Effect of Steroidal and Nonsteroidal Antiestrogens on the Growth of a Tamoxifen- stimulated Human Endometrial Carcinoma (EnCalOl) in Athymic Mice1

Tamoxifen (1AM), a nonsteroidal antiestrogen, is used in the adjuvant treatment of breast cancer. Previous studies, however, have indicated that some human breast and endometrial tumors are stimulated to grow with TAM in the athymic mouse. One such TAM-stimulated tumor is the EnCalOl human endometrial adenocarcinoma. Our aim was to evaluate the ability of different doses of TAM or other nonsteroidal antiestrogens to stimulate the growth of KnCalOI tumors in athymic mice. Additionally we have evaluated less estrogenic antiestrogens (two steroidal antiestro gens, KI 39.411 and ICI 164,384. and two nonsteroidal antiestrogens, keoxifcne and MKK-25) for their ability to inhibit TAM-stimulated growth. All experiments were done in ovariectomized athymic mice transplanted in the axillary mammary fat with l-nim" pieces of EnCalOl tumor. Sustained release preparations (0.5-2.0-cm Silastic capsule or 5mg TAM cholesterol pellet) of TAM caused similar tumor growth. The growth rate was not altered by an additional daily i.p. injection of l mg TAM in 0.1 ml peanut oil. A 3-mg TAM daily dose was toxic. Four weeks of treatment (100-Mg s.c. injections, every other day) with nonste roidal antiestrogens, trioxifene mesylate, enclomiphene, or nafoxidine, stimulated tumor growth. However, keoxifene stimulated this tumor to a lesser degree than TAM and partially inhibited TAM-stimulated growth. ICI 164,384 showed no stimulatory activity (1-mg s.c. injections every other day) alone compared to controls but inhibited TAM-stimulated (0.25-cm Silastic capsule) growth. In a parallel experiment, RU 39,411 (1-mg s.c. injections every other day) stimulated EnCalOl to grow. In contrast when KI 39.411 was administered in a sustained release prep aration (2.0-cm Silastic capsule) there was no stimulatory growth com pared to controls. Additionally RU 39,411 inhibited TAM-stimulated growth, but the low-potency antiestrogen. MER-25, was less effective in this regard. These data suggest that less "estrogenic" antiestrogens can inhibit TAM-stimulated tumor growth in vivo. Thus these compounds or derivatives may prove useful as a second-line endocrine therapy should TAM-stimulated tumor growth occur in the clinic.