Genotoxicity of pemetrexed in human peripheral blood lymphocytes

Abstract

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 μg/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 μg/mL (24- and 48-h treatment) and 50 μg/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.

Micronucleus assay in human lymphocytes after exposure to alloxydim sodium herbicide in vitro

“…These results contradict our findings. On the other hand, Alloxydim sodium has cytotoxic effect due to decreasing the NDI and similar results have been reported by Ila et al (2008) and İstifli and Topaktaş (2013).…”

Evaluation of genotoxic potential of pemetrexed by using in vitro alkaline comet assay

“…Pemetrekset, purin ve pirimidin sentezleri için gerekli olan folat bağımlı biyosentez döngülerini engelleyici etkiye sahip folik asit analoğu yeni nesil kemoterapötik bir ilaçtır. Pemetrekset, timidilat sentaz (TS), dihidrofolat redüktaz (DHFR) ve glisinamid ribonukleotid formil transferaz (GARFT) enzimlerinin de bulunduğu pek çok enzimin inhibisyonu ile kanser hücreleri üzerinde güçlü sitotoksik etkiye sahiptir (5)(6)(7). Mezotelyoma ve küçük hücreli olmayan akciğer kanseri tedavisinde geçerliliği kabul edilmiş bir ilaç olan pemetrekset'in, diğer solid tümörlerin tedavisi üzerine ÖZ Pemetrekset, mezotelyoma, küçük hücreli olmayan akciğer kanseri ve pek çok neoplazmın tedavisinde kullanılan kemoterapötik bir ilaçtır.…”

“…Ancak normal hücreler üzerine genotoksik etkileri ile ilgili in vitro çalışmalarda halen eksiklikler vardır (6). Yapılan literatür taramasında pemetrekset'in alkali tek hücre jel elektroforez yöntemi ile normal lökositler üzerine genotoksik etkisine ait bir dataya rastlanılmadı.…”

The role of natural indigo dye in alleviation of genotoxicity of sodium dithionite as a reducing agent

“…Chromosome Aberration (CA) and Sister Cromatid Exchange (SCE) assay in PBLs are recognized as a useful indicator for cytogenetic and genotoxic tests respectively (Timocin et al 2016;İstifli and Topaktaş 2013). High level of CA in PBLs is associated with an increased risk of cancer and also predicts genotoxic risk of potentially mutagenic and carcinogenic chemicals (Kocaman et al 2014;Norppa et al 2006).…”