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

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.