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dc.contributor.authorFox, Margaret
dc.contributor.authorHodgkiss, R J
dc.date.accessioned2011-07-01T12:04:10Z
dc.date.available2011-07-01T12:04:10Z
dc.date.issued1981-01
dc.identifier.citationMechanism of cytotoxic action of azaguanine and thioguanine in wild-type V79 cell lines and their relative efficiency in selection of structural gene mutants. 1981, 80 (1):165-85 Mutat Resen
dc.identifier.issn0027-5107
dc.identifier.pmid7207481
dc.identifier.urihttp://hdl.handle.net/10541/135104
dc.description.abstractThe cytotoxic effects of azaguanine and thioguanine have been compared in two wild-type V79 cells. To achieve equitoxic effects in both cell lines a 10-20-fold higher concentration of azaguanine than thioguanine was required. Affinity of HGPRT for azaguanine was 10-fold lower than for hypoxanthine in both cell lines and was similar to that for thioguanine in V79S cells. Affinity for thioguanine differed by a factor of 3 in the two cell lines. The rate of cell kill by azaguanine was markedly slower than by thioguanine in both cell lines. Reduction of whole cell uptake of [14C]hypoxanthine incorporation by unlabelled azaguanine was only demonstrable after prolonged incubation periods as was incorporation of [14C]azaguanine into acid-insoluble material. Experiments with cell-free extracts indicated that hypoxanthine acts as a non-competitive inhibitor of the enzyme. The slow rate of dissociation of the HGPRT-azaguanine complex is reflected in the slow rate of killing of wild-type cells. Clones resistant to the cytotoxic effects of these analogues have been selected from both cell lines and have been shown to possess HGPRT with altered kinetic properties. Our data suggest that azaguanine and thioguanine may select for mutations at different sites on the HGPRT molecule in V79 cells and provide possible explanations for the differences in effectiveness of these two agents reported in other cell lines.
dc.language.isoenen
dc.subject.meshAnimals
dc.subject.meshAzaguanine
dc.subject.meshCell Line
dc.subject.meshCricetinae
dc.subject.meshCricetulus
dc.subject.meshGenes
dc.subject.meshHypoxanthine Phosphoribosyltransferase
dc.subject.meshLung
dc.subject.meshMutagens
dc.subject.meshMutation
dc.subject.meshThioguanine
dc.titleMechanism of cytotoxic action of azaguanine and thioguanine in wild-type V79 cell lines and their relative efficiency in selection of structural gene mutants.en
dc.typeArticleen
dc.contributor.departmentPaterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, M20 9BX (Great Britain)en
dc.identifier.journalMutation Researchen
html.description.abstractThe cytotoxic effects of azaguanine and thioguanine have been compared in two wild-type V79 cells. To achieve equitoxic effects in both cell lines a 10-20-fold higher concentration of azaguanine than thioguanine was required. Affinity of HGPRT for azaguanine was 10-fold lower than for hypoxanthine in both cell lines and was similar to that for thioguanine in V79S cells. Affinity for thioguanine differed by a factor of 3 in the two cell lines. The rate of cell kill by azaguanine was markedly slower than by thioguanine in both cell lines. Reduction of whole cell uptake of [14C]hypoxanthine incorporation by unlabelled azaguanine was only demonstrable after prolonged incubation periods as was incorporation of [14C]azaguanine into acid-insoluble material. Experiments with cell-free extracts indicated that hypoxanthine acts as a non-competitive inhibitor of the enzyme. The slow rate of dissociation of the HGPRT-azaguanine complex is reflected in the slow rate of killing of wild-type cells. Clones resistant to the cytotoxic effects of these analogues have been selected from both cell lines and have been shown to possess HGPRT with altered kinetic properties. Our data suggest that azaguanine and thioguanine may select for mutations at different sites on the HGPRT molecule in V79 cells and provide possible explanations for the differences in effectiveness of these two agents reported in other cell lines.


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