Eight patients who had refractory
leukemia and 1 patient with refractory
multiple myeloma were treated with the
polyamine biosynthesis inhibitors methylgloxal bis(guanylhydrazone) (
MGBG) and
difluoromethylornithine (DFMO). After the first dose of
MGBG there was an increase in
polyamine content in the mononuclear cells of both the peripheral blood and the bone marrow despite the administration of DFMO in all patients with
leukemia.
Putrescine levels increased in the mononuclear cells of all patients, cellular
spermidine levels increased in 4 and cellular
spermine levels increased in 5 patients. The cellular
polyamine levels remained elevated above the pretreatment levels for up to 1 week in some patients. Subsequent treatment with
MGBG, administered after 1-2 weeks of DFMO treatment, also promoted increases in mononuclear cell
polyamine concentrations. Since enhanced
tumor cell uptake of
MGBG after DFMO priming is hypothesized to be dependent on a decrease in cellular
polyamine levels, the increase in cellular
polyamines after
MGBG has important implications for the scheduling of this
drug combination. From these observations, withholding
MGBG until DFMO treatment has produced a decrease in
tumor cell
polyamine concentrations would be the schedule most likely to enhance the uptake of
MGBG.