Clastogenicity of cyclophosphamide in Fanconi's anemia lymphocytes without exogenous metabolic activation

The indirect mutagen cyclophosphamide (CP) is known to induce chromosomal aberrations in human lymphocyte cultures only after exogenous metabolic activation. We document here that lymphocytes from five patients with Fanconi's anemia (FA) exhibited extensive chromosomal breakage when cultured in the continuous presence of 1 mM CP without deliberate activation of the drug, whereas, cultures from healthy subjects were not significantly susceptible to breakage under these conditions. CP exposure also enhanced the frequency of sister chromatid exchanges (SCE), but to similar extents in control and FA subjects, suggesting that there is a similar low level of CP metabolism in FA and normal lymphocytes. The direct clastogenic effect of nonactivated CP as demonstrated here in FA lymphocyte cultures may be of value in screening for possible hypersensitivity in patients considered for CP therapy.