Inhibition of tumor angiogenesis during cisplatin chemotherapy for bladder cancer improves treatment outcome

Abstract

Objectives: To investigate the effect of inhibiting tumor angiogenesis during cisplatinum-(II)-diamine dichloride (cisplatin) chemotherapy of bladder cancer (BC) in a rat model.

Methods: Bladder cancer was induced in 64 male rats using 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine in their water supply for 20 weeks. The animals were then divided randomly into four groups of 16 rats each: a control BC group (group 1); a BC group treated with cisplatin (0.25 mg/kg body weight) by intraperitoneal injection twice every week (group 2); a BC group treated with the antiangiogenic factor TNP-470 (30 mg/kg body weight) by intraperitoneal injection twice every week (group 3); and a BC group treated with cisplatin plus TNP-470 (group 4, treatment regimens as described). Per group, 4 rats were killed weekly after the start of treatment, for 4 weeks. BC was confirmed using histologic characteristics, and the treatment outcomes were determined by measuring tumor microvascular density and cell proliferation and apoptosis indexes (PI and AI, respectively).

Results: All animals had confirmed BC. Both group 3 (TNP-470) and group 4 (cisplatin plus TNP-470) had significantly decreased microvascular density compared with group 1 (P <0.05). Although both the PI and AI were significantly different between group 4 (cisplatin plus TNP-470) and group 1 (control BC; P <0.05), neither the PI nor AI was significantly different between group 2 (cisplatin) and group 4 (cisplatin plus TNP-470; P >0.05).

Conclusions: TNP-470 in conjunction with cisplatin chemotherapy resulted in a decrease in the microvascular density of BC in a rat model. However, TNP-470 did not appear to have a significant impact on the cisplatin effect against BC as measured by apoptosis and cell proliferation.