CHEMOTHERAPY FOLLOWING ESTROGEN-INDUCED EXPANSION OF THE GROWTH FRACTION OF HUMAN-BREAST CANCER

Abstract

We have evaluated the feasibility of a cytokinetically oriented regimen based on the induction of cell recruitment by diethylstilbestrol (DES) in locally advanced human breast cancer. Tumor proliferative activity was evaluated by the thymidine labeling index and the primer-dependent .alpha.-DNA polymerase labeling index, which gives an in vitro estimation of the growth fraction. Sixteen previously untreated patients received DES (1 mg daily for 3 days) followed by FAC [5-fluorouracil (600 mg/m2): Adriamycin (50 mg/m2): Cytoxan (600 mg/m2)] i.v. on day 4 every 21 days. Radical surgery was delayed to allow for three DES-FAC regimens in responsive patients. Proliferative activity on tumor biopsies was evaluated immediately before and after treatment with DES, 24 h after chemotherapy and, in nine patients, at the time of radical surgery. DES was able to induce a significant increase in thymidine labeling index in 8 of 16 patients, while the primer-dependent .alpha.-DNA polymerase labeling index was significantly increased in 13 of 16 tumors, independently of their estrogen receptor content. Subsequently administered chemotherapy induced an early decrease in tumor proliferation. In the nine patients submitted to surgery after three DES plus FAC courses, the average thymidine labeling index and primer-dependent .alpha.-DNA polymerase labeling index were 27.8 and 73% of the pretreatment values. Our preliminary results provide the rationale for the design of new therapeutic schemes in which antitumor drugs are given at the time of estrogen-induced tumor cell recruitment. Further extended studies are required to establish whether induction of tumor cell recruitment will actually translate into appreciable improvement of the clinical response to chemotherapy.