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Adenovirus-Mediated Thymidine Kinase Gene Therapy for Recurrent Ovarian Cancer: Expression of Coxsackie-Adenovirus Receptor and Integrins vß3 and vß5

Department of Obstetrics and Gynecology, Department of Pathology, University Medical Center, Freiburg, Germany; Department of Obstetrics and Gynecology, Department of Pediatrics/Hematology-Oncology, and Department of Pathology, Baylor College of Medicine, Houston, Texas; Harvard Gene Therapy Initiative, Boston, Massachusetts; Department of Obstetrics and Gynecology, University Medical Center, Maastricht, The Netherlands; Department of Obsterics and Gynecology 1, Freiburg University Medical Center, Hugstetter Strasse 55, 79106 Freiburg/Brsg., Germany ahastenb{at}frk.ukl.uni-freiburg.de

D.-C. Fischer, PhD

X.-W. Tong, MD

A. Rojas-Martinez, MD

R. H. Kaufman, MD

I. Ramzy, MD

P. Kohlberger, MD

M. Orlowska-Volk, MD

E. Aguilar-Cordova

D. G. Kieback, MD

Department of Obstetrics and Gynecology, Department of Pathology, University Medical Center, Freiburg, Germany; Department of Obstetrics and Gynecology, Department of Pediatrics/Hematology-Oncology, and Department of Pathology, Baylor College of Medicine, Houston, Texas; Harvard Gene Therapy Initiative, Boston, Massachusetts; Department of Obstetrics and Gynecology, University Medical Center, Maastricht, The Netherlands

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 vß3 and vß5 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 vß3 and vß5 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 vß3 was found in all tumors before and after GT. Expression of integrin vß5 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 vß3/vß5 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.

Key Words: Recurrent ovarian cancer • thymidine kinase gene therapy • intraperitoneal therapy • CAR • integrins vß3 and vß5

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