Clastogenic activity of 2-chlorodeoxyadenosine in mammalian somatic cells

Abstract

The base analogue 2-chlorodeoxyadenosine (2-CdA) used for therapy in chronic resistant and advanced lymphoproliferative disorders, is cytotoxic for both dividing and non-dividing lymphocytes. The present work evaluated the clastogenic potential of this drug in vitro in human lymphocytes in culture and in vivo in BALB/c mice bone marrow cells. In human lymphocytes, the clastogenic effect of 2-CdA was studied in G1, S and G2 phases of the cell cycle, using three different concentrations (10, 20 and 40 µg/mL). The endpoints analyzed included mitotic index (MI), proliferation index (PI), sister chromatid exchange (SCE), and chromosomal aberration (CA). Statistical analysis by a variance (ANOVA) test showed a significant increase (p < 0.05) in CA frequencies for cells treated during the S phase, but the MI did not vary. The concentrations tested did not produce a significant increase in the mean frequency of SCEs, nor did they change the cell PI in the G1 and S phases. The concentrations in vivo tested were 0.25, 0.375 and 0.5 mg/kg body weight. In this assay, alterations in CA frequencies and MI were not observed at the dose levels tested. Therefore, the results indicate a clastogenic effect of 2-CdA in human lymphocyte cultures.

An evaluation of 25 selected ToxCast chemicals in medium‐throughput assays to detect genotoxicity

“…Some of the results obtained from the flow MN assay were somewhat incongruous compared to literature reports. Cladribine, which is an anti‐metabolite that should not need metabolic activation [Yuh et al, ; Antonucci and Takahashi, ], was inactive in the flow MN assay without S9 but was active when S9 was used. This is similar to what was found with folpet, a direct‐acting mutagen, whose activity is reportedly reduced by activation [Moriya et al, ; Arce et al, ].…”