title: Patupilone acts as radiosensitizing agent in multidrug-resistant cancer cells in vitro and in vivo.
abstract: Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts. Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range. SW480 cells were only sensitive to patupilone, and combined treatment with low-dose patupilone (0.1 nmol/L) followed by clinically relevant doses of ionizing radiation (2 and 5 Gy) resulted in a supra-additive cytotoxic effect. Inhibition of the drug efflux protein P-glycoprotein with verapamil resensitized SW480 cells to treatment with low doses of paclitaxel alone and in combination with IR. In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 x 2 mg/kg plus 4 x 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest. Analysis by flow cytometry in vitro revealed an apoptosis- and G(2)-M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment.Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoprotein-overexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.
authors.affiliation: Department of Radiation Oncology, University Hospital Zurich, Ramistr. 100, CH-8091 Zurich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hofstetter
authors.forename: Van
authors.initials: V
authors.lastname: Vuong
authors.forename: Angela
authors.initials: A
authors.lastname: Broggini-Tenzer
authors.forename: Stephan
authors.initials: S
authors.lastname: Bodis
authors.forename: Ilja F
authors.initials: IF
authors.lastname: Ciernik
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.forename: Gerd
authors.initials: G
authors.lastname: Folkers
authors.forename: Martin
authors.initials: M
authors.lastname: Pruschy
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D034261:Epothilones / Q000494:pharmacology*; D016195:G2 Phase; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D034261:Epothilones; D011838:Radiation-Sensitizing Agents; D017239:Paclitaxel; C093788:epothilone B