COLUMBUS, OhioMitomycin (Mutamycin) can make some solid tumors flare high levels of topoisomerase-I and set them up for destruction by topoisomerase-I inhibitors such as irinotecan(Drug information on irinotecan) (Camptosar), according to Miguel A. Villalona, MD. Dr. Villalona is assistant professor in the Department of Medicine at Ohio State University Comprehensive Cancer Center in Columbus, Ohio.
"We hypothesized that administering mitomycin(Drug information on mitomycin) first would result in increased expression of topoisomerase-I, therefore enhancing the ability of irinotecan to interact with its target. This schedule would also decrease the chance that irinotecan would interfere with DT-diaphorase and the activation of mitomycin," Dr. Villalona said.
Testing the Strategy
Dr. Villalona tested this strategy in a phase I study in which patients were given mitomycin 6 mg/m² on day 1 of a 6-week cycle, followed by irinotecan in doses escalating from 50 to 100 mg/m² on days 2, 8, 15, and 22. Due to problems with late diarrhea, this was changed to a 4-week cycle, which included escalating irinotecan to 150 mg/m².
The study enrolled 38 patients with various advanced solid malignancies and no prior treatment with mitomycin, irinotecan, or nitrosourea, and no more than six prior courses of chemotherapy containing an alkylating agent. Due to inactivation of NQ01 by warfarin(Drug information on warfarin) (Coumadin), use of this medication was not permitted.
Pharmacokinetic sampling was done at the end of the irinotecan infusion and at 2, 4, and 24 hours postinfusion. RNA from peripheral lymphocytes was tested for NQ01, topoisomerase-I, and carboxylesterase expression.
The researchers found that the maximum tolerated dose (MTD) of irinotecan was 125 mg/m² with 6 mg/m² of mitomycin.