049452:Green Fluorescent Proteins; D016685:Mitomycin