SUSCEPTIBILITY OF FANCONIS ANEMIA LYMPHOBLASTS TO DNA-CROSS-LINKING AND ALKYLATING-AGENTS

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (10) , 4000-4006
Abstract
To develop the usefulness of Fanconi''s anemia (FA) [human] lymphoblast lines for biochemical and genetic studies, their sensitivity to a variety of DNA-damaging chemicals was determined. A growth inhibition protocol was used in which the sensitivity of a cell line was characterized by the drug concentration yielding a 50% inhibition of growth (EC50). The DNA-cross-linking agents mitomycin C, nitrogen mustard, melphalan, 1,3-butadiene diepoxide, cis-diamminedichloroplatinum(II) and cyclophosphamide were all more toxic to 4 FA cell lines than to 5 normal lines. Three lines, HSC-72 (FA), 99 (FA) and 230 (FA), had EC50 that were 10-20 times lower than that of controls while the 4th line , HSC-62 (FA), had an intermediate EC50. Three nitrosourea compounds [1,3-bis(2-chloroethyl)-N-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, 1-(2-chloroethyl)-3-trans-(4-methylcyclohexyl)-1-nitrosourea] were also more toxic to FA cells than to controls. Two normal cell lines (HSC-92 and 93) had nitrosourea EC50s 4-7 times lower than the other 9 controls and overlapped the sensitivity of the intermediate [HSC-62 (FA)] cell line. The same 2 normal cell lines were also more sensitive than 12 other controls, including FA heterozygotes, xeroderma pigmentosum and ataxia telangiectasia, to the monofunctional alkylating agents, ethyl methanesulfonate, methyl methanesulfonate, and N-methyl-N''-nitro-N-nitrosoguanidine. Heterogeneity was also found with FA lines. Two FA cell lines (HSC-72 and 230) had EC50 lower than all control lines while one FA line (HSC-99) had an EC50 similar to that of the resistant normal lines. FA and normal cells had nearly the same sensitivity to 4-nitroquinoline-1-oxide and bleomycin. FA lymphoblast lines are more sensitive than normal cell lines to all DNA-cross-linking agents examined. These cell lines should therefore be useful for the analysis of DNA cross-link repair and the biochemical defect in FA. We have also found an unexpected sensitivity of some FA and normal lines to monofunctional alkylating agents.