Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo.

PURPOSE: Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth. EXPERIMENTAL DESIGN: Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naïve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands. RESULTS: Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naïve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naïve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice. CONCLUSIONS: GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naïve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.

Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice.

BACKGROUND: In patients with early-stage breast cancer, 5 years of treatment with the selective estrogen receptor modulator (SERM) tamoxifen reduces breast cancer recurrence and mortality, whereas more than 5 years of tamoxifen does not further reduce breast cancer recurrence and doubles the risk of endometrial cancer. We evaluated the effects on tumor growth of raloxifene, another SERM, after tamoxifen treatment in mouse models of breast and endometrial cancers. METHODS: Athymic, ovariectomized mice were bitransplanted with tumors derived from human breast cancer and endometrial cancer cells that either were tamoxifen-naive or had been exposed to tamoxifen for short (6 months) or long (>5 years) terms. The effects of raloxifene (two dose levels) and tamoxifen on tumor growth in the presence and absence of low-dose estrogen were evaluated. All statistical tests were two-sided. RESULTS: Raloxifene was less effective than tamoxifen in blocking the stimulatory effects of low-dose estrogen on the growth of tamoxifen-naive breast (P<.001) and endometrial (P =.001) tumors. Raloxifene and tamoxifen had similar inhibitory effects on the growth of short-term tamoxifen-exposed breast tumors. Raloxifene and tamoxifen had similar stimulatory effects on the growth of breast and endometrial tumors that had been exposed to at least 5 years of tamoxifen. However, neither drug blocked the stimulatory effects of estrogen on the growth of these tumors. Raloxifene was less effective than tamoxifen (P<.001) in blocking the stimulatory effects of estrogen on endometrial tumors that had been exposed to tamoxifen in the past. CONCLUSIONS: Raloxifene and tamoxifen had similar effects on these mouse models of tamoxifen-naive and tamoxifen-resistant breast and endometrial cancer. Treatment with raloxifene following 5 years of adjuvant tamoxifen may not further decrease breast cancer recurrence and may increase endometrial cancer incidence.