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Biomedical subjects

W K Hong

Publications and source records attributed to W K Hong.

At least 127 records · Page 7Linked to original sources
PubMed1998

All-trans-retinoic acid inhibits Jun N-terminal kinase-dependent signaling pathways.

Retinoids, including retinol and retinoic acid derivatives, inhibit the growth of normal human bronchial epithelial (HBE) cells. The signaling pathways through which retinoids mediate this effect have not been defined. Normal HBE cell growth is stimulated by treatment with a variety of growth factors that increase mitogen-activated protein (MAP) activity. In this study, we examined MAP kinase-dependent pathways as potential targets of retinoid signaling and the role of MAP kinases in retinoid-induced c-fos gene regulation. All-trans-retinoic acid (t-RA) inhibited Jun N-terminal kinase (JNK) and, to a lesser extent, extracellular signal-regulated kinase activity in normal HBE cells. t-RA reduced c-fos mRNA and protein levels by decreasing c-fos gene transcription. The c-fos promoter was activated by co-transfection with a constitutively active JNK kinase (SEK)-1 and suppressed by a dominant negative JNK kinase kinase (MEKK)-1. Furthermore, c-fos expression was inhibited by agonists of retinoic acid receptors (RARs) or retinoid X receptors (RXRs), and suppression of c-fos promoter activity by t-RA was abrogated by treatment with antagonists of RAR-alpha or of all the RXRs. These findings provide the first evidence that t-RA inhibits JNK activity and demonstrate a potential role of JNK-dependent pathways in the suppression of c-fos expression by t-RA. Furthermore, c-fos expression was inhibited through activation of RAR- and RXR-dependent signaling pathways. In light of the growth activation induced by JNK/SEK-dependent pathways in a variety of cells, these data support further investigation into the role of JNK-dependent signaling in the growth-suppressive effects of retinoids.

Bronchi↗
PubMed1998

Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients.

BACKGROUND: Interindividual differences in the structure and expression of the dopamine receptor genes affect dopamine availability and may be the genetic basis for variation in vulnerability to tobacco smoking. In this study, prevalences of polymorphisms in the TaqIA allele (A1 and A2) and the TaqIB allele (B1 and B2) of the D2 dopamine receptor gene in 157 lung cancer case patients and 126 control subjects were determined to assess whether individuals homozygous or heterozygous for the less common A1 and B1 alleles are more vulnerable to nicotine addiction. METHODS: Case and control subjects were accrued from an ongoing epidemiologic study. Blood samples were collected from them and subjected to molecular genetic analyses. Subjects were interviewed to obtain relevant information. Current and former smokers were administered a questionnaire to quantify their addiction to nicotine. RESULTS: The combined B1B2 genotypes appeared to be more prevalent in ever smokers than in never smokers among case patients (30.3% versus 13.3%; two-sided P = .233) and among control subjects (30.9% and 0%; two-sided P = .02); statistically significant differences were not observed among those with A1 genotypes. Statistically significant correlations between the presence of the A1 and B1 alleles were observed (r = .73 for case subjects and r = .76 for control subjects; two-sided P<.001). Individuals with rarer genotypes reported having been substantially younger at the time of smoking initiation (statistically significant for both A1 and B1) and having attempted to quit smoking fewer times (statistically significant for only A1). CONCLUSION: Variant alleles of the D2 dopamine receptor gene may play a role in determining nicotine addiction, although the associations between the at-risk genotypes and measures of nicotine addiction were not entirely consistent.

Aged↗
PubMed1998

All-trans retinoic acid converts E2F into a transcriptional suppressor and inhibits the growth of normal human bronchial epithelial cells through a retinoic acid receptor- dependent signaling pathway.

Retinoids, including retinol and retinoic acid derivatives, maintain the normal growth and differentiation of human bronchial epithelial (HBE) cells and are under investigation as agents for lung cancer prevention. In this study, we examined the biologic effects of retinoids on normal HBE cells and the molecular mechanisms of retinoid actions. At a dose of 10(-6) M, all-trans retinoic acid (t-RA) suppressed the proliferation of normal HBE cells, which accumulated in the G0 phase. No evidence of programmed cell death was observed. The class of retinoid nuclear receptor that mediated the growth arrest was explored. Normal HBE cell growth was suppressed by a retinoid that selectively activates retinoic acid receptors but not by one that activates retinoid X receptors. The E2F transcription factor has demonstrated a role in G0 entry through transcriptional suppression of genes that induce cell cycle progression. To investigate the role of E2F in retinoid signaling, transient transfection assays were performed using reporter plasmids containing E2F-binding sites. Findings from these experiments suggested that t-RA treatment converted E2F into a transcriptional suppressor. Supporting this possibility, t-RA inhibited the expression of the E2F target genes B-myb, cyclin A, and cyclin E. Further, t-RA increased the levels of nuclear E2F-4, p107, and p130 and enhanced the binding of E2F-4 to p107, which have been associated with the conversion of E2F into a transcriptional suppressor in other cells. These findings point to retinoic acid receptor- and E2F-dependent pathways as potential mediators of retinoid-induced growth arrest in normal HBE cells and have implications for the use of retinoids in clinical trials on the prevention of lung cancer.

Apoptosis↗
PubMed1998

Cisplatin, ifosfamide, and prolonged oral etoposide in the treatment of patients with extensive small cell lung carcinoma.

BACKGROUND: The combination of cisplatin, ifosfamide, and prolonged oral etoposide (PIE) was studied in patients with extensive small cell lung carcinoma (SCLC) in a Phase I trial followed by a Phase II trial to determine the maximum tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates. METHODS: Thirty-three patients were treated between October 1991 and December 1994. Doses for the initial cohort were cisplatin 20 mg/m2/day, ifosfamide 1500 mg/m2/day with mesna (all given intravenously on Days 1-3), and oral etoposide 50 mg/m2 on Days 4-17. This cycle was repeated every 4 weeks for up to 6 cycles. The MTD was reached for the first 9 patients. For these 9 patients and the next 24 patients, who were entered in the Phase II trial, response and survival were estimated. RESULTS: Dose-limiting toxicity was manifested as Grade 4 neutropenia in 3 of 3 patients (associated with fever in 2 of 3), and Grade 4 thrombocytopenia was encountered in 2 of 3 patients at the second dose level. Of 6 patients treated at the first dose level, 4 achieved targeted myelosuppression (absolute granulocyte count nadir <1000), but only 1 experienced Grade 4 neutropenia, defining this level as the MTD. Grade 4 neutropenia and/or thrombocytopenia was observed in 36 (24%) of a total of 152 courses administered at or below the MTD. Nonhematologic toxicity above Grade 2 was uncommon, excluding nausea and vomiting. Overall objective response rate was 93% of 30 evaluable patients: 5 (17%) complete responses and 23 partial responses (76%). Median failure free and overall survival durations were 36 and 54 weeks, respectively. CONCLUSIONS: The combination of cisplatin, ifosfamide, and oral etoposide produced encouraging failure free and overall median survival rates in patients with extensive SCLC. These results warrant further evaluation of this regimen in the initial therapy of patients with limited stage disease.

Administration, Oral↗
PubMed1998

Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines.

Loss of heterozygosity (LOH) at chromosome 10q23-q25 is frequent in small cell lung cancer (SCLC), indicating the presence of putative tumor suppressor genes. PTEN/ MMAC1, a newly cloned candidate tumor suppressor gene at 10q23, was mutated in multiple human cancers. We investigated whether mutations of PTEN/MMAC1 play an important role in SCLC tumorigenesis. We examined 16 SCLC cell lines for PTEN/MMAC1 mRNA expression by reverse-transcriptase polymerase chain reaction (RT-PCR) and potential mutations by sequencing analysis of the PTEN/MMAC1 coding region. No mutation was observed in PTEN/MMAC1 cDNAs in 15 cell lines expressing PTEN/MMAC1. One SCLC cell line, DMS79, did not have detectable PTEN/ MMAC1 expression. Importantly, we identified a novel homologue of PTEN/MMAC1, termed PTH2, localized to chromosome 9p21-q13 and containing only ten amino acid substitutions compared with the PTEN/MMAC1 coding region. However, because the putative initiation codon for PTEN/MMAC1 gene was changed to arginine in PTH2, the translational initiation site of PTH2 is very likely to differ from that of the PTEN/MMAC1. PTH2 was expressed in two normal lung tissues and two normal colon tissues, but in only four of 16 SCLC cell lines. A missense mutation in PTH2 was identified in a SCLC cell line that did not express PTEN/MMAC1 mRNA. Our data suggest that inactivation of PTEN/ MMAC1 is a rare event in SCLC tumorigenesis. However, the PTEN/MMAC1 homologue PTH2 may play a role in SCLC tumorigenesis.

Amino Acid Sequence↗
PubMed1998

Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer.

Our previously reported randomized study of patients with untreated, potentially resectable clinical stage IIIA non-small-cell lung cancer found that patients treated with perioperative chemotherapy and surgery had a significant increase in median survival compared to patients treated with surgery alone. We have now re-analyzed the results of the study with a median time from random allocation to analysis for all patients of 82 months. The increase in survival conferred by perioperative chemotherapy was maintained during the period of extended observation.

Antineoplastic Agents↗
PubMed1998

Chemoprevention in head and neck cancer: basic science and clinical application.

The concept of field cancerization and the multistep carcinogenesis theory are the premises on which the development of chemoprevention efforts has been based. The first concept underlies the fact that patients who have been cured of a cancer in the aerodigestive tract are still at risk of developing additional primary tumors in the same field, and the multistep carcinogenesis theory implies that the conceivable arrest of one of the steps by chemoprevention might be enough to impede the development of cancer. There is ongoing research for development of new candidate-chemopreventive substances in most areas of oncology. Most of the clinical experience in chemoprevention of head and neck cancer is based on the use of retinoids. Retinoids in high doses have demonstrated activity in treating oral premalignant lesions (OPLs) but with frequent side effects and early relapse after cessation of therapy. Subsequent trials showed better tolerability of retinoids in lower doses. Ongoing trials are currently evaluating whether chemoprevention over 3 years might have longer-lasting effect both on OPLs and in the prevention of second primary tumors.

Chemoprevention↗
PubMed1998

The effect of 13-cis-retinoic acid chemoprevention on human serum retinol levels.

This study of the effect of 13-cis-retinoic acid on serum levels of retinol was a laboratory correlate of a clinical chemoprevention trial in asymptomatic chronic smokers. All study participants had squamous metaplasia of the bronchial epithelium and received 6 months' treatment of either 13-cis-retinoic acid (1 mg/kg/day) or placebo. Baseline serum retinol levels were compared with levels taken immediately post-treatment. The placebo group (N = 38) had little change, whereas the 13-cis-retinoic acid group, (N = 35) experienced a decline in retinol levels (p = 0.06). Within the 13-cis-retinoic acid group, women's (N = 13) mean serum retinol levels dropped significantly, from 531 +/- 191 ng/ml (baseline) to 436 +/- 115 ng/ml (post-treatment) (p = 0.03); men's (N = 22) levels virtually did not change (p = 0.43). Therefore, the borderline-significant overall decline in the 13-cis-retinoic acid group was due entirely to the decline among women subjects. The etiology of this effect is unknown. Our results suggest that chronic 13-cis-retinoic acid administration may lead to a clinically significant reduction in serum retinol levels in females. This finding may have implications for currently ongoing chemoprevention trials that administer 13-cis-retinoic acid for 3 years.

Adult↗
PubMed1998

Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma.

PURPOSE: To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS: Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS: Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION: TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.

Adult↗
PubMed1998

Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma.

PURPOSE: Standard therapies of head and neck squamous cell carcinoma (HNSCC) often cause profound morbidity and have not significantly improved survival over the last 30 years. Preclinical studies showed that adenoviral vector delivery of the wild-type p53 gene reduced tumor growth in mouse xenograft models. Our purpose was to ascertain the safety and therapeutic potential of adenoviral (Ad)-p53 in advanced HNSCC. PATIENTS AND METHODS: Patients with incurable recurrent local or regionally metastatic HNSCC received multiple intratumoral injections of Ad-p53, either with or without tumor resection. Patients were monitored for adverse events and antiadenoviral antibodies, tumors were monitored for response and p53 expression, and body fluids were analyzed for Ad-p53. RESULTS: Tumors of 33 patients were injected with doses of up to 1 x 10(11) plaque-forming units (pfu). No dose-limiting toxicity or serious adverse events were noted. p53 expression was detected in tumor biopsies despite antibody responses after Ad-p53 injections. Clinical efficacy could be evaluated in 17 patients with nonresectable tumors: two patients showed objective tumor regressions of greater than 50%, six patients showed stable disease for up to 3.5 months, and nine patients showed progressive disease. One resectable patient was considered a complete pathologic response. Ad-p53 was detected in blood and urine in a dose-dependent fashion, and in sputum. CONCLUSION: Patients were safely injected intratumorally with Ad-p53. Objective antitumor activity was detected in several patients. The infectious Ad-p53 in body fluids was asymptomatic, and suggests that systemic or regional treatment may be tolerable. These results suggest the further investigation of Ad-p53 as a therapeutic agent for patients with HNSCC.

Adenoviridae↗
PubMed1998

Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia.

alpha-Difluoromethylornithine (DFMO) is a suicide inhibitor of ornithine decarboxylase and potent antiproliferative chemopreventive agent. We conducted a dose de-escalation Phase I trial of DFMO in patients with grade 3 cervical intraepithelial neoplasia to determine an optimal dose of DFMO using ornithine decarboxylase activity and polyamine modulation as surrogate biomarkers and to evaluate its toxicity. Thirty patients with biopsy-confirmed grade 3 cervical intraepithelial neoplasia were assigned sequentially to one of five DFMO doses (1.000, 0.500, 0.250, 0.125, or 0.060 g/m2) given daily for 31 days. One patient was excluded from analysis for protocol violation. Polyamine levels were assessed in cervical tissue, plasma, and RBCs. Tissue and blood samples were obtained before and after treatment with DFMO. All patients underwent loop excision of the cervix at the end of the study for complete histological evaluation and definitive treatment of the premalignant condition. No major clinical toxicity was observed at any DFMO dose. A reduction in tissue spermidine to spermine (SPD:SPM) ratio and an increase in plasma arginine levels were observed among patients receiving 1.000 g/m2/day (P < 0.05). A nonsignificant reduction in SPD:SPM ratio was also observed in the 0.500 g/m2/day dose group, and a nonsignificant increase in plasma arginine level was observed down to the 0.125 g/m2/day dose level. There was no evidence of modulation of other polyamines or precursors. Fifteen patients experienced a complete (5 patients) or partial (10 patients) histological response. In conclusion, DFMO was well tolerated and significantly modulated tissue SPD:SPM ratio and plasma arginine level at the dose of 1.000 g/m2/day. To clarify whether DFMO has activity at lower doses, these results will be tested in a three-armed double-blinded Phase II study using placebo and DFMO doses of 0.500 and 0.125 g/m2/day.

Administration, Oral↗
PubMed1998

Reduced expression of hMLH1 and hGTBP/hMSH6: a risk factor for head and neck cancer.

Head and neck cancer, like lung cancer, is considered a paradigm of an environmentally induced disease. Genetically determined variation in DNA repair capacity is thought to contribute to susceptibility to tobacco-related cancers. In this molecular epidemiology study, we investigated the association between DNA mismatch-repair (MMR) gene expression and the risk of head and neck cancer. Using our newly developed multiplex reverse transcription-PCR assay, we simultaneously evaluated the relative expression levels of five MMR genes (hMSH2, hMLH1, hPMS1, hPMS2, and hGTBP/hMSH6) in the peripheral blood lymphocytes of 78 patients (mean age = 59.6 +/- 12.4 years) with newly diagnosed head and neck cancer and 86 healthy controls (mean age = 58.2 +/- 12.9 years). The relative MMR gene expression was not correlated with disease stage or tumor site in the cases or with smoking and alcohol use in the controls. The expression levels increased with age in both cases and controls, but the mean expression of hMLH1, hPMS1, and hGTBP/hMSH6 was significantly lower in the cases than in the controls (P < 0.05). Using the median expression level in controls as the cutoff value, significantly increased odds ratios (ORs) were associated only with low expression of hMLH1 (OR = 4.4; 95% confidence interval = 2.1-9.1) and hGTBP/hMSH6 (OR = 2.1; 95% confidence interval = 1.1-4.1) after adjustment for age, sex, ethnicity, smoking status, and alcohol use. The results suggest that low hMLH1 and hGTBP/hMSH6 expression is associated with an increased risk of head and neck cancer. Additional studies with a larger number of subjects are warranted to confirm these findings.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Role of paclitaxel, ifosfamide, and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

This phase I/II study investigated the efficacy and toxic effects of combination chemotherapy using paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), ifosfamide, and cisplatin (TIP) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Twelve patients were entered in the phase I part of the study, results of which were reported previously. Fifty-three patients were treated in the phase II part of the study with 175 mg/m2 paclitaxel in a 3-hour infusion on day 1; 1,000 mg/m2/d ifosfamide in a 2-hour infusion on days 1 to 3; and 60 mg/m2 cisplatin on day 1, repeated every 3 to 4 weeks. Thirty-five men and 18 women were treated; the median age was 55 years (range, 27 to 73 years). Sites of disease and types of previous therapy varied among the patients. Among those with recurrent disease, 30 had locoregional disease, four had locoregional disease with distant metastasis, and 17 had distant metastasis only. Two patients had distant metastatic disease (MI) at the time of diagnosis. Of the 53 patients entered, 52 were assessable for disease response and toxic effects. Complete response was achieved in nine (17%) of 52 patients and partial response in 21 (40%); five (10%) patients had stable disease and 17 (33%) had progressive disease. When response rate was analyzed by disease sites, patients with locoregional sites showed a 43% major response (complete and partial) rate, and those with distant metastatic sites demonstrated an 80% major response rate (P=.04). The median duration of disease response in all patients was 4.9 months at completion of the study. Among the nine patients with complete response, three had progressive disease and the median duration of response was 6.9 months (range, 4.9 to 17 months); six were still in remission at the time of this writing, with a median duration of response of 12.8 months (range, 6.3 to 18.8+ months). The median survival time was 8.8 months, and the 1- and 2-year survival rates were 40% and 21.9%, respectively. The median follow-up time of the study was 11.8 months. The major toxic effects included neutropenia, cumulative peripheral neuropathy, and fatigue. Mucositis was rare; grade 3 mucositis developed in only one patient. Other side effects included neutropenic fever in 14 patients, all of whom completely recovered after antibiotic treatment. Grade 3 orthostatic hypotension and grade 3 peripheral neuropathy developed in one patient; supportive care led to gradual recovery. No deaths were caused by toxic effects. In conclusion, these preliminary results indicate that the TIP chemotherapy regimen produced high rates of major responses in patients with recurrent or metastatic head and neck squamous cell carcinoma, and responses were durable. The median, 1-year, and 2-year survival times were particularly promising. The TIP regimen should be pursued further as an induction regimen for locally advanced head and neck cancer.

Adult↗
PubMed1998

Functional outcomes following treatment for advanced laryngeal cancer. Part I--Voice preservation in advanced laryngeal cancer. Part II--Laryngectomy rehabilitation: the state of the art in the VA System. Research Speech-Language Pathologists. Department of Veterans Affairs Laryngeal Cancer Study Group.

This two-part investigation assessed functional outcomes related to communication (including amount of speech therapy), swallowing and eating, and employment status for patients who received one of the two treatment modalities for advanced laryngeal cancer (stage III or IV laryngeal squamous cell carcinoma) in Veterans Administration Cooperative Study #268. One hundred sixty-six patients were randomized to primary surgery (laryngectomy) and radiotherapy (RT), and 166 to induction chemotherapy (CT) and RT. The first investigation dealt with examining and comparing functional outcomes for patients in the two treatment arms of the main study. Results showed clearly that patients with advanced laryngeal cancer are better off from the standpoint of speech communication if they can be treated for this disease without removal of the larynx. In contrast, there were few significant differences between patient groups for other non-speech-related measures. The second investigation focused on communication-related outcomes associated with the rehabilitation of total laryngectomy patients. Results revealed that only relatively small percentages of total laryngectomy patients (6%) developed usable esophageal speech or remained nonvocal (8%), and that a majority of patients ended up as users of artificial electrolarynx (55%) or tracheoesophageal (31%) speech. The results from both investigations are discussed with respect to factors that can influence the rehabilitation process and long-term outcome status of patients who are treated for advanced laryngeal cancer with these two strategies.

Adult↗
PubMed1998

Higher potency of N-(4-hydroxyphenyl)retinamide than all-trans-retinoic acid in induction of apoptosis in non-small cell lung cancer cell lines.

Most human non-small cell lung cancer (NSCLC) cell lines are refractory to all-trans-retinoic acid (ATRA). Recently, N-(4-hydroxyphenyl)retinamide (4HPR) was found to induce apoptosis in various tumor cells. In this study, we compared and contrasted the effects of 4HPR and ATRA on the growth and apoptosis of 10 NSCLC cell lines and normal human bronchial epithelial (NHBE) cells. All of the cancer cell lines and the NHBE cells were sensitive to 10 microM 4HPR, and their numbers decreased to <20% of the controls after a 5-day treatment, whereas ATRA decreased cell numbers to about 50% of the controls in three cell lines and was less effective in the rest of the tumor cell lines. ATRA inhibited the growth of the NHBE cells by 70-80%. 4HPR induced apoptosis in most of the cells, including the ATRA-resistant ones, as evidenced by a DNA fragmentation assay. No correlation was found between growth inhibition by 4HPR and the expression of retinoic acid receptor beta (determined by Northern blotting and PCR), p53, or Bcl-2 proteins (analyzed by Western blotting). These results demonstrate that 4HPR is more potent than ATRA in inducing apoptosis in NSCLC cells and suggest that further clinical trials for prevention and therapy of NSCLC using 4HPR are warranted.

Antineoplastic Agents↗
PubMed1998

Reduced DNA repair capacity in head and neck cancer patients.

Head and neck cancers (HNCs) are malignancies that can be induced by tobacco use, although host-specific factors such as the DNA repair capacity (DRC) may modulate individual susceptibility to tobacco carcinogenesis. To test the hypothesis that genetically determined DRC modulates HNC susceptibility, we measured the DRC in the peripheral blood lymphocytes of 55 patients with newly diagnosed, previously untreated HNC and 61 healthy controls by the host-cell reactivation assay using a reporter gene damaged by benzo(a)pyrene diol epoxide, an ultimate tobacco-related carcinogen. The mean DRC was significantly lower in cases (8.6%) than it was in controls (12.4%; P < 0.001). The DRC was an independent risk factor for HNC (P < 0.01); those in the middle and lowest tertiles of DRC had increased odds ratios [2.17 (95% confidence interval, 0.74-6.39) and 4.27 (confidence interval, 1.45-12.5), respectively] for HNC. These findings suggest that individuals with reduced DRC may be at increased risk of developing HNC.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1998

Mutagen sensitivity to benzo(a)pyrene diol epoxide and the risk of squamous cell carcinoma of the head and neck.

Genetic susceptibility appears to modulate an individual's risk of tobacco-induced carcinoma. One biomarker of such susceptibility, chromatid breaks induced in vitro in lymphocytes by the mutagen bleomycin, is an independent risk factor for several malignancies. To date, the more etiologically appropriate mutagen benzo(a)pyrene diol epoxide (BPDE) has only been used in one lung cancer study. Our objective was to evaluate the association between the BPDE-induced chromatid breaks per cell (b/c) values and the risk of squamous cell carcinoma of the head and neck (SCCHN) in a pilot case-control study. Blood samples were obtained from 60 SCCHN patients and 112 healthy controls matched for age, sex, ethnicity, and smoking status. After incubation and exposure to BPDE, metaphase spread slides were created, and the average b/c values were determined. Univariate analysis identified elevated BPDE-induced b/c values as a significant risk factor [P < 0.05, crude odds ratio (OR)=1.94, 95% confidence interval (CI)=1.00-3.74]. On multivariate analysis using logistic regression models and including age, sex, ethnicity, and smoking status, BPDE-induced b/c values remained an independent risk factor for disease (P < 0.05, adjusted OR=2.36, 95% CI=1.17-4.79). Furthermore, when b/c values were divided based on control values into low, medium, and high tertiles, there was a dose-response relationship: an adjusted OR of 1.28 (95% CI=0.49-3.33) for the middle tertile and an adjusted OR of 4.09 (95% CI=1.67-10.0) for the high tertile (trend test, P < 0.001). These findings suggest that high BPDE-induced b/c values in lymphocytes are an independent risk factor for SCCHN and a marker for genetic susceptibility to tobacco-induced carcinogenesis.

Adult↗