Biomedical subjects

J Cloos

Publications and source records attributed to J Cloos.

At least 19 recordsLinked to original sources

PubMed2006

Proteasome inhibition as novel treatment strategy in leukaemia.

Following its success in multiple myeloma (MM), proteasome inhibition has become a topic of interest as novel treatment strategy of cancer. By simultaneously affecting multiple pathways in the cancer cell, such as deregulation of the programmed degradation of many cellular proteins, proteasome inhibition causes rapid apoptosis of these cells. Both in rapidly proliferating leukaemic cell lines and in primary leukaemic cells isolated from patients, proteasome inhibition results in antileukaemic activity. The normal counterparts of these cells are much more resistant to proteasome inhibitors (PI), thereby resulting in a favourable therapeutic index. Importantly, while leukaemic stem cells are sensitive to proteasome inhibition, normal haematopoietic stem cells are still viable after drug exposure. Nowadays, many PIs are being identified; bortezomib is the most well known since obtaining Food and Drug Administration approval for clinical use in MM. This review summarises the biological and clinical aspects of proteasome inhibition and discusses the potential role of these inhibitors in the treatment of leukaemia.

Antineoplastic Agents↗

PubMed2006

Expression profiling and prediction of distant metastases in head and neck squamous cell carcinoma.

BACKGROUND: For breast and prostate cancer, a gene expression signature of the tumour is associated with the development of distant metastases. Regarding head and neck squamous cell carcinoma (HNSCC), the only known risk factor is the presence of > or =3 tumour-positive lymph nodes. AIM: To evaluate whether a HNSCC gene expression signature can discriminate between the patients with and without distant metastases. METHODS: Patients with HNSCC with and without distant metastases had >3 tumour-positive lymph nodes, and did not differ with respect to other risk factors. Statistical analysis was carried out using Student's t test, as well as statistical analysis of microarrays (SAM), to assess the false discovery rate for each gene. These analyses were supplemented with a newly developed method that computed deviations from gaussian-order statistics (DEGOS). To validate the platform, normal mucosa of the head and neck was included as control. RESULTS: 2963 genes were differently expressed between HNSCC and normal mucosa (t test; p<0.01). More rigorous statistical analysis with SAM confirmed the differential expression of most genes. The comparison of genes in HNSCC with and without metastases showed 150 differently expressed genes (t test; p<0.01), none of which, however, could be confirmed using SAM or DEGOS. CONCLUSIONS: No evidence for a metastasis signature is found, and gene expression profiling of HNSCC has seemingly no value in determining the risk of developing distant metastases. The absence of such a signature can be understood when it is realised that, for HNSCC in contrast with breast cancer, the lymph nodes are a necessary in-between station for haematogenous spread.

Adult↗

PubMed2006

Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples.

In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P<0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.

Adolescent↗

PubMed2005

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia.

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=-0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=-0.30; P=0.04), decitabine (rp=-0.29; P=0.04) and gemcitabine (rp=-0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=-0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=-0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=-0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML.

Acute Disease↗

PubMed2003

Comparison of bleomycin and radiation in the G2 assay of chromatid breaks.

PURPOSE: To compare bleomycin with radiation in the G2 chromatid break assay. Controversy exists in the literature about whether G2 bleomycin chromatid-break sensitivity links with cancer predisposition in the same way as the G2 chromatid radiosensitivity test (the so-called 'G2 assay'). Although bleomycin is referred to as a 'radiomimetic' agent, it differs from radiation in the way the damage is induced. MATERIALS AND METHODS: Epstein-Barr virus-immortalized lymphoblastoid cell lines from two head and neck squamous cell carcinoma patients, two breast cancer patients, two ataxia-telangiectasia patients and two normal control persons were used. Chromosomal damage was determined in cells exposed to 0.3-Gy radiation or 5 mU ml(-1) bleomycin. The numbers of chromatid breaks per cell and of aberrations per cell (i.e. breaks and gaps) were determined. RESULTS: A strong positive correlation was found between the two different damage inducers (r=0.99; p<0.001). This correlation was similar for both the breaks per cell and the total aberrations per cell. Inclusion of gaps in the scoring of chromatid breaks was associated with a higher variability of the data, but this did not influence the outcome of this study. CONCLUSIONS: Both bleomycin and radiation give the same sensitivity phenotypes as determined by the G2 assay of chromatid breaks. Thus, when no radiation facility is present, bleomycin seems to be a good alternative to radiation for this type of assay.

Bleomycin↗

PubMed2001

Evaluation of limited blood sampling in a preceding 99mTc-labeled diagnostic study to predict the pharmacokinetics and myelotoxicity of 186Re-cMAb U36 radioimmunotherapy.

UNLABELLED: 186Re-labeled chimeric monoclonal antibody U36 (cMAb U36) was recently evaluated in a phase I dose escalation study in head and neck cancer patients. All 13 patients received 99mTc-labeled cMAb U36 before 186Re-cMAb U36 radioimmunotherapy. The aim of this study was to evaluate the suitability of multiple or limited blood sampling to predict clearance, red marrow absorbed dose, and myelotoxicity of 186Re-cMAb U36. METHODS: Population pharmacokinetics of 186Re-cMAb U36 were analyzed with a nonparametric expectation algorithm (NPEM 2) and used for Bayesian analysis of individual patient data to predict cMAb U36 clearance. RESULTS: 186Re-cMAb U36 clearance was most accurately predicted (r = 0.91, P < 0.001) with limited sampling for sample points 4 and 72 h after administration of 186Re-cMAb U36. These predictions were less accurate with 99mTc-cMAb U36 (r = 0.51, P = 0.078 for multiple sampling; r = 0.47, P = 0.104 for sampling at 4 and 21 h after administration). Thrombocytopenia was found to be correlated with the red marrow absorbed dose and was equally well predicted by limited blood sampling after administration of 99mTc-cMAb U36 (r = 0.81, P < 0.01) or 186Re-cMAb U36 (r = 0.79, P < 0.01). CONCLUSION: Limited sampling seems useful to predict pharmacokinetics and myelotoxicity of 186Re-cMAb U36.

Aged↗

PubMed2000

Mutagen sensitivity in patients with familial and non-familial urothelial cell carcinoma.

Due to variation in individual susceptibility, only a fraction of all individuals exposed to environmental carcinogens will develop cancer. Our aim was to assess whether mutagen sensitivity plays a role in developing urothelial cell carcinoma (UCC) and whether this sensitivity is different in familial and non-familial cases. Intrinsic susceptibility was quantified by a mutagen sensitivity assay (mean number of chromatid breaks per cell after damage induction with bleomycin in the late S-G2 phase of the cell cycle). Patients were classified as sporadic (n = 25), familial (2 patients in 1 nuclear family, n = 23) or hereditary (2 patients <60 years or 3 patients in 1 nuclear family, n = 13) and compared with control subjects without a history of cancer. Information on demographic factors, smoking history and family history of UCC was collected by postal questionnaires. Differences in mutagen sensitivity were assessed by ANOVA and logistic regression analysis. Overall, UCC patients showed a higher mutagen sensitivity score compared with control subjects [mean number of chromatid breaks per cell 0.91, 95% confidence interval (CI) 0.84-0.97, and 0.74, 95% CI 0.69-0.79, respectively; p = 0.001). Sporadic and familial patients exhibited the highest susceptibility (0.94, 95% CI 0.82-1.06, and 0.93, 95% CI 0.83-1.03, respectively). Hereditary patients (0.79, 95% CI 0.72-0.86) showed a susceptibility similar to controls. Mutagen sensitivity increases the risk of non-hereditary UCC. The relatively low mutagen sensitivity score among hereditary patients points to a different carcinogenic pathway.

Adult↗

PubMed2000

Mutagen sensitivity as a biomarker for second primary tumors after head and neck squamous cell carcinoma.

The occurrence of second primary tumors after curative treatment of early stage head and neck squamous cell carcinoma negatively influences the overall survival. Our aim was to prospectively evaluate whether mutagen sensitivity (mean number of chromatid breaks per cell in cultured lymphocytes exposed to bleomycin) could be used as a biomarker to predict which patients will develop second malignancies in the respiratory or upper digestive tract. Patients treated for head and neck squamous cell carcinoma (n = 218) were followed for approximately 6 years. Nineteen patients developed a second primary tumor, and each of these patients was matched on age, gender, cumulative smoking, tumor site, and tumor stage to two patients who did not develop any second malignancy. No difference between the groups was found with respect to mutagen sensitivity. Smoking at the time of the index tumor had a significant influence on the occurrence of second primary tumors (log-rank, P = 0.019). There was a significantly (P = 0.005) higher mean breaks-per-cell value in those patients who had developed their second primary tumor > or = 3 years after the first tumor (0.97 +/- 0.24; n = 10) compared with early second primary tumor patients (0.69 +/- 0.09; n = 9). Conditional on a more than 3-year second primary tumor-free survival (n = 38), there is a significantly (log-rank, P = 0.036) higher probability of a second primary tumor for mutagen-sensitive patients [relative risk, 7.8 (95% confidence interval, 0.99-61.74; P = 0.05)]. Mutagen sensitivity is a potential biomarker for the occurrence of 'late' second malignancies (> 3 years between tumors), and additional studies on the inclusion of this biomarker in chemoprevention trials is commendable because it would greatly improve their efficiency.

Aged↗

PubMed1999

Inherited susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes.

BACKGROUND: Susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes may reflect the way a person deals with carcinogenic challenges. This susceptibility (also referred to as mutagen sensitivity) has been found to be increased in patients with environmentally related cancers, including cancers of the head and neck, lung, and colon, and, in combination with carcinogenic exposure, this susceptibility can greatly influence cancer risk. The purpose of this study was to assess the heritability of mutagen sensitivity. METHODS: Heritability was determined by use of a maximum likelihood method that employed the FISHER package of pedigree analysis. Bleomycin-induced breaks per cell values for 135 healthy volunteers without cancer were determined. These individuals were from 53 different pedigrees and included 25 monozygotic twin pairs (n = 50), 14 pairs of dizygotes (twin pairs and siblings, n = 28), and 14 families selected on the basis of a first-degree relative who was successfully treated for head and neck cancer and who had no sign of recurrence for at least 1 year. All data were analyzed simultaneously, and different models of familial resemblance were fitted to the data. All P values are two-sided. RESULTS: Our results showed no evidence for the influence of a shared family environment on bleomycin-induced chromatid breaks. Genetic influences, however, were statistically significant (P =. 036) and accounted for 75% of the total variance. CONCLUSIONS: The high heritability estimate of the susceptibility to bleomycin-induced chromatid breaks indicates a clear genetic basis. The findings of this study support the notion that a common genetic susceptibility to DNA damage--and thereby a susceptibility to cancer--may exist in the general population.

Antimetabolites, Antineoplastic↗

PubMed1999

Effect of cisplatin exposure on platinum accumulation and growth inhibition in human neoplastic and normal squamous epithelial cells of the mucosa of the upper-aerodigestive tract.

The aim of the present study was to investigate how normal head and neck epithelial cells (NHNEC) respond to cisplatin compared to their neoplastic counterparts with respect to intracellular platinum (Pt) levels and growth inhibition. A colorimetric assay was used to assess growth inhibition after exposure to cisplatin for 72 h. Growth inhibition did not differ between cultures of neoplastic (n = 5) and normal cells (n = 5). Intracellular Pt levels, determined with atomic absorption spectroscopy were about 30-fold higher in the normal epithelial cells. The main finding of this study is that normal epithelial cells from the head and neck region have a much higher tolerance for cisplatin than their neoplastic counterparts. Interestingly, this characteristic is without consequence for growth inhibition.

Adult↗

PubMed1999

A comparison of bleomycin-induced damage in lymphocytes and primary oral fibroblasts and keratinocytes in 30 subjects.

The number of chromatid breaks in peripheral blood lymphocytes (PBL) after exposure to bleomycin in the S/G2 phase of the cell cycle (in the literature referred to as 'mutagen sensitivity') is associated with an increased risk of environmentally related cancers, including oral cancer. The aim of this study was to elucidate whether mutagen sensitivity measured in lymphocytes actually reflects chromosomal instability of normal cells in the areas in which tumors develop. Therefore, bleomycin-induced chromosomal damage in and growth inhibition of cultured oral fibroblasts and oral keratinocytes from 30 persons were compared with the standard mutagen sensitivity score in PBL. A correlation was found for the percentage of aberrant metaphases between PBL and oral fibroblasts but not for the number of breaks per cell. These data do not allow a conclusion to be drawn on the use of fibroblasts to study cancer risk. Within the fibroblasts it was found that a high number of breaks per cell was associated with less growth inhibition, indicative of damage-resistant growth. Oral keratinocytes were extremely sensitive to bleomycin, as indicated by a strong cell cycle block which resulted in a mitotic index too low to determine chromosomal breaks. Moreover, in the cell proliferation assay keratinocytes were found to be 100 times more sensitive as compared with fibroblasts. There was no correlation between bleomycin sensitivity of keratinocytes compared with fibroblasts from a single patient as measured by growth inhibition. This may be due to the strong influence of alcohol consumption by the subjects, which was found to increase the sensitivity of keratinocytes but not of PBL and fibroblasts. In conclusion, oral fibroblasts but not keratinocytes can be used to measure sensitivity for chromatid breaks. The apparent influence of environmental factors on keratinocytes makes them a useful source to study exposure characteristics but limits their application for the determination of genetic factors.

Adult↗

PubMed1999

Mutagen sensitivity in common cutaneous malignant melanoma and dysplastic naevus syndrome.

Sunlight (ultraviolet radiation) has been identified as the major environmental risk factor for the development of cutaneous malignant melanoma and dysplastic naevi. This is, however, not sufficient to explain all melanoma cases. In recent years much emphasis has been given to genetic susceptibility to melanoma. A biomarker of susceptibility to environmentally related cancer is mutagen sensitivity. This is measured as the number of chromatid breaks in lymphocytes which are exposed to bleomycin in the G2 phase of the cell cycle. It has been described that patients with common melanoma show an increased mutagen sensitivity compared with controls. In the present study mutagen sensitivity was measured in 10 dysplastic naevus syndrome patients and compared with that in 11 patients with common melanoma. We found similar results for common melanoma patients as have been reported earlier: a relatively high mean breaks per cell value (0.93 +/- 0.31). In contrast, melanoma patients with dysplastic naevi showed a significantly (P<0.01) lower mutagen sensitivity value (0.46 +/- 0.34). This phenomenon was even more pronounced when only hereditary dysplastic naevi patients (one or more family members with dysplastic naevi) were considered (n = 5; 0.24 +/- 0.05). These results suggest a difference in the initiation of the carcinogenic process in melanoma with a dysplastic naevus as a precursor and melanoma without dysplastic naevi.

Adolescent↗

PubMed1997

Relationship between the parameters cellular differentiation, doubling time and platinum accumulation and cisplatin sensitivity in a panel of head and neck cancer cell lines.

Patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin show a large inter-individual variation in tumor response. Little is known about factors that contribute to this variation. The aim of our study was to correlate the sensitivity to cisplatin with a number of cellular parameters using a panel of 10 human HNSCC cell lines. A 7-fold variation in response after 72 hr of exposure to cisplatin as determined in a colorimetric proliferation assay was observed. The IC50 values did not correlate with the DNA index, the cellular doubling time or the expression of differentiation markers. Intracellular platinum (Pt) concentrations were measured by atomic absorption spectroscopy after exposing the cells to 10 microM cisplatin for 1-72 hr. The intracellular Pt levels increased up to 24 hr. One cell line, derived from the tumor of a patient previously treated with radiotherapy, accumulated much more Pt than the other cell lines. For these other cell lines, a significant positive correlation was found between Pt accumulation and sensitivity. In conclusion, cisplatin-induced growth inhibition in HNSCC in vitro is generally positively correlated with cellular Pt levels. However, the fact that occasionally cancer cells can survive despite high intracellular Pt levels indicates that additional parameters are needed to explain a response unequivocally.

Adult↗

PubMed1997

All-trans retinoic acid induced gene expression and growth inhibition in head and neck cancer cell lines.

Retinoids are natural and synthetic analogues of vitamin A and have proven activity in various types of cancer. As for head and neck squamous cell cancer (HNSCC), retinoids are especially active in leukoplakia and in preventing second primary cancers. The aim of this study was to assess the growth inhibiting activity of all-trans retinoic acid (all-trans RA) in a panel of six head and neck squamous cell cancer cell lines and to correlate this response to the mRNA expression of factors related to differentiation and receptor mediated signal transduction. Three lines showed minimal, two moderate and one strong growth inhibition after 72 h exposure to all-trans RA. Three lines with a dissimilar response were selected for further studies, the measurement of mRNA expression by northern blotting. It was found that neither the expression nor the induction of retinoic acid receptor (RAR)-alpha and -gamma and retinoic X receptor-alpha mRNA war related to sensitivity. The mRNA expression of RAR-beta was too low to be measured in the three cell lines. The most sensitive cell line was, however, the only one that expressed mRNA of squamous differentiation markers. These data suggest a relationship between the retinoid sensitivity profile and the degree of cellular differentiation.

Carcinoma, Squamous Cell↗

PubMed1997

Retinoid metabolism and all-trans retinoic acid-induced growth inhibition in head and neck squamous cell carcinoma cell lines.

Retinoids can reverse potentially premalignant lesions and prevent second primary tumours in patients with head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been reported that acquired resistance to all-trans retinoic acid (RA) in leukaemia is associated with decreased plasma peak levels, probably the result of enhanced retinoid metabolism. The aim of this study was to investigate the metabolism of retinoids and relate this to growth inhibition in HNSCC. Three HNSCC cell lines were selected on the basis of a large variation in the all-trans RA-induced growth inhibition. Cells were exposed to 9.5 nM (radioactive) for 4 and 24 h, and to 1 and 10 microM (nonradioactive) all-trans RA for 4, 24, 48 and 72 h, and medium and cells were analysed for retinoid metabolites. At all concentrations studied, the amount of growth inhibition was proportional to the extent at which all-trans-, 13- and 9-cis RA disappeared from the medium as well as from the cells. This turnover process coincided with the formation of a group of as yet unidentified polar retinoid metabolites. The level of mRNA of cellular RA-binding protein II (CRABP-II), involved in retinoid homeostasis, was inversely proportional to growth inhibition. These findings indicate that for HNSCC retinoid metabolism may be associated with growth inhibition.

Antineoplastic Agents↗

PubMed1997

A simple and reliable technique for culturing of human oral keratinocytes and fibroblasts.

Cultures of non-malignant oral cells are needed for many applications in the field of oral biology. We describe an efficient and rapid method for the culture of both keratinocytes and fibroblasts isolated from oral tissue, uvulas from patients undergoing reconstructive surgery and non-cancerous tissue from oral cancer patients. High cell yields with a high purity could be obtained. The technique is described in detail with respect to isolation of the cell types, the best way to propagate for over 5 passages and to measure cell proliferation in a colorimetric assay. Culture was successful in over 80% of cases for keratinocytes and over 63% for fibroblasts. Problems encountered were the risk of microbiological infection, the size of the specimen and the type of culture medium used. The potential applications of these primary cell cultures are mentioned.

Carcinoma, Squamous Cell↗

PubMed1996

DNA-damage processing in blood lymphocytes of head-and-neck-squamous-cell-carcinoma patients is dependent on tumor site.

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 squamous-cell 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 sensitivity 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-cavity-carcinoma 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.

Adult↗

PubMed1996

Genetic susceptibility to head and neck squamous cell carcinoma.

BACKGROUND: In addition to influences of exposure to carcinogenic compounds, the development of cancer may depend on an individual intrinsic cancer susceptibility. Biomarkers for cancer susceptibility can be powerful additions to epidemiologic analyses. PURPOSE: This multicenter, case-control analysis combines previously published data and new data to substantiate the value of mutagen sensitivity as a biomarker of susceptibility to head and neck squamous cell carcinoma and, more importantly, to gain insight into the interaction between susceptibility and exposure to carcinogens. METHODS: Mutagen sensitivity (mean number of chromatid breaks per cell of cultured lymphocytes treated with bleomycin in the late S-G2 phase of the cell cycle) was determined in 313 patients with head and neck cancer and in 334 control subjects at two major U.S. medical institutions and one European institution, yielding a unique study population. The ages of the case and control subjects, as well as their history of use of tobacco and alcohol, were also recorded. The relationships between variables were analyzed by use of Student's t tests, Spearman's rank correlations, and multiple linear regression. For estimation of cancer risk, crude odds rations (ORs) were measured and multiple logistic regression was performed. All P values were based on two-sided tests. RESULTS: There were no differences across institutions in the distribution of mutagen sensitivity (Kruskal-Wallis test) for both case subjects and control subjects. Values for case subjects were consistently and significantly (P<.0001) higher than values for control subjects in the overall analyses. Age and tobacco or alcohol use did not influence the outcome in terms of mutagen-sensitivity values for either the case or the control subjects. A mean number of breaks per cell dichotomized at 1.0 was found to be the best predictor of a hypersensitive phenotype. For nonsensitive, heavy smokers, the OR was 11.5 (95% confidence interval [CI] = 5.0-26.6). This risk increased dramatically in mutagen-hypersensitive, heavy smokers to 44.5 (95% CI = 17.4-114.0). Multiple logistic regression analysis confirmed these results, and a significant trend was found (P<.01) for the dose-dependent increase in cancer risk by smoking. The consumption of alcohol potentiated the effects of smoking, resulting in an OR of 57.5 (95% CI = 17.5-188.0) in hypersensitive persons. CONCLUSIONS: Mutagen sensitivity was found to be a biomarker of cancer susceptibility. This study underscores the importance of utilizing both susceptibility markers and the exposure data for the identification of persons at high risk of developing cancer. IMPLICATIONS: More accurate risk estimation can define susceptible subgroups who might be targeted for intensive behavioral interventions, surveillance through screening, and enrollment in chemoprevention programs.

Adult↗