mitoguazone and trimethylenediamine

The polyamines putrescine, spermidine, and spermine have been shown to sensitize Chinese hamster ovary (CHO) cells to the cytotoxic effects of elevated temperatures. This sensitization occurs in the order spermine greater than spermidine greater than putrescine. A series of homologs of the diamine putrescine demonstrated little variance in the degree of potentiation until a chain length equivalent to that of spermidine was employed (1,8-diaminooctane). Two compounds bearing structural similarities to spermidine gave rather different results when combined with heat. Methylglyoxal bis(guanylhydrazone) (MGBG), an antiproliferative drug, sensitized cells to heat, while S-2-(3-aminopropylamino)-ethyl phosphoric acid (WR-2721), a radioprotector, had no measureable effect on 43 degrees C-induced cytotoxicity. Together, these results point out the primary importance of two terminal amino groups separated by either carbon, or carbon and nitrogen, atoms in an aliphatic chain in the observed sensitization of heat-induced cytotoxicity by polyamines. These data suggest specific dimensional characteristics of the presumed negatively charged structure(s) with which the polyamines are interacting to elicit this effect.

Topics: Amifostine; Animals; Cadaverine; Cell Line; Cell Survival; Cricetinae; Cricetulus; Diamines; Dose-Response Relationship, Drug; Hot Temperature; Mitoguazone; Polyamines; Putrescine; Spermidine

The effects of inhibitors of polyamine synthesis on DNA synthesis in rat liver regenerating after partial hepatectomy were studied. Neither 1,1'-[(methylethanediylidene)-dinitrilo]-bis-(3-aminoguanidine), a potent irreversible inhibitor of S-adenosylmethionine decarboxylase, nor 1,3-diaminopropane, an indirect inhibitor of ornithine decarboxylase, strongly inhibited [3H]thymidine incorporation into DNA when given as a single injection 1 h after operation and 23 h before DNA synthesis was measured. However, when the two inhibitors were given together, DNA synthesis was completely prevented. The incorporation of [14C]leucine into protein was not affected by this treatment. Combined administration of the inhibitors partially prevented the rise in hepatic spermidine levels normally seen during liver regeneration, but neither drug was effective alone. Hepatic putrescine content measured 12 h after treatment was increased by the combined inhibitors whereas, spermine levels were not significantly changed. By 24 h after operation the effects of the combined inhibitors on spermidine levels had almost worn off but DNA synthesis was greatly inhibited. However, by 40 h after operation the inhibitor treatment had no effect on [3H]thymidine incorporation into DNA. Also treatment with the combined inhibitors abolished DNA synthesis at 24 h after partial hepatectomy only when given more than 6 h before measurement suggesting that the effect was indirect and required time to become apparent. These results are consistent with other recent studies in which prior accumulation of spermidine appeared to be required for normal DNA replication and cell division.

Topics: Adenosylmethionine Decarboxylase; Animals; Carboxy-Lyases; Diamines; DNA; Female; Hepatectomy; Liver; Liver Regeneration; Mitoguazone; Ornithine Decarboxylase Inhibitors; Polyamines; Protein Biosynthesis; Rats