Activity of oxaliplatin against human tumor colony-forming units.
This study was conducted to identify tumor types warranting Phase II clinical trials of oxaliplatin using the human tumor cloning assay. Oxaliplatin was tested at concentrations ranging from 0.5 to 50.0 microg/ml in 1-h and 14-day continuous exposures along with 1.4 microg/ml carboplatin and 0.2 microg/ml cisplatin for comparison. We defined in vitro response as tumor growth inhibition >50% of control. In the 1-h exposure schedule, in vitro responses were observed in 9 of 116 (8%), 18 of 115 (16%), 38 of 103 (37%), and 7 of 13 (54%) tumor specimens at concentrations of 0.5, 5.0, 10.0, and 50.0 microg/ml oxaliplatin, respectively. In the 14-day exposure schedule, in vitro responses were observed in 10 of 121 (8%), 37 of 121 (31%), 57 of 106 (54%), and 15 of 15 (100%) tumor specimens at concentrations of 0.5, 5.0, 10.0, and 50.0 microg/ml oxaliplatin, respectively. Activity was observed against colon cancer, non-small cell lung cancer, gastric cancer, and melanoma colony-forming units. In both cisplatin-resistant and cisplatin-sensitive tumors, the activity of oxaliplatin was concentration and time dependent. A 1-h exposure to 5.0 and 10.0 microg/ml oxaliplatin led to 7.4 and 23.4% in vitro responses, respectively, in specimens resistant to 1-h exposure of 0.2 microg/ml cisplatin. Moreover, 1-h exposures to 5.0 microg/ml and 10.0 microg/ml oxaliplatin showed in vitro antitumor responses in 10.2 and 24.3%, 17.2 and 34.5%, 10.0 and 20.0%, 6.7 and 16.7%, and 11.4 and 34.3% of specimens resistant to 1.4 microg/ml carboplatin, 6.0 microg/ml 5-fluorouracil, 3.0 microg/ml irinotecan, 10.0 microg/ml paclitaxel, and 0.04 microg/ml doxorubicin, respectively. The effect in those drug-resistant specimens was improved when oxaliplatin was used on the protracted exposure regimen. Our data indicate that oxaliplatin is an active drug in vitro against a large variety of human tumors. Both concentration and duration of exposure are important factors for oxaliplatin cytotoxicity. The broad spectrum of activity and the in vitro activity against some tumors primarily resistant to conventional anticancer drugs encourage further clinical investigations of oxaliplatin in patients with advanced cancer refractory to conventional chemotherapy.
Raymond
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Nordan Colon Cancer Research & Translational Research Laboratory, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245, USA. Eric_Raymond@msn.com
Lawrence
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Izbicka
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Faivre
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Von Hoff
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D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000503:physiopathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin