title: In vitro assessment of cytotoxic agent combinations for hormone-refractory prostate cancer treatment.
abstract: We have investigated new drug combinations of potential clinical value for treatment of hormone-refractory prostate cancer. Combinations of paclitaxel, carboplatin and mitoxantrone, and combinations of these three drugs with compounds targeting important pathways for cancer progression, 13-cis-retinoic acid and chelerythrine, were assessed. The drugs combinations were incubated for 72 h in steroid-free conditions with two androgen-independent cell lines, DU145 and PC3. Cytotoxicity assay was performed using resazurin and Hoescht 33342. Synergism and antagonism were measured by the combination index, and calculated for each combination by the median-effect method. All six compounds exhibited cytotoxic effects when tested alone. Paclitaxel exhibited the highest and 13-cis-retinoic acid the lowest effect on both cell lines. Paclitaxel demonstrated synergism or additivity with 13-cis-retinoic acid in both cell lines, whereas antagonistic effects were observed when it was tested in combination with carboplatin. Chelerythrine showed additive effects with mitoxantrone in both cell lines and with paclitaxel in PC3 cells. Our results suggest that combination of paclitaxel and 13-cis-retinoic acid, and of chelerythrine with mitoxantrone and paclitaxel, may have clinical value for the treatment of hormone-refractory prostate cancer.
authors.affiliation: UMR484 INSERM, Centre Jean Perrin, Université d'Auvergne, Clermont-Ferrand, France. Recherche.CLINIQUE@cjp.fr
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cabrespine
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Bay
authors.forename: Chantal
authors.initials: C
authors.lastname: Barthomeuf
authors.forename: Hervé
authors.initials: H
authors.lastname: Curé
authors.forename: Philippe
authors.initials: P
authors.lastname: Chollet
authors.forename: Eric
authors.initials: E
authors.lastname: Debiton
mesh_terms: D000470:Alkaloids; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D053119:Benzophenanthridines; D016190:Carboplatin / Q000008:administration & dosage; D004336:Drug Antagonism; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D015474:Isotretinoin / Q000008:administration & dosage; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D010617:Phenanthridines / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D010617:Phenanthridines; D016190:Carboplatin; D008942:Mitoxantrone; C016299:chelerythrine; D015474:Isotretinoin; D017239:Paclitaxel