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Objective:Ten patients with recurrent ovarian cancer received a combined treatment of optimal tumor debulking, adenovirus-mediated herpes simplex virus thymidine kinase gene therapy (GT), and systemic application of acyclovir or valacyclovir and topotecan. Biopsies were taken at the time of secondary debulking about 1 month after the application of GT and chemotherapy and were analyzed for expression of coxsackie-adenovirus receptor (CAR) and integrins αvβ3 and αvβ5 with respect to treatment response.Methods:Treatment modalities and study design have been described recently. Immunohistochemistry was used to visualize expression of CAR and integrins αvβ3 and αvβ5 in tumor samples taken before and after application of GT.Results:Before GT six of ten patients presented with CAR-positive and four with CAR-negative tumors. After GT all tumors showed CAR expression. Integrin αvβ3 was found in all tumors before and after GT. Expression of integrin αvβ5 was seen in eight of ten tumor samples before GT and in all samples after GT.Conclusion:Despite the importance of CAR and integrin expression for successful adenovirus internalization, other cell surface receptors might be involved in this process. It is too early to decide whether expressions of CAR and integrin αvβ3/αvβ5 on tumor cells are appropriate additional inclusion criteria for the enrollment of patients in GT trials. Further research is necessary to evaluate the effect of GT plus chemotherapy on CAR and integrin expression.

Objective: Ten patients with recurrent ovarian cancer received a combined treatment of optimal tumor debulking, adenovirus-mediated herpes simplex virus thymidine kinase gene therapy (GT), and systemic application of acyclovir or valacyclovir and topotecan. Biopsies were taken at the time of secondary debulking about 1 month after the application of GT and chemotherapy and were analyzed for expression of coxsackie-adenovirus receptor (CAR) and integrins avß3 and avß5 with respect to treatment response. Methods: Treatment modalities and study design have been described recently. Immunohistochemistry was used to visualize expression of CAR and integrins avß3 and avß5 in tumor samples taken before and after application of GT. Results: Before GT six of ten patients presented with CAR-positive and four with CAR-negative tumors. After GT all tumors showed CAR expression. Integrin avß3 was found in all tumors before and after GT. Expression of integrin avß5 was seen in eight of ten tumor samples before GT and in all samples after GT. Conclusion: Despite the importance of CAR and integrin expression for successful adenovirus internalization, other cell surface receptors might be involved in this process. It is too early to decide whether expressions of CAR and integrin avß3/avß5 on tumor cells are appropriate additional inclusion criteria for the enrollment of patients in GT trials. Further research is necessary to evaluate the effect of GT plus chemotherapy on CAR and integrin expression.

Objective.Patients with recurrent ovarian cancer were treated intraperitoneally (ip) with a replication-deficient recombinant adenovirus (ADV) containing the herpes simplex virus thymidine kinase gene. Vector delivery was followed by intravenous administration of an antiherpetic prodrug and a topoisomerase I inhibitor.

Efficacy and toxicity of adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene followed by administration of ganciclovir were studiedin vivo.A human epithelial ovarian cancer animal model was established in nude mice using the serous ovarian adenocarcinoma cell line Ov-ca-2774. Intraperitoneal (ip) injection of 1 × 108Ov-ca-2774 cells resulted in tumor growth and formation of malignant ascites in all 15 animals. In a prospective randomized experimental design mice were treated 1, 3, or 7 days after ip injection of 1 × 108cells with ip injection of 2 × 108, 6.7 × 108, or 2 × 109pfu ADV.RSV-TK followed by administration of ganciclovir (10 μg/ml, ip, bid) for 6 consecutive days. End points were survival and toxicity. Mice treated with GCV or HSV-TK alone died from 14.4 ± 1.7 to 19.5 ± 3.5 days after treatment as did untreated controls. No toxicity of ADV.RSV-TK was found up to 2 × 109pfu (2 × 1011particles). The mice with the highest tumor burden treated with the lowest viral dose lived significantly longer than controls (P< 0.05). Median survival in all other groups of mice treated with ADV.RSV-TK plus GCV was even longer (P< 0.01). Treatment benefit was dependent on ADV/RSV-TK dose and tumor burden. Adenovirus-mediated thymidine kinase gene therapy is a realistic approach to ovarian cancer treatment that warrants investigation in the clinical setting.