Sensitivity to genotoxic effects of bleomycin in humans: Possible relationship to environmental carcinogenesis

Abstract

Responses to the genotoxic effect of bleomycin in lymphocytes of blood cultures, expressed as the average number of chromatid breaks per cell (b/c), varied from less than 0.20 to more than 2.00 in 335 normal individuals. More than 11% of the subjects tested showed a b/c rate above 1.00 and more than 22% showed a b/c rate above 0.80. These individuals are considered sensitive to this radiomimetic drug. The distributional profile of bleomycin responses of the control individuals appears to be representative of the normal human population. In patients with cancers of the colon (83), upper aerodigestive tract (head/neck) (77), and lung (71), the frequencies of subjects in the hypersensitive class were found to be between 40 and 50%, and the response profiles were distinctly different from those of the control population. On the other hand, in a group of elderly cigarette smokers, who exhibited no symptoms of lung cancer, the bleomycin sensitivity profile was significantly skewed toward the more resistant stratum, with only one hypersensitive case among 56 individuals tested (1.78%). The sensitivity profile of patients with breast cancer (82) was similar to that of the control population. Our data suggest that: (1) mutagen sensitivity may play an important role in carcinogenesis of organs and tissues that have direct contact with the external environment (respiratory, digestive, and integumentary systems); (2) it appears to have no significant influence on carcinogenesis of tissues that are not directly exposed to the environment (e.g., breast, brain); and (3) it also has little impact on carcinogenesis in individuals with a hereditary predisposition to cancer (e.g., retinoblastoma, Gardner's syndrome). Development of more effective and precise test systems for carcinogen sensitivity is highly desirable for identification of persons at risk.

Radiosensitivity in breast cancer assessed by the Comet and micronucleus assays

“…Consistent with the G2 MN data presented here, the G0 MN assay also has failed to discriminate a group of cervical, head and neck cancer patients from healthy individuals (Slonina et al, 2000). In addition, the radiomimetic drug bleomycin induces similar rates of chromatid breaks in lymphocytes from BC patients and from healthy controls (Hsu et al, 1989).…”

Chromosomal radiosensitivity as a marker of predisposition to common cancers?

“…Patients with colorectal or lung cancer show enhanced sensitivity to the chromosome-damaging effects of bleomycin in G 2 lymphocytes (Hsu et al, 1989). However, breast cancer patients were similar to normals, so the response of G 2 cells to bleomycin cannot be regarded as a surrogate for G 2 radiation sensitivity.…”

Bleomycin-induced chromosomal damage in tuberous sclerosis

“…A predisposition to site-or tissue-specific oncogenesis could also be associated with the changes in the distribution of induced chromosomal damage in the peripheral lymphocytes, as has been shown for testicular cancer (Vorechovsky and Zaloudik, 1989a) and for neuroblastoma (Vernole et al, 1989). It is likely that chromosomal sensitivity to mutagens plays an important role in carcinogenesis of organs and tissues that have direct contact with the external environment, such as respiratory, digestive, and integumentary systems (Hsu et al, 1989). Furthermore, a similar increase in number of chromosomal aberrations was also found in some heritable cancer-prone conditions after X-irradiation or BLM treatment in vitro (Parshad et al, 1983;Sanford et al, 1987;Vorechovsky et al, 1989b).…”

“…It has repeatedly been reported that in the lymphocytes of some patients with malignant tumors there is an increase in number of BLM-induced chromosomal aberrations compared with the normal healthy population (Hsu et al, 1985;Cherry and Hsu, 1983;Hsu et al, 1989;Vorechovsky and Zaloudik, 1989a). A predisposition to site-or tissue-specific oncogenesis could also be associated with the changes in the distribution of induced chromosomal damage in the peripheral lymphocytes, as has been shown for testicular cancer (Vorechovsky and Zaloudik, 1989a) and for neuroblastoma (Vernole et al, 1989).…”