The ex vivo effect of high concentrations of doxorubicin on recurrent ovarian carcinoma

The cardiotoxicity of anthracyclines has largely prevented dose intensifica tion, but the use of liposomal preparations (e.g. Caelyx/Doxil) allows much higher intra-tumoral concentrations to be achieved without cardiotoxicity. However, it is uncertain how much this will improve response rates over st andard anthracycline therapy. The ATP-based chemosensitivity assay (ATP-TCA ) has been used to develop new regimens for several tumor types, to investi gate the molecular basis of chemosensitivity and shows considerable promise as a clinical method for individualizing chemotherapy. In this study, we h ave used the ATP-TCA to determine the concentration responsiveness of tumor -derived cells to concentrations of doxorubicin. The 22 tumor samples inclu ded were obtained from 20 heavily pretreated patients with recurrent ovaria n cancer. Eight had previous anthracycline exposure, four as part of the CA P regimen. The results show more than 95% inhibition at clinically achievab le concentrations in 11 of 22 tumors tested. Of the rest, seven showed a pl ateau effect between 80 and 95% inhibition, suggesting that there might be a subset of resistant cells present that is not inhibited by high concentra tions of doxorubicin. Two tumors showed complete resistance and neither of these had previously received anthracycline therapy. As it has been suggest ed that gemcitabine might enhance anthracycline sensitivity in combination and we have had good results with gemcitabine modulation of alkylating agen ts in the assay, we have tested the combination of doxorubicin+gemcitabine under assay conditions in 11 tumors with little indication of improvement, In conclusion, doxorubicin at concentrations achievable with liposomal prep arations shows strong ex vivo activity against pretreated recurrent ovarian cancer in just over half of the cases tested. [(C) 2000 Lippincott William s & Wilkins.].