Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer

To reveal the antiangiogenic capability of cancer chemotherapy, we develope d an alternative antiangiogenic schedule for administration of cyclophospha mide. We show here that this antiangiogenic schedule avoided drug resistanc e and eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not po ssible with the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant before therapy, the antiangiogenic s chedule suppressed tumor growth 3-fold more effectively than the convention al schedule. When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of cyclophosphamide, drug-resistant Lewis lung car cinomas were eradicated. Each dose of the antiangiogenic schedule of fyclop hosphamide induced the apoptosis of endothelial cells within tumors, and en dothelial cell apoptosis preceded the apoptosis of drug-resistant tumor tel ls. This antiangiogenic effect was more pronounced in p53-null mice in whic h the apoptosis of p53-null endothelial cells induced by cyclophosphamide w as so vigorous that drug-resistant tumors comprising 4.5% of body weight we re eradicated. Thus, by using a dosing schedule of cyclophosphamide that pr ovided more sustained apoptosis of endothelial cells within the vascular be d of a tumor, we show that a chemotherapeutic agent can more effectively co ntrol tumor growth in mice, regardless of whether the tumor cells are drug resistant.