Phase I study of alpha-difluoromethylornithine and methyl-GAG.
alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of the synthesis of putrescine (pu) and spermidine (sd) in some benign and malignant tissues. Intracellular deprivation of pu and sd has been shown to induce an enhanced uptake of polyamine-analogs such as methyl-GAG (MGBG). The purpose of this study was to investigate the tolerance and the toxicity of the combination of DFMO and MGBG. Thirty-six patients received 4 X 2 g of DFMO/day orally and every 2 weeks 250-500 mg/m2 of MGBG as a 2-hr infusion, starting on day 14. Besides the well known acute and late side-effects of methyl-GAG, dose-limiting toxicity consisted also of thrombocytopenia, leucopenia, dyspnea, hemolysis and jaundice. The maximal tolerated dose of MGBG for one course was 350 mg/m2 and for repeated courses 250 mg/m2, due to cumulative toxicity. Furthermore, after 8 weeks of continuous administration of DFMO 70% of the patients had a severe hearing loss, which was reversible after a treatment delay of 4-6 weeks. Since the hearing loss prohibited the continuous use of DFMO, two different schedules of intermittent DFMO-administration together with two different infusion periods of MGBG have been investigated in 15 patients. In none of these patients did hearing loss occur. The schedule of continuous administration of 4 X 2 g of DFMO/day orally for 21 days and 250 mg/m2 of MGBG as a 24-hr infusion on days 7, 14 and 21, repeated on day 42, was tolerated best. In 28 evaluable patients two partial remissions were seen. Pretreatment with DFMO significantly enhanced the toxicity of MGBG and the combination of both drugs produced side-effects not seen with either drug alone.
Splinter
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TA
Romijn
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JC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000743:Anemia, Hemolytic / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003638:Deafness / Q000139:chemically induced; D004341:Drug Evaluation; D000518:Eflornithine; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008875:Middle Aged; D008935:Mitoguazone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy; D009952:Ornithine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced
D009952:Ornithine; D008935:Mitoguazone; D000518:Eflornithine