Increased survival of L1210 leukemic mice by prevention of the utilization of extracellular polyamines. Studies using a polyamine-uptake mutant, antibiotics and a polyamine-deficient diet.
When L1210 leukemia cells are inhibited in their polyamine synthesis by treatment with alpha-difluoromethylornithine (DFMO), their growth in culture is strongly suppressed. In striking contrast, the survival of L1210 leukemic mice is only marginally prolonged by DFMO treatment. This inconsistency is due to the fact, that in the mouse the tumor cells can utilize extracellular polyamines to compensate for the decrease in putrescine and spermidine synthesis caused by DFMO treatment. In the present study, we demonstrate that a reduction in the transport of polyamines into the tumor cells is a more effective means of increasing the therapeutic effect of DFMO than is a reduction in the supply of extracellular polyamines. DFMO treatment cured 30-75% of leukemic mice bearing mutant L1210-MGBGr cells deficient in polyamine uptake, but only slightly increased the survival time of leukemic mice bearing the parental L1210 cells despite the fact that the supply of extracellular polyamines was reduced (by feeding the mice a polyamine-deficient diet containing antibiotics). The effectiveness by which DFMO cured leukemic mice bearing L1210-MGBGr cells appeared to be sex dependent. Thus, 58% of the female mice, as compared to 30% of the male mice, were cured by DFMO treatment.
Ask
A
A
Department of Oncology, University of Lund, Sweden.
Persson
L
L
Heby
O
O
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport; D002250:Carbon Radioisotopes; D004351:Drug Resistance; D000518:Eflornithine / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008935:Mitoguazone / Q000494:pharmacology; D009154:Mutation; D011073:Polyamines / Q000378:metabolism* / Q000493:pharmacokinetics*; D012737:Sex Factors; D013095:Spermidine / Q000493:pharmacokinetics; D013096:Spermine / Q000493:pharmacokinetics; D014316:Tritium
D000900:Anti-Bacterial Agents; D002250:Carbon Radioisotopes; D011073:Polyamines; D014316:Tritium; D013096:Spermine; D008935:Mitoguazone; D013095:Spermidine; D000518:Eflornithine