A number of studies have demonstrated that pretreatment of
tumor-bearing animals with the inhibitor of
polyamine biosynthesis,
alpha-difluoromethylornithine (DFMO), potentiates the antitumor activity of
methylglyoxal bis(guanylhydrazone) (
MGBG). The present study examines whether this phenomenon is related to a DFMO-mediated increase in the selectivity of
MGBG for
tumor tissue. Specifically, the effect of DFMO pretreatment on the tissue distribution and content of
MGBG was investigated in mice bearing
ascites L1210 leukemia. At 3 and 18 h following a single i.v. injection of [14C]
MGBG (50 mg/kg), L1210 cells and seven tissues from nonpretreated (control) and DFMO-pretreated (3% by
drinking water for 3 days) animals were compared for their [14C]
MGBG content. In control mice, the greatest amount of
drug was found in L1210 cells, small intestine, and kidney (in decreasing order of magnitude) at both 3 and 18 h. This distribution was not altered following DFMO pretreatment, but the relative
MGBG content of other tissues was shifted. On an average, DFMO pretreatment increased the accumulation of
MGBG by 30% in normal tissues and 32% in
tumor tissues at 3 h and 56% and 69%, respectively, at 18 h. Thus, pretreatment of leukemic mice with DFMO fails to improve the selectivity of
MGBG for L1210 cells. It is possible that other
tumor systems might demonstrate sufficient DFMO-mediated increases in
MGBG uptake to enhance
drug selectivity but not without significantly increasing
MGBG uptake (and hence toxicity) in normal tissues.