Difluoromethylornithine (DFMO) depletes endogenous
putrescine and enhances the uptake of and retention of [3H]
putrescine in vitro. To determine if DFMO also enhances uptake of [3H]
putrescine in vivo, DFMO and trace doses of [3H]
putrescine, dissolved in artificial CSF, were infused into growing (6-9 day) 9L
brain tumors by means of osmotic pumps. When 7-day osmotic pumps were loaded with 1 microCi [3H]
putrescine, with or without 10 or 100 mM DFMO, pumped at 1 microl/h, the mean uptake after 3 days was 168 +/- 62 cpm/mg
tumor (17 rats) without DFMO, 300 +/- 197 cpm/mg
tumor (11 rats) with 10 mM DFMO and 1088 +/- 421 cpm/mg
tumor (11 rats) with 100 mM DFMO (p < or = 0.05 vs. control). Significantly less radioactivity was detected in the contralateral brain and in nonbrain tissues (0.5 +/- 0.1 to 14 +/- 5 cpm/mg). To measure the extent of [3H]
putrescine distribution in the
tumor, the same dose of drugs was delivered for a longer period of time, using 14-day pumps to allow
tumors to become large enough to be divided into 1.4 mm thick transections. The mean radioactivity in the sections from eight control rats receiving [3H]
putrescine without DFMO were not significantly different between the sections (174 +/- 61 cpm/mg
tumor for sections containing the cannulas, 273 +/- 61 and 259 +/- 91 cpm/mg for adjacent sections). In the six rats given 100 mM DFMO there was a significant increase in mean radioactivity in the
cannula containing section (2251 +/- 919 cpm/mg
tumor). Mean counts from adjacent sections in these rats were 97 +/- 44 and 33 +/- 13 cpm/mg. Values for contralateral corpus striatum and nonbrain tissues ranged from 0.7 +/- 0.3 to 4.3 +/- 1.5 cpm/mg tissue. When DFMO was delivered directly to the
tumors while [3H]
putrescine was infused intraperitoneally, the uptake in the
tumor slices was low (5-10 cpm/mg in different slices). These results demonstrate that infusion of DFMO directly into growing 9L
brain tumors can selectively enhance the uptake of exogenous [3H]
putrescine by rapidly dividing cells which are within a 1.4 mm diameter area at the
cannula tip. Although these studies used [3H]
putrescine at trace doses, it is estimated that infusion of higher doses of [3H]
putrescine plus DFMO will selectively kill
tumor cells.