FLOW-CYTOMETRY - POTENTIAL UTILITY IN MONITORING DRUG EFFECTS IN BREAST-CANCER

Flow cytometric analysis of DNA ploidy and S-phase fraction are well r ecognized prognostic indicators in breast cancer. The present paper de als with the widening of the applications of flow cytometry to monitor ing the effectiveness of antiestrogen therapy, detecting clonal select ion and emergence of drug resistance, and monitoring chemosensitizing properties of drugs. Antiestrogen activity can be studied by DNA flow cytometry to address clinical research problems such as patient-specif ic pharmacokinetics, dosing compliance, and acquired antiestrogen resi stance. Patient plasma specimens containing various concentrations of triphenylethylenes can be monitored for drug-induced effects using cel l cycle measurements and correlated to in vivo drug levels. DNA flow c ytometry has also been instrumental in the study of the effects of pro longed low-dose (0.5 mu M for > 100 days) tamoxifen treatment on human estrogen receptor negative MDA-MB-231 cells, where it was shown that tamoxifen may significantly alter cell cycle kinetics and tumorigenici ty of these cells, selecting a new, more aggressive, and rapidly growi ng clone. Lastly, it has been shown that the chemosensitizing properti es of another triphenylethylene antiestrogen, toremifene, on estrogen receptor negative, multidrug resistant MDA-MB-231-A1 human breast canc er cells can be studied using flow cytometric analysis. Toremifene (an d its metabolites N-desmethyltoremifene and toremifene IV) are able to ''resensitize'' MDA-MB-231-A1 cells to vinblastine and doxorubicin, a s reflected in a marked shift of cells to G(2)/M phase of the cell cyc le. Flow cytometry is a widely available technique that might be appli ed clinically to monitor, at the cellular level, drug effects on tumor s, including the modulators of drug resistance.