The reduction of intracellular polyamines by sequential inhibition of the synthesis of decarboxylated S-adenosylmethionine: effects on rat leukemia.
Decarboxylated S-adenosylmethionine (SAM) is an aminopropyl donor in the synthesis of the polyamines, spermidine and spermine. The decarboxylation of SAM is inhibited by the toxic cytostatic drug methylglyoxalbis-(guanylhydrazone) (MGBG). To achieve more specific and less toxic effects of MGBG, this drug was combined with cycloleucine, which inhibits SAM synthesis, and with nitrous oxide, which inhibits methionine synthetase. This treatment thus aimed at sequential inhibition of the synthesis of decarboxylated SAM, and was studied in a rat leukemia model (BNML). Combined treatment further decreased the level of spermine, but not of spermidine, in leukemic cells, compared to the effects of MGBG alone. The therapeutic effects of this combination were additive or less than additive, however. MGBG was not very effective in reducing leukemic growth and severely toxic, although less with combined treatment. Another inhibitor of SAM decarboxylase, berenil, was also used, and although this drug was about equally active in inhibition of leukemic growth, alterations in intracellular polyamines were not observed. The combination of nitrous oxide and cycloleucine, which effectively reduced leukemic growth at non-toxic dosages, selectively inhibited spermine synthesis, and therefore may be used to interfere with polyamine metabolism. The relevance of this polyamine deprivation to the treatment of leukemia could not be demonstrated.
Kroes
A C
AC
Institute of Hematology, Erasmus University, Rotterdam, The Netherlands.
Ermens
A A
AA
Lindemans
J
J
Schoester
M
M
Abels
J
J
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D003515:Cycloleucine / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008935:Mitoguazone / Q000494:pharmacology; D009609:Nitrous Oxide / Q000494:pharmacology; D011073:Polyamines / Q000032:analysis*; D011506:Proteins / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D012436:S-Adenosylmethionine / Q000378:metabolism*
D011073:Polyamines; D011506:Proteins; D003515:Cycloleucine; D012436:S-Adenosylmethionine; D004247:DNA; D012437:Adenosylmethionine Decarboxylase; D009609:Nitrous Oxide; D008935:Mitoguazone