Prevention of chemotherapy-related toxic side effects by infection with adeno-associated virus type 2.

Abstract

Drug resistance and toxic side effects are major limiting factors in the clinical use of antineoplastic chemotherapy. Patients with pancreatic cancer generally do not benefit from chemotherapy. The nonpathogenic adeno-associated virus type 2 (AAV-2) has been shown to sensitize human tumor cells to gamma irradiation and chemotherapeutic drugs. In the present study, we characterized the therapeutic role of AAV-2 infection in combination with 5-fluorouracil (5-FU)-based chemotherapy on pancreatic cancer cells in an animal model. In Lewis rats bearing s.c. implants of syngeneic DSL6A pancreatic cancer cells, intratumoral infection with AAV-2 (MOI 10E8 i.u.) in combination with 5-FU (5 or 50 mg/kg body weight) resulted in significantly reduced tumor growth and prolonged survival time compared with 5-FU single therapy. Most surprisingly, AAV-2-infected rats remained in a much better physical condition compared to their noninfected counterparts. While rats treated with 5-FU single therapy lost weight, were sluggish and died within 4 months after tumor implantation, animals infected with AAV showed much better vigilance, with body weight, leukocyte number and hemoglobin levels similar to healthy rats. In particular, 5-FU-related side effects like thrombocytopenia and leukopenia were significantly reduced in animals treated with the combination regimen. By in vitro analysis, human (Capan-1 and DANG) pancreatic cancer cell lines were shown to be sensitized to 5-FU chemotherapy to an extent similar to DSL6A cells. AAV-2 infection enhanced 5-FU-induced apoptosis by a factor of 8 to 14 in both human and rat pancreatic cancer cell lines. The data suggest that infection with the nonpathogenic AAV-2 significantly improves both chemotherapy efficacy and physical appearance and offers a novel strategy in cancer treatment.