Mutagen sensitivity is a constitutional factor which may be used to identify head-and-neck squamous-cell carcinoma (HNSCC) patients at high risk for the development of multiple primary tumors (MPT). In this retrospective study, mutagen sensitivity was measured in HNSCC patients with a single primary tumor (SPT), HNSCC patients who have already developed MPT and control subjects with no tumor history. In vitro, lymphocytes were challenged with bleomycin and chromosomal damage was quantified by scoring chromatid breaks of 100 cells. A significant difference in the mean number of breaks per cell (b/c) was found between SPT patients and controls. Patients with MPT showed a significantly higher mean b/c value than SPT patients. This increase in mutagen sensitivity in HNSCC patients was not related to well-known cancer risk factors such as age, or life-style factors such as smoking and alcohol drinking habits. In addition, tumor site but not tumor stage was found to be related to mutagen sensitivity. On the basis of our findings, we propose that mutagen sensitivity is not an independent risk factor but a constitutional factor which reflects the way in which genotoxic compounds are dealt with and is thereby directly related to cancer risk.

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Bleomycin is considered to be a useful model compound for studying environmental carcinogenesis, due to its broad spectrum of DNA damaging properties. In addition, bleomycin is a useful antitumor drug because of its cytotoxic properties. To investigate the influence of the antioxidant N-acetylcysteine and its metabolites glutathione and cysteine on bleomycin-induced DNA damage and more importantly to gain insight into the biological relevance of such damage, PM2 DNA was exposed to Cu(2+)-bleomycin in the presence and absence of the thiols N-acetylcysteine, glutathione and cysteine. It was found that the presence of these thiols led to a considerable enhancement of bleomycin-induced single- and double-strand breaks and a concomitant decrease in the biological activity of PM2 DNA in a dose-dependent way. A similar observation was made when ascorbic acid was used. Bleomycin showed no DNA damaging activity when PM2 DNA was pretreated with the strong Fe ion chelator desferal and its activity was strongly inhibited by the addition of Cu2+ ions or under hypoxic (N2) conditions. Cu(2+)-bleomycin under our conditions is not active by itself, but most probably after binding to DNA exchanges Cu2+ for Fe3+ bound to DNA. Fe(3+)-bleomycin is then reduced to Fe(2+)-bleomycin, a process potentiated by the added antioxidants, and subsequently activated by O2. The contribution to biological inactivation of bleomycin alone or in the presence of ascorbic acid is only approximately 15%. The contribution to lethality in the presence of thiols is higher. These results indicate that ascorbic acid only enhances the DNA damaging properties of bleomycin, whereas the thiol compounds in addition influence the type of DNA damage. The remainder of the biological inactivation is probably caused by double damage, such as single-strand breaks with closely opposed alkali-labile sites or base damage.

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It has been reported that an intrinsic susceptibility to cancer is related to the way an individual responds to DNA-damaging agents. The aim of this study was to evaluate whether, in addition to bleomycin-induced chromosomal instability, radiation-induced initial DNA damage and subsequent repair is associated with the development of head-and-neck squamouscell carcinoma. In this study, 2 assays were performed to measure DNA damage in human peripheral-blood lymphocytes. One was a chromosomal aberration assay which determines sensitivii to chromatid breaks induced by bleomycin, the other an elegant immunochemical assay which measures the level of radiation-induced strand breaks as well as subsequent repair. Age, smoking and alcohol-drinking behavior did not influence the number of chromatid breaks, initial DNA damage or repair capacity. As has been found in previous studies, the mean number of Chromatid breaks per cell was significantly different between patients (n = 18) and control persons (n = 19). whereas the amount of initial DNA damage was not. No correlation was found between the outcome of the 2 assays in the subject groups. In contrast to laryngeal-carcinoma patients, oral-cavitycarcinoma patients showed significantly slower repair capacity than controls. Our hypothesis is that the way DNA damage is processed by the patients determines at which site cancer develops in the head and neck area.6 1996 Wiley-Liss, Inc.It is becoming increasingly accepted that the risk for the development of cancer depends not only on exposure to carcinogens, but also upon individual susceptibility to cancer (Markham et al., 1994). This latter predisposition may be related to a deficiency in DNA maintenance, such as found in chromosomal instability syndromes such as Ataxia telangiectasia (Meyn, 1995). Suitable assays to measure intrinsic sensitivity to DNA damage are based on determination of chromosomal damage in peripheral-blood lymphocytes after induction of strand breaks in the G? phase of the cell cycle (Hsu, 1987;Sanford et al., 1990; Scott, 1994). In the assay of Hsu (1987), chromosomal damage (also referred to as mutagen sensitivity) is measured as the mean number of chromatid breaks per cell (b/c) in mitogen-stimulated peripheral-blood lymphocytes (PBL) challenged in vitro with bleomycin (BLM). By the use of this assay in a retrospective case-control study, it was demonstrated that the PBL of head-and-neck-squamous-cell-carcinoma(HNSCC) patients exhibited a significantly higher b/c level than controls. Values were highest in patients who had developed multiple primary tumors (Cloos et al., 1994). This test may therefore be a useful tool for identifying those patients at high risk for multiple primary tumors. Each year, about 3% of curatively treated HNSCC patients develop a second primary tumor. Identification of high-risk individuals is important, so that they can be followed up more frequently for early detection of further primary tumors and improved patient survival (Snow, 1992).The chromosomal aberration assay, eit...