Cell Proliferation in Dimethylbenz(A)Anthracene(Dmba)- Induced rat Mammary Carcinoma Treated with Antiestrogen Toremifene

Abstract

Cell proliferation during antiestrogen toremifene treatment was studied using the DMBA-induced rat mammary carcinoma model. The volume corrected mitotic index (M/V INDEX) and the S-phase fraction (SPF) determined by flow cytometry (FCM) were used as proliferation markers. Two series of rats (A and B) treated with two dose levels of toremifene were used. The two series of tumors appeared to have different growth properties. In series A the tumors were rapidly growing with high proliferation rate. In this series, toremifene (3 mg/kg for 4 weeks) reduced significantly the mean MV/INDEX, but the slight reduction of the mean SPF was not significant. In series B the tumors grew slowly and had low levels of proliferation markers. One-third of the tumors were spontaneously stable in the untreated group. Higher dose of toremifene was used in this series (12 mg/kg for 4 weeks), and the number of regressing or stable tumors was 58% compared with 31% in series A. Taking into consideration the high number of spontaneously stable tumors in series B, it may be concluded that about one-third of the tumors regressed or remained stable due to toremifene treatment in both series. The reduction of the M/V INDEX was significant only when the regressing treated tumors were compared with the growing controls. The reduction of the SPF was not significant. We think that the M/V INDEX is a more appropriate method to measure cell proliferation than is the SPF in this tumor model, where the tumors are heterogenous and, e.g., spontaneous apoptosis is known to be frequent.