The
cardiotoxicity of
anthracyclines has largely prevented dose intensification, 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 standard
anthracycline therapy. The
ATP-based chemosensitivity assay (
ATP-TCA) has been used to develop new regimens for several
tumor types, to investigate the molecular basis of chemosensitivity and shows considerable promise as a clinical method for individualizing
chemotherapy. In this study, we have used the
ATP-TCA to determine the concentration responsiveness of
tumor-derived cells to concentrations of
doxorubicin. The 22
tumor samples included were obtained from 20 heavily pretreated patients with recurrent
ovarian cancer. Eight had previous
anthracycline exposure, four as part of the CAP regimen. The results show more than 95% inhibition at clinically achievable concentrations in 11 of 22
tumors tested. Of the rest, seven showed a plateau effect between 80 and 95% inhibition, suggesting that there might be a subset of resistant cells present that is not inhibited by high concentrations of
doxorubicin. Two
tumors showed complete resistance and neither of these had previously received
anthracycline therapy. As it has been suggested that
gemcitabine might enhance
anthracycline sensitivity in combination and we have had good results with
gemcitabine modulation of
alkylating agents 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 preparations shows strong ex vivo activity against pretreated recurrent
ovarian cancer in just over half of the cases tested.