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 hum an breast cancer. Shown to induce a G1 transition delay in vitro, the kinetic effects of TAM on breast carcinoma cells growing as tumor xeno grafts in nude mice have been less well characterized. In this study, we demonstrate a significant increase in the tumor potential doubling time (T(pot)) and decrease in the labeling index (%LI) of estradiol (E 2)-stimulated MCF-7 xenografts following TAM treatment or E2 deprivati on. MCF-7 tumor pieces were transplanted s.c. into nude mice supplemen ted with Silastic capsules containing E2. After 2-4 weeks, animals wer e randomized to continued E2 treatment, E2 and TAM treatment, or E2 de privation. At times ranging from 0 to 23 days after treatment, animals were given injections of bromodeoxyuridine and tumors excised for kin etic analysis. Using flow-cytometric techniques, the T(pot) and %LI we re estimated for all tumors. Seven independent experiments were perfor med and data pooled for statistical analysis. At the time of hormonal manipulation, E2-stimulated tumors had a volume doubling time of 5 day s, a T(pot) of 2.3 days, and a %LI of 23%. Continued E2 treatment resu lted in only minimal changes in T(pot) and %LI over the remainder of t he observation period. Treatment with TAM resulted in a slowing of tum or growth (tumor doubling time, 12 days), a significant (P < 0.001) in crease in T(pot) to 6.6 days, and a decrease in %LI to 8% by 23 days p osttreatment. E2 deprivation resulted in a cessation of tumor growth a nd similar changes in T(pot) 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 tumo r cell proliferation in MCF-7 xenografts.