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 (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,
"We hypothesized that administering 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 (Coumadin), use of this medication was not
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.