Dose-dependent cytotoxic and mutagenic effects of antineoplastic alkylating agents on human lymphoblastoid cells.
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 IC50s for each of the drugs tested. The IC50s, for 1 hr exposure, ranged from 4 x 10(-7) M for nitrogen mustard to 5 x 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 (IC50), the frequency of induced mutants ranged from approximately 3 x 10(-6) for 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) to 2 x 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.
Sanderson
B J
BJ
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland 97201.
Johnson
K J
KJ
Henner
W D
WD
D000477:Alkylating Agents / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D002273:Carcinogens; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D009153:Mutagens; D007041:Hypoxanthine Phosphoribosyltransferase