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Independence of Drug Action on Mitochondria and Polyamines in L1210 Leukemia Cells Treated with Methylglyoxal-bis(guanylhydrazone)¹

Department of Natural Sciences, Daemen College, Amherst, New York 14226 [A. P.], and Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263 [D. L. K., E. K., C. W. P.]

The relationship between inhibition of polyamine biosynthesis and interference with mitochondrial structure and function by the antitumor agent, methylglyoxal-bis(guanylhydrazone) (MGBG), was examined by studying the temporal sequence of events relevant to these two drug actions. In ascites L1210 cells treated in vivo with a single dose of MGBG (75 mg/kg), significant inhibition of pyruvate utilization, used here as a measure of mitochondrial function, occurred within 1 hr after initiation of drug treatment and continued to decrease for 24 hr. Ultrastructural damage to mitochondria, in the form of swelling, was first apparent in 50% of the cells after 6 hr of treatment and in > 90% of the cells after 20 hr. Inhibition of S-adenosylmethionine decarboxylase, a key enzyme in spermidine and spermine biosynthesis, occurred within 1 hr of drug treatment. Enzyme levels increased dramatically after 8 hr of treatment as a result of MGBG stabilization of the enzyme. Beginning at 8 hr, ornithine decarboxylase, the enzyme responsible for putrescine synthesis, increased slightly and continued to rise slowly during the next 16 hr. As a consequence of S-adenosylmethionine decarboxylase inhibition by MGBG, intracellular putrescine pools began to accumulate after 2 hr of treatment and increased rapidly after 12 hr. In contrast, spermine pools decreased slowly after 4 hr while spermidine pools decreased even more slowly. However, even after 24 hr, significant amounts of both polyamines were still present intracellularly.

Since MGBG-induced changes in mitochondrial function precede significant alterations in polyamine pools, it is concluded that the two effects are separable. This conclusion is further supported by the finding that, in cultured L1210 cells treated with -methylornithine at concentrations which effectively inhibited putrescine and spermidine biosynthesis, the mitochondrial ultrastructure was unaffected. Results of the present study raise the possibility that MGBG interference with mitochondrial function might be responsible for the early antiproliferative action of the drug.

¹ This investigation was supported by Research Grants CA-22153 and CA-24538 from the National Cancer Institute, Department of Health, Education and Welfare.

² To whom requests for reprints should be addressed.

Received 5/19/80. Accepted 9/ 8/80.

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