Tamoxifen-induced increase in the potential doubling time of MCF-7 xenografts as determined by bromodeoxyuridine labeling and flow cytometry.
The anti-estrogen tamoxifen (TAM) is widely used in the therapy of human breast cancer. Shown to induce a G1 transition delay in vitro, the kinetic effects of TAM on breast carcinoma cells growing as tumor xenografts in nude mice have been less well characterized. In this study, we demonstrate a significant increase in the tumor potential doubling time (Tpot) and decrease in the labeling index (%LI) of estradiol (E2)-stimulated MCF-7 xenografts following TAM treatment or E2 deprivation. MCF-7 tumor pieces were transplanted s.c. into nude mice supplemented with Silastic capsules containing E2. After 2-4 weeks, animals were randomized to continued E2 treatment, E2 and TAM treatment, or E2 deprivation. At times ranging from 0 to 23 days after treatment, animals were given injections of bromodeoxyuridine and tumors excised for kinetic analysis. Using flow-cytometric techniques, the Tpot and %LI were estimated for all tumors. Seven independent experiments were performed and data pooled for statistical analysis. At the time of hormonal manipulation, E2-stimulated tumors had a volume doubling time of 5 days, a Tpot of 2.3 days, and a %LI of 23%. Continued E2 treatment resulted in only minimal changes in Tpot and %LI over the remainder of the observation period. Treatment with TAM resulted in a slowing of tumor growth (tumor doubling time, 12 days), a significant (P < 0.001) increase in Tpot to 6.6 days, and a decrease in %LI to 8% by 23 days posttreatment. E2 deprivation resulted in a cessation of tumor growth and similar changes in Tpot and %LI to 5.3 days and 10%, respectively (P < 0.001). In contrast to previous reports, these data demonstrate that TAM treatment and E2 deprivation both significantly decrease tumor cell proliferation in MCF-7 xenografts.