The interaction of dietary fat and antiestrogen treatment on DMBA‐induced mammary tumors in the rat

Abstract

This study was designed to determine whether an estrogenic mechanism is involved in dietary fat-modulated tumor development and growth. Female Sprague-Dawley rats were placed on a semipurified low-fat (2% fat), high-saturated fat (20% fat), or high-polyunsaturated fat (20% fat) diet at 21 days of age. A single dose of 7,12-dimethylbenz[a]anthracene (DMBA, 10 mg) was administered intragastrically at 50 days of age. Two studies were performed. One tested the effectiveness of antiestrogen treatment (either tamoxifen or analog II) on tumor development when it was given one week prior to and one week after DMBA treatment in animals consuming a high-polyunsaturated fat diet. The second six-week study tested the antiestrogen effectiveness in arresting tumor growth and in producing regressions of established DMBA-induced tumors in rats consuming various levels and types of fat. The results of these studies indicate that both antiestrogens employed reduced the rate of growth and increased the number of regressions of established DMBA-induced tumors. In general, this was true in animals fed diets with a high content of either saturated or polyunsaturated fats and to a lesser extent in animals fed a low-fat diet. Tamoxifen produced a somewhat greater reduction in the growth of established tumor than did analog II. However, analog II, which is a more biologically "pure" antiestrogen, reduced the incidence of animals with mammary tumors and total tumor burden when administered one week before and one week after DMBA dosing. Tamoxifen, which is a partial estrogen-agonist, did not alter tumor incidence, but it did reduce the total tumor burden under these same experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Structural comparison of a gem-dichlorodiarylcyclopropane antiestrogen and three of its derivatives

“…Early antiestrogenic studies of (1) and its trans isomer have shown that: (i) compound (1) is a weaker antiestrogen than tamoxifen but is devoid of intrinsic agonist activity (Magarian & Benjamin, 1975;Pento et al, 1981); (ii) compound (1) and tamoxifen were equally effective in reducing the growth of established 7,12-dimethylbenz[a]-anthracene (DMBA)-induced rat mammary tumors, but (1) induced greater reduction in the occurrence of new tumors (Pento, Magarian & King, 1982;King, Pento, Magarian & Brueggemann, 1985;King, Magarian, Terao & Brueggemann, 1985); (iii) the trans isomer of (1) is devoid of any biological action (Pento et al, 1981).…”

Synthesis and Chiral Separation of Some Antitumor Agents

“…Reports from our laboratory (15,16) and others (20,23) have demonstrated that the introduction of a dichlorocyclopropyl or dihydroclopropyl moiety in place of the olefinic bridge in estrogenic stilbenes greatly reduces or abolishes their estrogenic action. One compound, analog II (Chart 1), has antiestrogenic properties without estrogen agonist activity in the mouse and is comparable in activity to tamoxifen against the hormone-dependent 7,12-dimethyl benz[a]anthracene-induced rat mammary tumor model (24,25). Structure-activity relationship studies of some of the analog II derivatives (15)(16)(17)26) led us to design more effective cyclopropyl antiestrogens.…”