MULTIPLE RESISTANCE MODULATORS COMBINED WITH CARBOPLATIN FOR RESISTANT MALIGNANCIES - A PILOT-STUDY

Background: Chemotherapy resistance is probably multifactorial; hence, we assessed the feasibility of adding to carboplatin 6 concurrent res istance modulators in 53 patients with resistant cancers. Methods: Pen toxifylline and dipyridamole were added to carboplatin 400 mg/m(2) in cohort 1, and metronidazole was also given in cohort 2. Mannitol and s aline were administered in each cohort with the theoretical objective of improving carboplatin delivery to tumors by reducing blood viscosit y. Because of excessive toxicity in cohort 2, cohort 3 received the sa me modulators as in cohort 2 but with a reduced dose of carboplatin (2 00 mg/m(2)). Subsequent patients had the following drugs added to thos e in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5), ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 mo dulators along with carboplatin 300 mg/m(2). Results: Thrombocytopenia was excessive in early cohorts with a carboplatin dose of 400 mg/m(2) , but was minimal at lower doses. Other toxicity was generally tolerab le and reversible, particularly at carboplatin doses I 300 mg/m(2), al though gastrointestinal and neurological toxicity tended to worsen as additional modulators were added. No major responses (but 4 minor resp onses) were seen in this patient population with heavily pretreated or primarily resistant cancers. Conclusions: Acceptable doses for phase II studies are carboplatin 300 mg/m(2), 20% mannitol 250 ml plus norma l saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/ m(2)/day p.o. from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m(2) p.o. q6h x 6 days starting 24 hr before carbo platin, metronidazole (750 mg/m(2) p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m(2) suppository p.r. 12 hr and im mediately before, and 6 and 24 hr after carboplatin; and 500 mg/m(2) i .v. right after carboplatin), novobiocin 600 mg/m(2) p.o. q12h x 6 day s starting 24 hr before carboplatin, and tamoxifen 100 mg/m(2)/day plu s ketoconazole 700 mg/m(2)/day x 3 days starting the day before carbop latin, with oral dexamethasone and ondansetron as antimetics.