The Effect of Tamoxifen and Pentosan Polysulfate on the Microvessel Density and Cell Proliferation of Dimethylbenzanthracene-Induced Rat Mammary Carcinoma

Park, Chan Heun; Piao, Zhe; Lee, Kwang Gil

Abstract

Antiestrogen tamoxifen (TMX) is thought to elicit its therapeutic effect by competing with endogenous estrogens for the estrogen receptor. Several more recent studies asserted that the antitumor effect of TMX is not due solely to the inhibition of estrogen receptor-mediated action, but due partly to its capacity to inhibit angiogenesis and impair neovascularization. Despite extensive research and clinical experience with this drug, its exact mode of action in inducing tumor regression is still not clear. The present study is aimed toward the investigation of the effects of TMX on dimethylbenzanthracene- induced rat mammary carcinomas with respect to the tumor response to the drugs, histological changes, cell proliferative acitivity and angiogenesis inhibition, and if TMX has antiangiogenic action, to compare it with that of pentosan polysulfate (PPS), an already known antiangiogenic substance. Female Sprague-Dawley rats, aged 50 days, were divided into normal control, test control (tumor induction by dimethylbenzanthracene), TMX (TMX administration after tumor induction), and PPS (PPS administration after tumor induction) groups. Tumor response to the drug administration was classified according to changes of tumor volume as follows; complete response (CR), partial response (PR), no response (NR), and progressive disease (PD). The response rate of rat mammary carcinomas to the drug administration was significantly higher (p<0.05) in the TMX and PPS groups as compared with the test control group. There was, however, no statistical significance between the TMX and PPS groups. Necrosis was considerably frequent in tumors of the TMX and PPS groups. Hyaline change of the stroma was strikingly more common and marked in the TMX group and it was associated with atrophy of epithelial cells of the tumor glands. Proliferating cell nuclear antigen (PCNA)- labeling index of the tumors was significantly higher (p<0.05) in the tumors with NR and PD of the TMX group when compared with those with PR of the same group, which suggested a higher cell proliferative activity in these response groups. In the PPS group, however, there was no significant difference in PCNA index according to response. Microvessel density of the tumors was significantly lower (p<0.05) in the PPS group as compared with the test control and TMX groups and it was not related with response. The TMX group, however, did not show any significant difference in microvessel density when compared with the test control group. Microvessel density was significantly higher (p<0.05) in tumors with PD than those with PR in all 3 groups, which suggested a positive relation of increase in tumor size and angiogenesis. Based on these results it is thought that TMX and PPS inhibit growth of chemically-induced rat mammary carcinomas. It seems that the antitumor action of PPS is related with its antiangiogenic capability, but that of TMX does not have a relationship with angiogenenesis inhibition.