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 metastasis of bladder cancer (transitional cell carcinoma, TCC) through binding to VEGF receptor-2 (VEGFR-2). In this study, we evaluated whether the anti-VEGFR monoclonal antibody (Mab) DC101 in combination with paclitaxel inhibited tumorigenesis, angiogenesis, and metastasis of human TCC growing within the bladder of athymic nude mice. In vivo therapy with Mab DC101 and paclitaxel induced significant regression of bladder tumors compared with either agent alone. Median bladder weights were reduced from 601 mg in untreated 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 received combination therapy (P < 0.0005). Only one of nine mice developed spontaneous lymph node metastasis after combined treatment, compared with seven 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 treatment with both paclitaxel and DC101 inhibited tumor-induced neovascularity compared with all other groups (P < 0.005), without altering the expression of VEGF or flk1. Mab DC101 and paclitaxel combined enhanced apoptosis in the tumor and endothelial cells compared with other treatment (P < 0.005). These studies indicate that Mab DC101, which blocks VEGFR-2 function, has significant efficacy against human TCC, especially when combined with the chemotherapeutic agent paclitaxel. The antitumor effect was mediated by inhibition of angiogenesis and induction of both tumor cell and endothelial cell apoptosis.
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
K
K
Inoue
J W
JW
Slaton
D W
DW
Davis
D J
DJ
Hicklin
D J
DJ
McConkey
T
T
Karashima
R
R
Radinsky
C P
CP
Dinney
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008222:Lymphokines / Q000235:genetics; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D017239:Paclitaxel / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D017978:Receptors, Growth Factor / Q000276:immunology*; D040262:Receptors, Vascular Endothelial Growth Factor; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D020780:Matrix Metalloproteinase 9; D017239:Paclitaxel