Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel

Vascular endothelial cell growth factor (VEGF) regulates angiogenesis and m etastasis of bladder cancer (transitional cell carcinoma, TCC) through bind ing to VEGF receptor-2 (VEGPR-2). In this study, we evaluated whether the a nti-VEGFR monoclonal antibody (Mab) DC101 in combination with paclitaxel in hibited tumorigenesis, angiogenesis, and metastasis of human TCC growing wi thin the bladder of athymic nude mice. In vivo therapy with Mab DC101 and p aclitaxel induced significant regression of bladder tumors compared with ei ther agent alone. Median bladder weights were reduced from 601 mg in untrea ted controls, 422 mg in mice treated with paclitaxel alone (P < 0,005), 361 mg in mice treated with DC101 alone (P < 0,005), and 113 mg in mice that r eceived combination therapy (P < 0,0005), Only one of nine mice developed s pontaneous lymph node metastasis after combined treatment, compared with se ven of seven untreated controls (P < 0,0005), six of eight after DC101 (P < 0.01), and five of eight mice after paclitaxel (P < 0,05), Combined treatm ent with both paclitaxel and DC101 inhibited tumor-induced neovascularity c ompared with all other groups (P < 0,005), without altering the expression of VEGF or flk1. Mab DC101 and paclitaxel combined enhanced apoptosis in th e tumor and endothelial cells compared with other treatment (P < 0,005), Th ese studies indicate that Mab DC101, which blocks VEGFR-2 function, has sig nificant efficacy against human TCC, especially when combined with the chem otherapeutic agent paclitaxel, The antitumor effect was mediated by inhibit ion of angiogenesis and induction of both tumor cell and endothelial cell a poptosis.