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Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
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Published on: February 24, 2014

Dose-dependent cytotoxic and mutagenic effects of antineoplastic alkylating agents on human lymphoblastoid cells

B J Sanderson1, K J Johnson, W D Henner

  • 1Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland 97201.

Environmental and Molecular Mutagenesis
|January 1, 1991
PubMed

Insights

Eight antineoplastic alkylating agents were tested for mutagenicity and cytotoxicity in human cells. All agents were found to be both cytotoxic and mutagenic, with varying mutagenic efficiency.

Area of Science:

  • Pharmacology
  • Toxicology
  • Genetics

Background:

  • Alkylating agents used as antineoplastics are suspected human carcinogens based on animal and human studies.
  • Quantitative data on mutagenicity and its correlation with cytotoxicity in normal human cells is limited.

Purpose of the Study:

  • To quantify the mutagenic and cytotoxic effects of eight antineoplastic alkylating agents on human lymphoblastoid cells.
  • To assess the correlation between mutagenicity and cytotoxicity of these agents.

Main Methods:

  • Human lymphoblastoid cells (WIL2-NS) were exposed to varying doses of eight antineoplastic alkylating agents.
  • Cell killing (cytotoxicity) and mutation induction at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus were measured.
  • IC50 values (concentration for 50% inhibition of survival) were calculated for each drug.

Main Results:

  • All eight alkylating agents demonstrated dose-dependent cytotoxicity and induced detectable mutations.
  • IC50 values ranged from 4 x 10(-7) M (nitrogen mustard) to 5 x 10(-4) M (busulfan) after 1-hour exposure.
  • At equitoxic doses, induced mutant frequencies varied, with 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) showing approximately 3 x 10(-6) and busulfan/cisplatin showing 2 x 10(-5).

Conclusions:

  • Antineoplastic alkylating agents are both cytotoxic and mutagenic to human cells.
  • A strong correlation exists between the cytotoxicity and mutagenicity of these agents.
  • The mutagenic efficiency of these bifunctional alkylating agents varies significantly.

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