title: Amifostine protects normal tissues from paclitaxel toxicity while cytotoxicity against tumour cells is maintained.
abstract: The objectives of this study were to evaluate the protective effects of amifostine against paclitaxel-induced toxicity to normal and malignant human tissues. Haematopoietic progenitor colony assays were used to establish the number of CFU-GEMM and BFU-E colonies after incubation with WR-1065 alone, Amifostine alone, paclitaxel (2.5 or 5 microM) +/- WR-1065 or amifostine. MTT and alkaline elution assays evaluated the in vitro growth inhibitory and DNA damaging effects, respectively, of paclitaxel with or without amifostine against normal human fibroblasts and human non-small cell lung cancer (NSCLC) cells. This combination was also evaluated in vivo using severe combined immune deficient (scid) mouse models of early (non-palpable tumours) and advanced (palpable tumours) human ovarian cancer. Human 2780 ovarian cancer cells were inoculated subcutaneously while paclitaxel and amifostine were administered intraperitoneally. A brief exposure (15 min) to amifostine not only protected human haematopoietic progenitor colonies from paclitaxel toxicity, but stimulated the growth of CFU-GEMM and BFU-E beyond control values. Amifostine protected normal human lung fibroblasts from paclitaxel-induced cytotoxicity and DNA single-strand breaks. However, paclitaxel cytotoxicity and DNA single-strand breaks were actually enhanced by pretreatment with amifostine in the NSCLC model. Importantly, amifostine did not interfere with paclitaxel antitumour activity even with prolonged exposure (24.5 h) of the lung cancer cells to high concentrations (1.2 mM) in vitro or following five repetitive high doses (200 mg/kg) given to scid mice with human ovarian cancer xenografts. Indeed, under certain circumstances, amifostine resulted in sensitisation of tumour cells to paclitaxel. Our results confirm previous reports of the ability of amifostine to protect normal tissues from the toxic effects of chemotherapy drugs and now extend these observations to paclitaxel.
authors.affiliation: Department of Medicine, Arizona Cancer Center, University of Arizona College of Medicine, Tucson 85724, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Taylor
authors.forename: L M
authors.initials: LM
authors.lastname: Wang
authors.forename: A F
authors.initials: AF
authors.lastname: List
authors.forename: D
authors.initials: D
authors.lastname: Fernandes
authors.forename: G D
authors.initials: GD
authors.lastname: Paine-Murrieta
authors.forename: C S
authors.initials: CS
authors.lastname: Johnson
authors.forename: R L
authors.initials: RL
authors.lastname: Capizzi
mesh_terms: D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011838:Radiation-Sensitizing Agents; D004999:Amifostine; D017239:Paclitaxel