Antitumor efficacy of conventional anticancer drugs is enhanced by the vascular targeting agent ZD6126

Abstract

Purpose: The present report reviews the preclinical data on combined chemotherapy/vascular targeting agent treatments. Basic principles are illustrated in studies evaluating the antitumor efficacy of the vascular targeting agent ZD6126 (N-acetylcochinol-O-phosphate) when combined with the anticancer drug cisplatin in experimental rodent (KHT sarcoma) and human renal (Caki-1) tumor models.Methods and Materials: C3H/HeJ and NCR/nu-nu mice bearing i.m. tumors were injected i.p. with ZD6126 (0–150 mg/kg) or cisplatin (0–20 mg/kg) either alone or in combination. Tumor response to treatment was assessed by clonogenic cell survival.Results: Treatment with ZD6126 was found to damage existing neovasculature, leading to a rapid vascular shutdown. Histologic evaluation showed dose-dependent morphologic damage of tumor cells within a few hours after drug exposure, followed by extensive central tumor necrosis and neoplastic cell death as a result of prolonged ischemia. ZD6126 doses that led to pathophysiologic effects also enhanced the tumor cell killing of cisplatin when administered either 24 h before or 1–24 h after chemotherapy. In both tumor models, the administration of a 150 mg/kg dose of ZD6126 1 h after a range of doses of cisplatin resulted in an increase in tumor cell kill 10–500-fold greater than that seen with chemotherapy alone. In contrast, the inclusion of the antivascular agent did not increase bone marrow stem cell toxicity associated with this anticancer drug.Conclusion: The results obtained in the KHT and Caki-1 tumor models indicate that ZD6126 effectively enhanced the antitumor effects of cisplatin therapy. These findings are representative of the marked enhancements generally observed when vascular targeting agents are combined with chemotherapy in solid tumor therapy.