Yoshiki Takai

A new triphenylethylene derivative, TAT-59; hormone receptors; insulin-like growth factor 1; and growth suppression of hormone-dependent MCF-7 tumors in athymic mice.

TAT-59 {(E)-4-[1-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4-isopropyl)phenyl-1-butenyl]-phenyl-monophosphate} treatment was performed on hormone-dependent MCF-7 tumors in athymic mice. TAT-59 given at 1, 5, and 20 mg/kg inhibited the estrogen-stimulated growth of MCF-7 tumors in athymic mice in a dose-dependent fashion. The most clear decrease in tumor growth was shown in the TAT-59 alone group, although it was not dramatic. Average serum concentrations of DP-TAT-59 {(Z)-[1-[4-[2-(dimethylamino)-ethoxy]phenyl]-2-(4-isopropyl)phenyl-1-butenyl]-4-hydroxybenzene} and DM-DP-TAT-59(desmethyl-DP-TAT-manner. Much higher levels of DP-TAT-59 and DM-DP-TAT-59 wer shown in tumors (target tissues of estrogen) as compared with muscles (nontarget tissues of estrogen) or serum. A serum concentration of DP-TAT-59 or DM-DP-TAT-59 corresponding to the physiologic levels of serum estradiol in premenopausal women was sufficient to inhibit the estrogen-stimulated growth of MCF-7 tumors in mice. TAT-59 induced a dose-dependent increase in estrogen receptor levels in the MCF-7 tumors. In contrast, it prevented the estradiol (E2)-induced increase in progesterone receptor levels in a dose-dependent manner. Insulin-like growth factor 1 levels measured in the MCF-7 tumors significantly decreased in the TAT-59 alone group and in the no treatment group as compared with the E2 alone group. These results show the pronounced antiestrogenic action of TAT-59 on hormone-dependent MCF-7 tumors in athymic mice.

Effect of toremifene on the growth, hormone receptors and insulin-like growth factor-1 of hormone-dependent MCF-7 tumors in athymic mice

Toremifene given in different sizes of silastic capsules was used to treat MCF-7 tumors in athmic mice. Toremifene inhibited the estradiol-stimulated growth of MCF-7 tumors in athymic mice. Average serum concentrations of toremifene obtained using a sustained-release preparation of the drug (in 0.5-, 1.0-, and 2.0-cm silastic capsules) increased gradually in a capsule-size-dependent fashion. Much higher levels of toremifene orN-demethyltoremifene were detected in tumors(target tissues of estrogen) as compared with muscles (non-target tissues of estrogen). The concentration of toremifene in serum (i.e., 10–30 ng ml−1) was sufficient to inhibit the estrogen-stimulated growth of MCF-7 tumors at physiological (i.e., 200–400 pg ml−1) serum estradiol concentrations in premenopausal women. No significant difference in estrogen receptor (ER) levels was found between the estradiol-alone group and the toremifene-treated groups. However, the ER levels in the toremifene-alone group and the no-treatment group (no toremifene or estradiol) tended to increase as compared with the estradiol-alone group. Toremifene blocked the estradiol-induced increase in progesterone receptor levels in a dose-dependent fashion. Insulin-like growth factor-1 (IGF-1) levels in the MCF-7 tumors significantly decreased in the toremifene-alone group as compared with the estradiol-alone group. These results show the antiestrogenic action of toremifene on hormone-dependent MCF-7 tumors in athymic mice.

Breast-conserving therapy versus modified radical mastectomy in the treatment of early breast cancer in Japan

BackgroundBreast-conserving therapy has been widely utilized as a treatment option for women with early breast cancer. However, no randomized study comparing modified radical mastectomy and breast-conserving therapy has been conducted in Japan.MethodsTwo hundred and twenty-eight Japanese women with early breast cancer enrolled in the Gunma Breast Conserving Therapy Study between 1991 and 1994 were examined to determine whether there is any difference in disease-free survival or overall survival between radical mastectomy and breast-conserving therapy. After informed consent was obtained, a total of 119 patients underwent breast-conserving therapy and 109 underwent mastectomy.ResultsMastectomy was a more frequently utilized treatment than breast-conserving therapy in patients with clinical stage II lesions, older age, larger tumor size or shorter distance between tumor and nipple. The mean follow-up period for all patients was 81 months (median 86 months). There was no significant difference in overall survival or disease-free survival between breast-conserving therapy and mastectomy even after adjusting for the clinical stage of the disease. A multivariate analysis of tumor size, lymph node status, estrogen receptor status and operation method using the Cox proportion hazard model confirmed that only lymph node status was an independent prognostic factor.ConclusionBreast-conserving therapy is comparable to modified radical mastectomy in overall survival and disease-free survival.