BIOCHEMICAL AND ULTRASTRUCTURAL CHARACTERIZATION OF HUMAN CELL VARIANTS RESISTANT TO THE ANTI-PROLIFERATIVE EFFECTS OF METHYLGLYOXAL BIS(GUANYLHYDRAZONE)

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (12) , 5943-5950
Abstract
Stable variants of the human cell line, VA2-B [a transformed line] were developed which are 10- to 20-fold less sensitive to the antiproliferative effects of methylglyoxal bis(guanylhydrazone) (MGBG) than the parent cell line and which are not drug transport deficient. The lines were characterized biochemically giving particular attention to parameters related to the 2 known sites of MGBG action, mitochondria and polyamine metabolism. Dose-response studies with MGBG (0-30 .mu.M for 40-48 h) revealed that, of the parameters related to polyamine metabolism (i.e., polyamine pools, S-adenosylmethionine and ornithine decarboxylase activities), only spermine pool size reduction seemed to correlate with inhibition of cell growth by MGBG. Decreases in pyruvate oxidation (used here as a measure of mitochondrial function) closely paralleled growth inhibition in all cell lines. MGBG-induced changes in mitochondrial ultrastructure were less conspicuous in the variants than in the parent cell line and also corresponded with growth inhibition. Respiration of isolated mitochondria from one of the variant lines was .apprx. 2-fold more resistant to the inhibitory effects of MGBG than mitochondria from the VA2 cells. Treatment with .alpha.-difluoromethylornithine, a potent inhibitor of polyamine biosynthesis having no known effect on mitochondrial function, resulted in comparable inhibition of growth in variant and parent cell lines. Apparently, a phenotypic alteration in mitochondrial function, rather than in polyamine metabolism, may represent the basis for MGBG resistance in these variant cell lines.