CORRESPONDENCE

RESPONSE: Re: Benzo[a]pyrene Diol Epoxide and Bleomycin Sensitivity and Susceptibility to Cancer of Upper Aerodigestive Tract

Xifeng Wu, Margaret R. Spitz, Christopher I. Amos, T. C. Hsu

Affiliations of authors: X. Wu, M. R. Spitz, C. I. Amos (Department of Epidemiology) and T. C. Hsu (Department of Cancer Biology) University of Texas, M.D. Anderson Cancer Center, Houston, Texas.

Correspondence to: Xifeng Wu, M.D., PhD., Department of Epidemiology, Box 189, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: xwu{at}notes.mdacc.tmc.edu).

We thank Dr. Nersesyan for his interesting comments on our manuscript and take this opportunity to clarify aspects of our analysis.

We believe that Nersesyan has misinterpreted the data from the study by Tomanin et al. (reference 3 in the Nersesyan correspondence). Tomanin et al. reported that bleomycin-induced chromatid breaks were significantly higher in ataxia-telangiectasia (AT) patients than in control subjects, which is consistent with our findings. Nersesyan refers to this paper to support his statement that "chromosomes of homozygote individuals are very sensitive to mutagens, whereas those of the heterozygotes are not." Tomanin et al. used bleomycin in their assay to determine if there was "a possible increased sensitivity of heterozygotes to possible diffusible clastogenic factors present in the plasma of L-B (Louis-Bar) serum." This assay was not designed to test the sensitivity of heterozygotes to bleomycin itself nor did Tomanin et al. indicate that it was designed to do so.

Secondly, Nersesyan states that bleomycin was less effective in inducing DNA damage in leukocytes from children with thyroid cancer than those from healthy subjects. In previous studies, we have demonstrated that, although bleomycin sensitivity is consistently elevated in patients with cancers of the head and neck, colon, and lung, bleomycin sensitivity of patients with tumors of the breast or central nervous system did not differ from those shown by control individuals (1). Different carcinogens or mutagens act on cells through different molecular mechanisms, and they affect different repair pathways and show different sensitivities. We have found that a person who is sensitive to one mutagen can be resistant to others (2). The bleomycin sensitivity assay has also been expanded to measure the risk of other cancers by replacing the test mutagen, bleomycin, with 4-nitroquinoline-oxide (4-NQO), {gamma}-radiation, and benzo[a]pyrene diol epoxide (BPDE). Our research group and others have shown that 4-NQO sensitivity can be used to predict melanoma risk (3), that {gamma}-radiation sensitivity can be used to determine glioma risk (4), and that BPDE sensitivity can be used to estimate smoking-related cancer risk (5). Therefore, it is possible that the thyroid cancer patients are not sensitive to bleomycin. Furthermore, Nersesyan refers to a paper by Frenzilli et al. (reference 4 in the Nersesyan correspondence) that employs the Comet assay and not a mutagen-sensitivity assay. We do not know whether these two assays measure the same mechanisms of DNA repair. Further studies are needed to evaluate the relationship between these two mutagen-sensitivity measures.

Nersesyan seems to consider all micronuclei formation to be the result of chromosome breakage. Whereas some broken chromatid or isochromatid fragments can indeed form micronuclei, most micronuclei are caused by mitotic disturbances (6). Under the influence of a mitotic poison (e.g., vinca alkaloids, Taxol, etc.), mitotic cells fail to enter anaphase. The chromosomes enter the so-called c-anaphase and c-telophase states and eventually become micronuclei. Even when the mitosis-arresting substance is removed under experimental conditions, and the arrested metaphases can resume anaphase movement, lagging chromosomes can become micronuclei.

Nersesyan contrasts our findings with those of Hagmar et al. (reference 6 in the Nersesyan correspondence), who reported that chromosomal aberrations were a relevant biomarker of cancer risk. It must be stressed that that study was conducted on a cohort of workers occupationally exposed to a variety of potential mutagens. Hsu et al. (7) examined the spontaneous chromosome breakage frequencies in untreated lymphocytes in 182 randomly selected normal individuals and 232 cancer patients. He found that the frequencies of spontaneous chromatid breakage were low (break per cell, range = 0.00-0.12). The average break per cell number was 0.0183 for normal subjects and was 0.0223 for cancer patients. Please also note that Hagmar et al. (reference 6 in the Nersesyan correspondence) evaluated chromosome aberrations, not chromatid breaks. Furthermore, they did not present mean spontaneous aberration values nor did they evaluate bleomycin-induced chromatid breaks in that paper.

We agree that further study of cohorts using mutagen-sensitivity measures would provide valuable insights.

REFERENCES

1 Hsu TC, Spitz MR, Schantz SP. Mutagen sensitivity: a biological marker of cancer susceptibility. Cancer Epidemiol Biomarkers Prev 1991;1:83-9.[Abstract]

2 Hsu TC, Feun L, Trizna Z, Savaraj N, Shirley L, Furlong CL, et al. Differential sensitivity among three human subpopulations in response to 4-nitroquinoline-1-oxide and to bleomycin. Int J Oncol 1993;3:827-30.

3 Wu X, Hsu TC, Spitz MR. Mutagen sensitivity exhibits a dose-response relationship in case-control studies. Cancer Epidemiol Biomarkers Prev 1996;5:577-8.[Abstract]

4 Bondy ML, Kyritsis AP, Gu J, de Andrade M, Cunningham J, Levin VA, et al. Mutagen sensitivity and risk of gliomas: a case-control analysis. Cancer Res 1996;56:1484-6.[Abstract]

5 Wu X, Gu J, Hong WK, Lee JJ, Amos CI, Jiang H, et al. Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract. J Natl Cancer Inst 1998;90:1393-9.[Abstract/Free Full Text]

6 Hsu TC, Satya-Prakash KL. Aneuploidy induction by mitotic arrestants in animal cell systems: possible mechanisms. Basic Life Sci 1985;36:279-89.[Medline]

7 Hsu TC, Johnston DA, Cherry LM, Ramkissoon D, Schantz SP, Jessup JM, et al. Sensitivity to genotoxic effects of bleomycin in humans: possible relationship to environmental carcinogenesis. Int J Cancer 1989;43:403-9.[Medline]



             
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