Abstract B90: Doses of selective estrogen receptor modulations (SERMs) required for prevention and therapy of chemically induced mammary cancers

Abstract

Abstract Selective Estrogen Receptor Modulators (SERMs) interfere with the activity of estrogen. SERMs have been shown to be effective for both treatment and prevention of breast cancer. Here we examine the ability of Tamoxifen and Arzoxifene, a more easily absorbed form of Raloxifene, to prevent mammary tumors at a significantly lower dosage than those used for treatment. For prevention studies, treatment of female Sprague-Dawley rats (50 days of age) with a single dose of MNU resulted in the development of multiple ER-positive mammary tumors beginning 7 weeks after carcinogen treatment. When examined in a chemoprevention setting, rats were administered the preventive agent beginning five days after carcinogen administration. When the agents were tested at does varying between 0.15–3.3 ppm in the diet, both agents caused a dose dependent increase in preventive activity. The highest doses of tamoxifen (3.3 ppm) and Arzoxifene (3.0 ppm) both decreased tumor multiplicity greater than 90%. Both of these doses are less than one-fifth the human equivalent dose (HED) based on standard FDA scaling factors. Both doses also resulted in substantial decreases in mammary gland development. These dosages were then used in a therapy setting to compare the efficacy. For these studies, MNU treated rats were allowed to develop their first palpable mammary tumor (70–150 mm2) before initiating treatment. Tumor growth or regression was followed by caliper measurements. Neither of the higher preventive doses of these SERMs exhibited substantial therapeutic activity, although substantially higher doses of tamoxifen (33 or 100 ppm) were relatively effective. These results are in contrast to our prior findings with other classes of agents (RXR agonists, EGFR inhibitors, and aromatase inhibitors) in which highly effective preventive doses were effective as the therapeutic doses in this model. These results demonstrate the unique dose differential regarding prevention and therapy with SERMs. It raises the question of whether this class of agents might be used at significantly lower doses in a pure prevention setting. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B90.