title: The ex vivo effect of high concentrations of doxorubicin on recurrent ovarian carcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, Institute of Ophthalmology, University College London,UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Neale
authors.forename: A
authors.initials: A
authors.lastname: Lamont
authors.forename: A
authors.initials: A
authors.lastname: Hindley
authors.forename: C M
authors.initials: CM
authors.lastname: Kurbacher
authors.forename: I A
authors.initials: IA
authors.lastname: Cree
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000903:Antibiotics, Antineoplastic; D003841:Deoxycytidine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D000093542:Gemcitabine