ACTIVITY OF OXALIPLATIN AGAINST HUMAN TUMOR COLONY-FORMING-UNITS

This study was conducted to identify tumor types warranting Phase II c linical trials of oxaliplatin using the human tumor cloning assay, Oxa liplatin was tested at concentrations ranging from 0.5 to 50.0 mu g/ml in l-h and 14-day continuous exposures along with 1.4 mu g/ml carbopl atin and 0.2 mu g/ml cisplatin for comparison, We defined in vitro res ponse as tumor growth inhibition >50% of control, In the l-h exposure schedule, in vitro responses mere observed in 9 of 116 (8%), 18 of 115 (16%), 38 of 103 (37%), and 7 of 13 (54%) tumor specimens at concentr ations of 0.5, 5.0, 10.0, and 50.0 mu g/ml oxaliplatin, respectively, In the 14-day exposure schedule, in vitro responses mere observed in 1 0 of 121 (8%), 37 of 121 (31%), 57 of 106 (54%), and 15 of 15 (100%) t umor specimens at concentrations of 0.5, 5.0, 10.0, and 50.0 mu g/ml o xaliplatin, respectively, Activity was observed against colon cancer, non-small cell lung cancer, gastric cancer, and melanoma colony-formin g units, In both cisplatin-resistant and cisplatin-sensitive tumors, t he activity of oxaliplatin was concentration and time dependent, A I-h exposure to 5.0 and 10.0 mu g/ml oxaliplatin led to 7,4 and 23.4% ill vitro responses, respectively, in specimens resistant to l-h exposure of 0.2 mu g/ml cisplatin, Moreover, l-h exposures to 5.0 mu g/ml and 10.0 mu g/ml oxaliplatin showed in vitro antitumor responses in 10.2 a nd 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 mu g/ml carboplatin, 6.0 mu g/ml 5 -fluorouracil, 3.0 mu g/ml irinotecan, 10.0 mu g/ml paclitaxel, and 0. 04 mu g/ml doxorubicin, respectively, The effect in those drug-resista nt specimens was improved when oxaliplatin was used on the protracted exposure regimen, Our data indicate that oxaliplatin is an active drug ill vitro against a large variety of human tumors, Both concentration and duration of exposure are important factors for oxaliplatin cytoto xicity. The broad spectrum of activity and the in vitro activity again st some tumors primarily resistant to conventional anticancer drugs en courage further clinical investigations of oxaliplatin in patients wit h advanced cancer refractory to conventional chemotherapy.