mitoguazone and Cell-Transformation--Neoplastic

Topics: Cell Division; Cell Transformation, Neoplastic; Chemical Phenomena; Chemistry; Humans; Lactoylglutathione Lyase; Lyases; Mitoguazone; Neoplasms; Pyruvaldehyde; Thiolester Hydrolases

Three independent variants (G2, G4, G5), resistant to methylglyoxal bis(guanylhydrazone), an anticancer drug, have been isolated by single step selection from an adenovirus-transformed rat brain cell line (1). These variants display selective cross-resistance to several natural product drugs of dissimilar structure and action. Multidrug resistance has recently been shown to be caused by overexpression of the membrane-associated p-glycoprotein, most often caused by amplification of the mdr gene. Several types of experiments were conducted to determine whether the observed drug resistance in our cell lines could be due to changes at the mdr locus. The following results were obtained: (a) the mdr locus was not amplified; (b) transcription of the mdr gene and p-glycoprotein synthesis were not increased; (c) multidrug resistance cell lines, which carry an amplified mdr locus, were not cross-resistant to methylglyoxal bis(guanylhydrazone); (d) verapamil did not reverse the resistance of G cells or mdr cells to methylglyoxal bis(guanylhydrazone), nor that of G cells to vincristine; and (e) methylglyoxal bis(guanylhydrazone) resistance was recessive and depended on a block to drug uptake, as opposed to mdr cells which are dominant and express increased drug efflux. The results obtained suggest that the drug resistance in the G2, G4, and G5 cells was atypical and may be due to a mechanism distinct from that mediated by the mdr locus.

Topics: Adult; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood Proteins; Brain; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Colchicine; Drug Resistance; Gene Amplification; Gene Expression; Humans; Kinetics; Membrane Glycoproteins; Mitoguazone; Rats; Verapamil

Four independent variant cell lines resistant to the toxic action of methylglyoxal bis(guanylhydrazone), an anticancer drug and inhibitor of polyamine synthesis, have been isolated by single step selection from an adenovirus type 2-transformed rat brain cell line. Drug-resistance was accompanied by loss of tumorigenic potential in athymic nude mice. MGBG resistance was attributable to decreased drug uptake.

Topics: Adenosylmethionine Decarboxylase; Adenoviridae; Animals; Brain; Cell Division; Cell Line; Cell Transformation, Neoplastic; Cell Transformation, Viral; Drug Resistance; Mice; Mice, Nude; Mitoguazone; Mutation; Neoplasm Transplantation; Rats; Spermidine

Topics: Animals; Cell Cycle; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Drug Resistance; Guanidines; Hydroxyurea; Mice; Mitoguazone; Polyamines; Simian virus 40

The objective of this study was to determine the points in the cell cycle at which normal and transformed cells become arrested as a result of polyamine deprivation. Treatment of normal (human fibroblast line PA2 and mouse 3T3) and transformed (CHO, HeLa and SV3T3) cells with methylglyoxal bis-(guanyl-hydrazone) resulted in a significant decrease in the levels of spermidine and spermine which was associated with an inhibition of growth. Examination of the prematurely condensed chromosomes (PCC) of the polyaminedepleted cells, revealed that normal fibroblasts were preferentially arrested in early G1 phase while a majority of cells in the transformed lines were blocked in S phase. A close examination of the PCC of the transformed cells indicated a significant decrease in the number of DNA replication sites suggesting that polyamines have an important role in DNA chain initiation.

Topics: Animals; Cell Cycle; Cell Transformation, Neoplastic; Cells, Cultured; Chromosomes; Cricetinae; DNA Replication; Female; Fibroblasts; HeLa Cells; Humans; Mitoguazone; Ovary; Polyamines; Spermidine; Spermine