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.