Abstract：
:Stable variants of the human cell line, VA2-B, have been developed which are 10- to 20-fold less sensitive to the antiproliferative effects of methylglyoxal bis(guanylhydrazone) (MGBG) than the parent cell lines and which are not drug transport deficient. The lines were characterized biochemically giving particular attention to parameters related to the two known sites of MGBG action, mitochondria and polyamine metabolism. Dose-response studies with MGBG (0 to 30 microM for 40 to 48 hr) 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. By contrast, decreases in pyruvate oxidation (used here as a measure of mitochondrial function) closely paralleled growth inhibition in all cell lines. Similarly, 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 about 2-fold more resistant to the inhibitory effects of MGBG than mitochondria from the VA2 cells. Finally, 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. Overall, the data suggest that a phenotypic alteration in mitochondrial function, rather than in polyamine metabolism, may represent the basis for MGBG resistance in these variant cell lines.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Kramer DL,Zychlinski L,Wiseman A,Porter CWsubject
Has Abstractpub_date
1983-12-01 00:00:00pages
5943-50issue
12 Pt 1eissn
0008-5472issn
1538-7445journal_volume
43pub_type
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