MVAC chemotherapy-induced apoptosis and p53 alterations in the rat model of bladder cancer

Abstract

Objectives. To investigate the induction of apoptosis by methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy as well as p53 alterations in a rat model of bladder cancer induced by N-butyl- N-(4-hydroxybutyl)nitrosamine (BBN). Methods. At 20 and 28 weeks after starting the administration of BBN, 60 rats (30 at 20 weeks, and 30 at 28 weeks) were divided into an MVAC treatment group (20 rats) and a control group of untreated rats (10 rats). After one intraperitoneal injection of MVAC, the rat bladder was obtained on day 1 or 7 for evaluation of apoptosis by biohistochemical and electron microscopic observations, and of p53 alterations immunohistochemically. Results. All tumors were noninvasive transitional cell carcinoma (TCC) at 20 weeks and invasive TCC at 28 weeks. In comparison with untreated tumors, a threefold increase of apoptotic indexes (AIs) was noted in invasive TCC and a twofold increase in noninvasive TCC on day 1 after MVAC therapy. Both decreased AIs and a frequent occurrence of apoptotic necrosis were observed on day 7. Occurrence of tumor necrosis was not affected by MVAC therapy, and the extent of necrosis was not related to apoptosis. Detection of p53 alterations, 45% and 40% in MVAC treated and untreated tumors, respectively, did not correlate with AIs. Conclusions. MVAC therapy may act through the induction of apoptosis, and invasive TCC cells may be much more sensitive to MVAC therapy in the rat model of bladder cancer. Neither spontaneous nor MVAC-induced apoptosis may be related to p53 alterations in the rat model of bladder cancer.