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Dose‐dependent cytotoxic and mutagenic effects of antineoplastic alkylating agents on human lymphoblastoid cells
Author(s) -
Sanderson Barbara J. S.,
Johnson Kara J.,
Henner W. David,
Skopek T. R.
Publication year - 1991
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.2850170404
Subject(s) - hypoxanthine guanine phosphoribosyltransferase , nitrogen mustard , cytotoxicity , cytotoxic t cell , chemistry , carcinogen , chinese hamster , mutagen , lymphoblast , pharmacology , cell culture , mutant , biology , biochemistry , in vitro , genetics , chemotherapy , cyclophosphamide , gene
The alkylating agents in clinical use as antineoplastics are strongly implicated as human carcinogens on the basis of animal studies and human epidemiologic studies. However, there is little quantitative information on the extent to which exposure to these drugs is mutagenic for normal (non‐malignant) cells and the extent to which such mutagenicity correlates with cytotoxicity of these agents. Human lymphoblastoid cells (WIL2‐NS) were exposed to graded doses of eight antineoplastic alkylating agents. Cell killing and mutation induction at the hypoxanthine ‐guanine phosphoribosyltransferase (HPRT) locus were measured by cloning in microplates in the presence and absence of 6‐thioguanine. Dose‐dependent decreases in survival were used to calculate IC 50 s for each of the drugs tested. The IC 50 s, for 1 hr exposure, ranged from 4 × 10 −7 M for nitrogen mustard to 5 × 10 −4 M for busulfan. The eight drugs tested each induced detectable increases in the frequency of mutant cells. The mutagenicity of these agents is correlated strongly with cytotoxicity. However, at equitoxic doses (IC 50 ), the frequency of induced mutants ranged from approximately 3 × 10 −6 for 1,3‐bis(2‐chlorethyl)‐1‐nitrosourea (BCNU) to 2 × 10 −5 for busulfan and cisplatin. These results quantitate the dose‐dependent cytotoxic and mutagenic effects of these bifunctional alkylating agents on human cells. All are cytotoxic and mutagenic, although their mutagenic efficiency varies.