Vorozole (Vz) is a competitive non-steroidal inhibitor of
aromatase, which has been used to treat
breast cancer in postmenopausal women and in various
chemoprevention pre-clinical studies. Recently, we assessed the inhibitory effect of Vz on MNU-induced mammary
carcinogenesis (Lubet et al., 1994), as well as on the progression of mammary
tumors (Lubet et al., 1998). In this study we evaluated the effects of Vz on
tumor growth, serum
estradiol, cell proliferation, apoptotic and non-apoptotic cell death to determine whether any of these '
surrogate' markers might reflect the efficacy of various doses of Vz. Vz at doses of 2.5 (Hi), 0.32 (Md), and 0.08 (Lo) mg/kg
body weight induced complete (100%), 60%, and 20% regression of mammary
tumors, respectively. Vz at Hi and Md doses caused a decrease in serum
estradiol within the first two days of treatment, and the
estradiol values remained low with additional treatment for 4 and 10 days. When Vz was administered to animals bearing palpable
tumors a time and dose-dependent decrease in the proliferating cells (BrdU-L1) was observed. The percentage of apoptotic cells (A1) sharply increased 2 days after initiation of Vz treatment and then decreased followed by an increase in non-apoptotic dead cells. Interestingly even the Lo dose of Vz, which was only moderately effective in suppressing
tumor growth, decreased cell proliferation and increased cell death in the peripheral
tumor areas at 4 and 10 days after initiation of treatment. The time- and dose-dependent alterations in various cell parameters suggest two different phases of Vz-induced cellular responses: (1) an early phase (2-4 days of treatment) with a sharp increase in apoptotic cells and decrease in proliferating cells, and (2) a later phase (10 days) with disintegration of
tumor parenchyma, increase in non-apoptotic dead cells, and decrease in apoptotic cells. The dose-dependent decrease in proliferating cells and increase in apoptotic and non-apoptotic cell death in Vz-treated animals suggest that these
biomarkers might be used as potential
surrogate endpoints for efficacy in
breast cancer chemoprevention and
therapy studies with
aromatase inhibitors.