Susceptibility of Fanconi's anaemia fibroblasts to chromosome damage by carcinogens

Abstract

INDIVIDUALS with certain genetic syndromes associated with chromosome damage show markedly increased incidence of cancer¹. In one such syndrome, Fanconi's anaemia (FA), chromosomal breakage and rearrangement has been found in lymphocytes and fibroblasts^2,3 years before the development of malignant tumours. There is some evidence that cells from FA patients are especially sensitive to oncogenic agents. FA fibroblasts are abnormally susceptible to SV40 transformation⁴, and lymphocytes from patients show increased chromosome aberrations after exposure to ionising radiation⁵, or to alkylating agents^6,7. In these reports, however, evaluation was based on cells which entered metaphase during brief and possibly toxic exposures to chemicals. We report here experiments in which FA fibroblasts were exposed to a direct-acting mutagen or carcinogen for a period of 6 d, ensuring chronic exposure of the cells during one or more cell cycles, until increased cell density inhibited further cell division. After subculture we could then assay chromosome damage in cells capable of entering a new cycle of cell division after removal from the chemical. We found that viable FA fibroblasts showed increases in chromosome aberrations after exposure to the mutagen or carcinogen at concentrations that had no effect in other cell strains tested. Since fibroblasts can be maintained in serial passage, their use in this protocol makes it possible to examine residual and possibly lasting effects of the treatment.