Genotoxicity of pemetrexed in human peripheral blood lymphocytes

Creative Commons License

İstifli E. S. , Topaktaş M.

CYTOTECHNOLOGY, vol.65, pp.621-628, 2013 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 65
  • Publication Date: 2013
  • Doi Number: 10.1007/s10616-012-9516-4
  • Title of Journal : CYTOTECHNOLOGY
  • Page Numbers: pp.621-628
  • Keywords: Chromosome aberration, Micronucleus, Sister chromatid exchange, Cytotoxicity, Pemetrexed, MOUSE BONE-MARROW, CHROMOSOME-ABERRATIONS, MICRONUCLEUS TEST, WORKING GROUP, METHOTREXATE, CELLS, MECHANISM, TOXICITY, CANCER, DAMAGE


Pemetrexed (PMX) is an antineoplastic antifolate used in the treatment of non-small cell lung cancer, mesothelioma and several types of neoplasms. Its toxicity in tumor cells has been linked with the potent inhibition of thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase, and subsequent depletion of both purine and pyrimidine nucleotides. However, cytogenetic toxicity of PMX in non-diseased cells has not been adequately studied; despite the increasing data on the DNA-damaging potential of antineoplastic agents on normal cells. In the present study, the genotoxic potential of PMX was evaluated in peripheral blood lymphocytes obtained from healthy human subjects using chromosome aberration (CA), sister chromatid exchange (SCE) and micronucleus (MN) assays as the cytogenetic damage markers. Human peripheral blood lymphocytes were exposed to four different concentrations (25, 50, 75 and 100 mu g/mL) of PMX for 24- and 48-h treatment periods. PMX significantly increased the formation of CA in 24-h treatment, but not in 48-h treatment. PMX did not increase the mean SCE frequency in 24- and 48-h treatment periods; however, there was a striking increase (although not statistically significant, p > 0.05) in the number of SCEs at 25 mu g/mL (24- and 48-h treatment) and 50 mu g/mL (24-h treatment) due to an increase of SCE at the single-cell level. Interestingly, PMX did not induce MN formation in either 24- or 48-h treatment periods. PMX strongly decreased the mitotic index (MI), proliferation index (PI) and nuclear division index (NDI) in 24- and 48-h treatment periods. Our results suggest that PMX has a potent cytotoxic effect against human peripheral blood lymphocytes at concentrations which are reached in vivo in the blood plasma.