DNA-SYNTHESIS ENZYME-ACTIVITY - A BIOLOGICAL TOOL USEFUL FOR PREDICTING ANTI-METABOLIC DRUG-SENSITIVITY IN BREAST-CANCER

Thymidine kinase (TK) and thymidylate synthase (TS) play a key role in , respectively, the salvage and the de novo DNA synthesis pathways, TS is a crucial target for 5-fluorouracil(5-FU) and may also influence m ethotrexate(MTX) efficiency, Tyrosine kinase(TPK) has been associated with the cytoplasmic domain of growth factor receptors as well as onco proteins. We investigated whether TK, TS and TPK are predictive factor s for drug sensitivity evaluated in terms of relapse-free improvement in breast-cancer patients receiving adjuvant chemotherapy. TK, TS and TPK activities were determined in the cytosols of 154 node-positive pr imary breast cancers. All patients received 5-FU containing adjuvant c hemotherapy, Measurements were performed using radioenzymatic methods. The levels of TK were correlated with those of TS and TPK. The levels of TS and TPK were less strongly correlated with each other. High TK levels were more often found in larger tumours, and the levels of both TK and TPK were negatively correlated with those of PgR. Patients who se tumours contained high levels of TK had increased risks of relapse and death, TS was not of prognostic value, while a high level of TPK w as associated with early death. In Cox analysis, TK and TPK retained t heir independent dent prognostic value. While target enzyme activities on the de novo DNA synthesis pathway could determine response to anti -metabolics mainly inhibiting this pathway, high activities on the alt ernative salvage pathway could circumvent induced growth inhibition. ( C) 1997 Wiley-Liss, Inc.