Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma

Michael Mullerad, Bernard H. Bochner, Prasad S. Adusumilli, Amit Bhargava, Eiji Kikuchi, Chen Hui-Ni, Michael W. Kattan, Ting Chao Chou, Yuman Fong

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Purpose: 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. Materials and Methods: We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICPO 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.

Original languageEnglish
Pages (from-to)741-746
Number of pages6
JournalJournal of Urology
Volume174
Issue number2
DOIs
Publication statusPublished - 2005 Aug
Externally publishedYes

Fingerprint

Transitional Cell Carcinoma
Human Herpesvirus 1
Mitomycin
Simplexvirus
Genetic Therapy
Urinary Bladder
Oncolytic Viruses
Urinary Bladder Neoplasms
Therapeutics
Viral Genes
Drug Combinations
L-Lactate Dehydrogenase
Cell Survival
Cell Line
Growth
Neoplasms

Keywords

  • Bladder
  • Carcinoma, transitional cell
  • Gene therapy
  • Herpesvirus 1, human
  • Mitomycin

ASJC Scopus subject areas

  • Urology

Cite this

Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma. / Mullerad, Michael; Bochner, Bernard H.; Adusumilli, Prasad S.; Bhargava, Amit; Kikuchi, Eiji; Hui-Ni, Chen; Kattan, Michael W.; Chou, Ting Chao; Fong, Yuman.

In: Journal of Urology, Vol. 174, No. 2, 08.2005, p. 741-746.

Research output: Contribution to journalArticle

Mullerad, M, Bochner, BH, Adusumilli, PS, Bhargava, A, Kikuchi, E, Hui-Ni, C, Kattan, MW, Chou, TC & Fong, Y 2005, 'Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma', Journal of Urology, vol. 174, no. 2, pp. 741-746. https://doi.org/10.1097/01.ju.0000164730.38431.5c
Mullerad, Michael ; Bochner, Bernard H. ; Adusumilli, Prasad S. ; Bhargava, Amit ; Kikuchi, Eiji ; Hui-Ni, Chen ; Kattan, Michael W. ; Chou, Ting Chao ; Fong, Yuman. / Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma. In: Journal of Urology. 2005 ; Vol. 174, No. 2. pp. 741-746.
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abstract = "Purpose: 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. Materials and Methods: We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICPO 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.",
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AU - Bochner, Bernard H.

AU - Adusumilli, Prasad S.

AU - Bhargava, Amit

AU - Kikuchi, Eiji

AU - Hui-Ni, Chen

AU - Kattan, Michael W.

AU - Chou, Ting Chao

AU - Fong, Yuman

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N2 - Purpose: 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. Materials and Methods: We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICPO 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.

AB - Purpose: 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. Materials and Methods: We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICPO 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.

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