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Biomedical subjects

Qingyi Wei

Publications and source records attributed to Qingyi Wei.

At least 109 records · Page 6Linked to original sources
PubMed2003

Association of a functional tandem repeats in the downstream of human telomerase gene and lung cancer.

Chemoprevention has been widely explored as a promising strategy for controlling the incidence of lung cancer, the leading cause of cancer-related death. To maximize the benefit of lung cancer chemoprevention, it is important to identify individuals at high risk for the disease. The genetic background has been shown to play an important role in one's risk of developing lung cancer. We report here the identification of a polymorphic tandem repeats minisatellite (termed MNS16A) in the downstream region of the human telomerase gene. This minisatellite is located upstream of an antisense transcript from the human telomerase gene locus and was demonstrated to have promoter activity. The promoter activity was significantly lower in the construct containing the shorter repeats, suggesting that the MNS16A variant may have a relevance of functionality. To explore the role of this novel polymorphism in lung cancer, we conducted a pilot hospital-based case-control study by identifying the MNS16A genotype with genomic DNA from 53 lung cancer patients and 72 cancer-free controls. We found four different alleles and classified them as shorter (S) or longer (L) on the functional basis of the length of the repeats in the controls. The MNS16A genotype distributions of the SS, SL, and LL genotypes were 11, 32, and 57%, respectively, in the cases, and 14, 40, and 46%, respectively, in the controls. Compared with the SS+SL genotype, the LL genotype was associated with greater than twofold increased risk of lung cancer (odds ratio=2.18; 95% confidence interval=0.92, 5.20) after adjustment for age, sex, ethnicity, and smoking status, suggesting a potential role of MNS16A in lung cancer susceptibility. Larger studies are needed to verify our findings.

Base Sequence↗
PubMed2003

Genomic instability and endoreduplication triggered by RAD17 deletion.

Cell cycle checkpoints are critical for genomic stability. Rad17, a component of the checkpoint clamp loader complex (Rad17/Rfc2-5), is required for the response to DNA damage and replication stress. To explore the role of Rad17 in the maintenance of genomic integrity, we established somatic conditional alleles of RAD17 in human cells. We find that RAD17 is not only important for the Atr-mediated checkpoint but is also essential for cell viability. Cells lacking RAD17 exhibited acute chromosomal aberrations and underwent endoreduplication at a high rate. Therefore, RAD17 links the checkpoint to ploidy control and is essential for the maintenance of chromosomal stability.

Blotting, Southern↗
PubMed2003

Repair of UV light-induced DNA damage and risk of cutaneous malignant melanoma.

BACKGROUND: The mechanism underlying the role of UV light exposure from sunlight in the etiology of cutaneous malignant melanoma (CMM) is unclear. Patients with xeroderma pigmentosum, a disease characterized by severe sensitivity to UV radiation and a defect in nucleotide excision repair, have a high incidence of CMM, which suggests that DNA repair capacity (DRC) plays a role in sunlight-induced CMM in the general population as well. METHODS: We conducted a hospital-based case-control study of DRC and CMM among 312 non-Hispanic white CMM patients who had no prior chemotherapy or radiation therapy, and 324 cancer-free control subjects who were frequency-matched to case patients on age, sex, and ethnicity. Information on demographic variables, risk factors, and tumor characteristics was obtained from questionnaires and medical records. We used the host-cell reactivation assay to measure the DRC in study subjects' lymphocytes. All statistical tests were two sided. RESULTS: Case patients had a 19% lower mean (+/- standard deviation [SD]) DRC (8.5 +/- 3.4%) than control subjects (10.5 +/- 5.1%), a statistically significant difference (P<.001). DRC that was at or below the median value (i.e., 9.4%) in control subjects was associated with increased risk for CMM after adjustment for age, sex, and other covariates (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.45 to 2.82). We observed a dose-response relationship between decreased DRC and increased risk of CMM (P(trend)<.001). Patients with tumors on sun-exposed skin had statistically significantly lower DRC than patients with tumors on unexposed skin (8.2 +/- 3.3% versus 9.5 +/- 3.5%; P =.004). CONCLUSIONS: Reduced DRC is an independent risk factor for CMM and may contribute to susceptibility to sunlight-induced CMM among the general population.

Adult↗
PubMed2003

Overexpression of hMTH in peripheral lymphocytes and risk of prostate cancer: a case-control analysis.

Oxidative damage is an important factor in prostate carcinogenesis, and overexpression of human MutT homolog (hMTH), a repair gene that removes oxidative damage, is a molecular marker of cellular oxidative stress. Therefore, we tested the hypothesis that overexpression of hMTH in unaffected (normal) surrogate tissue is associated with risk of prostate cancer in a pilot study of 51 patients with diagnosed prostate cancer and 50 age- and ethnicity-matched controls. Total RNA was extracted from phytohemagglutinin-stimulated peripheral blood lymphocytes of these subjects. We performed the real-time reverse transcription-polymerase chain reaction assay to evaluate the relative mRNA expression of three oxidative-damage-repair genes, human MutM homolog (hMMH), hMTH, and human MutY homolog (hMYH), with beta-actin and human O(6)-methylguanine DNA methyltransferase (hMGMT) as the internal controls. The relative gene expression levels of hMMH and hMTH were borderline higher in the cases than in controls (15.3% and 28.8% higher, respectively; P = 0.046 and P = 0.035, respectively), whereas no increase was observed for hMYH and hMGMT. With the median of the controls' values as the cutoff point, we observed that a high expression level of hMTH, but not of other genes, was associated with a significantly increased risk of prostate cancer (odds ratio = 2.62; 95% confidence interval = 1.13-6.75) after adjustment for age and ethnicity. These results suggested that increased expression of hMTH in peripheral lymphocytes may be a risk factor for prostate cancer and support our priori hypothesis. Although our findings were biologically plausible and consistent with the literature, they were preliminary and need to be confirmed in larger studies. In addition, a correlation between the expression level of hMTH and the level of oxidative DNA damage in the target tissues needs to be established as well.

Actins↗
PubMed2003

Fas A670G polymorphism, apoptotic capacity in lymphocyte cultures, and risk of lung cancer.

Tobacco carcinogens can damage DNA, leading to apoptosis. There may be individual variation in apoptotic capacity (AC), and this variation may explain difference in AC associated with risk of lung cancer, if genome integrity is not restored by efficient DNA repair. To test the hypothesis that genetically determined AC is associated with risk of lung cancer, we conducted a pilot case-control study of 68 patients with newly diagnosed, untreated lung cancer and 74 cancer-free controls. We measured the AC of their cultured peripheral blood lymphocytes in response to in vitro exposure to an ultimate tobacco carcinogen, benzo[a]pyrene diol epoxide (BPDE), by using terminal dUTP nucleotide end labeling and flow cytometry. We also investigated the frequency of the -A670G polymorphism in Fas, a gene involved in controlling the apoptotic pathway, by using polymerase chain reaction-restriction fragment length polymorphism analysis. After exposing the cells to 4 microM BPDE for 5 h, we observed a significantly lower AC in lung cancer patients (155.2+/-143.9%) than in the controls (216.6+/-184.6%) (P<0.05). Low AC was an independent risk factor (adjusted odds ratio (OR)=2.69, 95% confidence interval (CI)=1.18-6.15) for lung cancer after adjustment for age, sex, ethnicity, smoking status and apoptotic baseline in a logistic regression model. Although the Fas -A670G polymorphism was not an independent risk factor for lung cancer, it appeared to modulate the risk. The adjusted ORs for lung cancer risk associated with lower AC were 4.00 (95% CI=1.48-10.80) among those with the Fas -670 AG and GG genotypes and 0.97 (95% CI=0.18-5.30) among those with the Fas -670AA genotype. These data suggest that alteration in the apoptotic pathway may be a risk factor for lung cancer and this risk may be modulated by the Fas -A670G polymorphism. Larger prospective studies are needed to verify these findings.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2003

Sample size for biomarker studies: more subjects or more measurements per subject?

PURPOSE: In molecular epidemiologic studies, optimizing the use of available biological specimens while minimizing the cost is always a challenge. This is particularly true in pilot studies, which often have limited funding and involve small numbers of biological samples too small for assessment of recently developed biomarkers. METHODS: In this study we examined several statistical approaches for determining how many experimental subjects to use in a biomarker study and how many repeated measurements to make on each sample, given specific funding considerations and the correlated nature of the repeated measurements. RESULTS: A molecular epidemiology study of DNA repair and aging in basal cell carcinoma was used to illustrate the application of the statistical methods proposed. CONCLUSIONS: Our methods extend traditional designs on biomarker studies with repeated measurements to including funding constraints.

Adult↗
PubMed2003

p53 codon 72 Arg homozygotes are associated with an increased risk of cutaneous melanoma.

The p53 gene plays an important role in cell cycle control, facilitating DNA repair activities in response to DNA damage. Aberrant cell cycle control impairs DNA repair and increases the probability of mutations that can lead to carcinogenesis. The p53 gene is polymorphic at codon 72 (Arg/Pro) of its protein, which is functionally distinct, leading to inquiry into its role in carcinogenesis. In this hospital-based case-control study of 289 newly diagnosed patients with melanoma and 308 cancer-free control subjects, we evaluated whether the p53 codon 72 variant is associated with risk of cutaneous melanoma (CM). The controls were frequency-matched to the cases by age, sex, and ethnicity. The frequency of the p53 Arg allele was 78.2% in cases and 73.2% in controls (p=0.045), and the genotype frequencies of p53 Arg/Arg, Arg/Pro, and Pro/Pro were 62.6%, 31.1%, and 6.3%, respectively, in the cases, and 53.9%, 38.6%, and 7.5%, respectively, in the controls (p=0.096). Logistic regression analysis revealed that the p53 Arg/Arg genotype was associated with a significantly increased risk of melanoma (adjusted odds ratio (OR)=1.43; 95% confidence interval (CI)=1.02-2.02) compared with other genotypes, and this association was more evident in subgroups of older subjects (OR=2.32; 95% CI=1.39-388), and subjects with Fitzpatrick's skin type III or IV (OR=1.69; 95% CI=1.11-2.59). In conclusion, this study found some evidence that in subjects over 50, p53 Arg/Arg genotype is associated with increased risk of CM as compared to genotypes Arg/Pro or Pro/Pro. Further larger studies are needed to substantiate our findings.

Adolescent↗
PubMed2003

XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity.

XPA, a DNA binding protein in the nucleotide excision repair (NER) pathway, modulates damage recognition. Recently, a common single-nucleotide polymorphism (A --> G) of unknown function was identified in the 5' non-coding region of the XPA gene. Because a deficiency in NER is associated with an increased risk of lung cancer, we evaluated the role of this polymorphism in 695 lung cancer case patients and 695 age-, sex-, ethnicity- and smoking-matched control subjects. We also studied the effect of this polymorphism on NER capacity in a subset sample for whom the host cell reactivation data were available. The presence of one or two copies of the G allele was associated with a reduced lung cancer risk for Caucasians [adjusted odds ratio (ORadj) = 0.69 [95% confidence interval (CI) = 0.53-0.90]], Mexican-Americans [ORadj = 0.32 (95% CI = 0.12-0.83)] and African-Americans [ORadj = 0.45 (95% CI = 0.16-1.22)]. In Caucasians, ever smokers with one or more copies of the G allele were observed to have a significantly reduced risk of lung cancer. Control subjects with one or two copies of the G allele demonstrated more efficient DRC than did those with the homozygous A allele. Our data suggest that the XPA 5' non-coding region polymorphism modulates NER capacity and is associated with decreased lung cancer risk, especially in the presence of exposure to tobacco carcinogens.

Base Sequence↗
PubMed2003

Genetic susceptibility for lung cancer: interactions with gender and smoking history and impact on early detection policies.

OBJECTIVES: To identify a subgroup of former, current and never smokers (males and females) at high risk for developing lung cancer, based on their genetic susceptibility profiles, to estimate their lifetime probabilities of the disease, and to assess the potential mortality reduction that could be achieved by screening the high-risk group. METHODS: Case-control data (764 cases and 677 matched controls), on two assays of DNA damage and repair (mutagen susceptibility and DNA repair capacity, DRC) in different smoking categories were used to obtain estimates of susceptibility using the formula of total probability. The estimates were inserted into a model of lung cancer natural history and detection by screening to assess mortality reduction due to screening of high-risk individuals. RESULTS: The high-risk group was defined as that 12.5% of the population who were above the third quartile for bleomycin sensitivity and below the median for DRC. High-risk male current, former, and never smokers had lifetime probabilities for developing lung cancer of 38, 21, and 5%, respectively. Females had lower probabilities to develop lung cancer: 15, 8, and 1.5% for high-risk current, former, and never smokers, respectively. Screening of high-risk smokers (12.5% of all smokers) reduced overall mortality by 7% compared to 30% reduction if all smokers were screened. Analogous results were obtained for former and never smokers. CONCLUSIONS: Genetic susceptibility constitutes an important factor in the selection of a high-risk group for early lung cancer detection.

Age of Onset↗
PubMed2003

Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: a matched pair analysis.

PURPOSE: Infection with human papillomavirus (HPV) type 16 has been suggested to be a risk factor for squamous cell carcinoma of the head and neck (SCCHN) and to be more commonly associated with SCCHN occurring in the oropharynx and in never-smokers. We hypothesized that HPV-16 exposure, as evidenced by seropositivity, is a risk factor for SCCHN and may be of particular importance in never-smokers. EXPERIMENTAL DESIGN: To test this hypothesis, we conducted a hospital-based case-control study of 120 patients with SCCHN (60 never-smokers and 60 matched smokers) and 120 cancer-free matched controls. We compared the presence of HPV-16 antibodies in ever-smoker and never-smoker patients matched on age (+/-5 years), sex, and tumor site. Each patient was also matched with a corresponding ever-smoker or never-smoker cancer-free control on age (+/-5 years) and sex. Serum was collected from study subjects and assayed for IgG reactivity to HPV-16 L1 virus-like particles by using an ELISA. RESULTS: Forty-nine of the 120 case subjects (40.8%) but only 11 (9.2%) of the control subjects tested positive for HPV-16 antibodies (adjusted odds ratio, 6.69; 95% confidence interval, 3.01-14.90). Among cases, HPV-16 seropositivity was more common in those with oropharyngeal cancer (41 of 70, 58.6%) and poorly differentiated tumors (25 of 43, 58.1%). HPV-16 seropositivity was associated with a significantly increased risk of oropharyngeal cancer (adjusted odds ratio, 59.53; 95% confidence interval, 5.71-620.20). Whereas HPV-16 seropositivity was more common in never-smokers with SCCHN than in ever-smokers (43.3% versus 38.3%, respectively), this difference was not statistically significant. CONCLUSIONS: HPV-16 infection is associated with a significant increased risk for oropharyngeal cancer but not oral cavity cancer. Furthermore, HPV-16 infection does not appear to be more common in never-smokers than ever-smokers with SCCHN.

Aged↗
PubMed2003

Association between low dietary folate intake and suboptimal cellular DNA repair capacity.

Both reduced DNA repair capacity (DRC) and folate deficiency are associated with increased cancer risk. Furthermore, folate is involved in DNA repair through de novo DNA synthesis and methylation. To determine whether low dietary folate intake is associated with low cellular DRC in humans, we assessed total dietary folate intake using a food frequency questionnaire in 559 non-Hispanic white cancer-free subjects enrolled from 1995 through 2001 as controls for ongoing molecular epidemiological studies from among enrollees in a community-based multispecialty physician practice in the Houston metropolitan area. We assessed cellular DRC using the host-cell reactivation assay that measures nucleotide-excision repair capacity in peripheral blood lymphocytes. The distribution of DRC was approximately normal in this study population. In univariate analysis, subjects in the lowest tertile of total dietary folate intake (<170 microg/1000 kcal/day) exhibited a significant reduction (-18%) in DRC compared with those in the upper tertile (>225 microg/1000 kcal/day; P < 0.001). In multivariate linear regression analysis, calorie-adjusted total folate intake remained an independent predictor of DRC (P < 0.001). Additional stratification analysis indicated that this association was more pronounced in those who did not use folate supplementation (n = 230; P < 0.001) compared with those who did (n = 329; P = 0.177). Our findings suggest that low dietary folate intake is associated with suboptimal cellular DRC. Once replicated by other investigators, this finding has public health implications by reinforcing the need for folate supplementation or dietary modification for the at-risk population.

Adult↗
PubMed2003

Dietary folate intake and lung cancer risk in former smokers: a case-control analysis.

No studies have focused on the role of dietary folate intake in risk of lung cancer in former smokers, in whom dietary folate intake is less likely confounded with current smoking. Therefore, we evaluated the association between dietary folate intake and risk of lung cancer in a population of 470 histopathologically confirmed incident lung cancer cases from M. D. Anderson Cancer Center and 472 cancer-free controls from enrollees at a community-based multispecialty physician practice, frequency-matched on age (5 years), sex, and ethnicity. Dietary folate intake levels were estimated from a National Cancer Institute standard food frequency questionnaire. Unconditional logistic regression analyses were used to calculate the crude and adjusted ORs and their 95% CIs. Dietary folate intake from natural food was significantly higher among the controls than among the cases (P < 0.001), and folate intake above the control median value was associated with a 40% decreased risk of lung cancer (adjusted OR, 0.60; 95% CI, 0.45-0.79). A significant inverse dose-response relationship between increasing dietary folate and decreasing risk of lung cancer was also evident (adjusted OR, 1.02; 95% CI, 0.71-1.47; OR, 0.67; 95% CI, 0.46-0.99; and OR, 0.53; 95% CI, 0.35-0.80 for the second, third, and fourth quartiles of average folate intake, respectively; P for trend <0.001). A more pronounced inverse association between dietary folate intake and lung cancer risk was observed among subjects who drank alcohol, had smoked relatively more, those who did not take supplemental folate, and those who reported a family history of lung cancer. Our data suggest that there is a possible protective role of dietary folate in lung carcinogenesis, a finding which may have implications in public health and cancer prevention.

Aged↗
PubMed2002

Rapid assessment of repair of ultraviolet DNA damage with a modified host-cell reactivation assay using a luciferase reporter gene and correlation with polymorphisms of DNA repair genes in normal human lymphocytes.

As DNA repair plays an important role in genetic susceptibility to cancer, assessment of the DNA repair phenotype is critical for molecular epidemiological studies of cancer. In this report, we compared use of the luciferase (luc) reporter gene in a host-cell reactivation (HCR) (LUC) assay of repair of ultraviolet (UV) damage to DNA to use of the chloramphenicol (cat) gene-based HCR (CAT) assay we used previously for case-control studies. We performed both the assays on cryopreserved lymphocytes from 102 healthy non-Hispanic white subjects. There was a close correlation between DNA repair capacity (DRC) as measured by the LUC and CAT assays. Although these two assays had similar variation, the LUC assay was faster and more sensitive. We also analyzed the relationship between DRC and the subjects' previously determined genotypes for four polymorphisms of two nucleotide-excision repair (NER) genes (in intron 9 of xeroderma pigmentosum (XP) C and exons 6, 10 and 23 of XPD) and one polymorphism of a base-excision repair gene in exon 10 of X-ray complementing group 1 (XRCC1). The DRC was significantly lower in subjects homozygous for one or more polymorphisms of the two NER genes than in subjects with other genotypes (P=0.010). In contrast, the polymorphic XRCC1 allele had no significant effect on DRC. These results suggest that the post-UV LUC assay measures NER phenotype and that polymorphisms of XPC and XPD genes modulate DRC. For population studies of the DNA repair phenotype, many samples need to be evaluated, and so the LUC assay has several advantages over the CAT assay: the LUC assay was more sensitive, had less variation, was not radioactive, was easier to perform, and required fewer cryopreserved cells. These features make the LUC-based HCR assay suitable for molecular epidemiological studies.

Cell Line, Transformed↗
PubMed2002

P53 codon 72 polymorphism and risk of squamous cell carcinoma of the head and neck: a case-control study.

p53 plays an important role in cell-cycle control, as it facilitates DNA repair activities in response to DNA damage. An aberrant cell cycle impairs DNA repair and increases the probability of mutations that lead to carcinogenesis. The p53 codon 72 Arg/Pro polymorphism has been suggested to be associated with susceptibility to tobacco-related cancers, but this association remains controversial. In this hospital-based case-control study of 304 patients newly diagnosed with squamous cell carcinoma of the head and neck (SCCHN) and 333 cancer-free controls, we evaluated the association between this p53 polymorphism and the risk of SCCHN. All subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (+/-5 years), sex and smoking status. Our results suggested that there was no difference in the distributions of p53 codon 72 genotypes between cases and controls (odds ratio (OR)=1.04, 95% confidence interval (CI) 0.75-1.44 for Pro/Pro vs. Arg/Arg and OR=1.01, 95% CI 0.54-1.91 for Arg/Pro vs. Arg/Arg). However, there was evidence that the Pro allele was associated with an early age of onset of SCCHN. The median ages of onset of SCCHN were 59, 56 and 53 years for Arg/Arg, Arg/Pro and Pro/Pro cases, respectively (P=0.151 among three genotypes; P=0.057 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). The median ages at onset of oral cancers were 62, 57 and 51 years for Arg/Arg, Arg/Pro and Pro/Pro, respectively (P=0.091 among three genotypes; P=0.046 for Pro/Pro vs. Arg/Arg; P=0.066 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). While the results suggest that the P53 codon 72 polymorphism may contribute to oral cancer susceptibility, larger studies are needed to confirm these findings.

Adult↗
PubMed2002

A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer.

DNA repair is central to genomic integrity. Reduced expression of several nucleotide excision repair genes has been demonstrated to be associated with increased risk of lung cancer. Because methylation of gene promoters is one of the major regulatory mechanisms of gene expression and most nucleotide excision repair gene promoters have not been fully characterized, we hypothesized that genetic variants of the genes that are responsible for regulating genomic methylation are associated with increased risk of lung cancer. Recently, we identified a C-->T transition at a novel promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) and found that this polymorphic transition significantly increases the promoter activity. In this hospital-based case-control study of 319 patients with incident lung cancer and 340 healthy controls frequency matched on age (+/-5 years), sex, ethnicity, and smoking status, we genotyped subjects for this DNMT3B promoter polymorphism to determine the association between this genetic variant and risk of lung cancer. Compared with CC homozygotes, CT heterozygotes had a >2-fold increased risk of lung cancer [adjusted odds ratio (OR), 2.13; 95% confidence interval (CI), 1.47-3.08] and TT homozygotes an OR of 1.42 (95% CI, 0.91-2.21). The combined variant genotype (CT + TT) was associated with a nearly 2-fold increased risk (adjusted OR, 1.88; 95% CI, 1.32-2.66). These results suggest that this novel variant of DNMT3B is associated with increased risk of lung cancer and may contribute to identifying individuals genetically susceptible to tobacco-induced cancers. Additional studies on the underlying molecular mechanism of this polymorphism are warranted.

Aged↗
PubMed2002

An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is frequently resistant to chemotherapy, and this resistance has been associated with elevated nucleotide excision repair (NER) in tumor tissue. We hypothesized that patients with NSCLC who had effective systemic (host) NER would have poorer survival than patients with suboptimal NER and that the association between NER effectiveness and survival would be most marked in patients receiving chemotherapy. METHODS: 375 patients with newly diagnosed NSCLC were accrued for a case-control study between July 1995 and December 1999. NER activity was estimated as the DNA repair capacity (DRC) measured in the patient's peripheral lymphocytes by the host cell reactivation assay. Cox proportional hazards models were used to assess the association between DRC and survival. All statistical tests were two-sided. RESULTS: For every unit (percentage) increase in DRC, the relative risk (RR) of death was 1.05 (95% confidence interval [CI] = 1.00 to 1.10; P =.05) for the 345 patients for whom weight loss information was available and 1.06 (95% CI = 1.00 to 1.12; P =.03) for the 275 patients with complete follow-up information. In 86 patients treated with chemotherapy only, the RR of death increased to 1.11 (95% CI = 1.02 to 1.21; P =.01) for every unit (percentage) increase in DRC. Of those 86 patients, patients in the top quartile of the DRC distribution were at twice the RR of death as those in the lowest quartile (RR = 2.72; 95% CI = 1.24 to 5.95; P =.01). Effective DRC was not a risk factor for death in patients who were not treated with chemotherapy. CONCLUSIONS: Our data suggest that effective host DRC may be associated with poorer survival in patients with NSCLC who are treated with chemotherapy.

Aged↗
PubMed2002

N-(4-hydroxyphenyl)retinamide (4-HPR) modulates GADD45 expression in radiosensitive bladder cancer cell lines.

We previously demonstrated that N-(4-hydroxyphenyl)retinamide (4-HPR) and gamma-irradiation, when used in combination, had a synergistic effect in inducing apoptosis in bladder cancer cells, suggesting that 4-HPR may increase radiosensitivity in bladder cancer cells. To unravel molecular correlates in this radiosensitizing effect of 4-HPR, we examined the baseline and 4-HPR-induced expression of GADD45 to elucidate possible mechanisms by which 4-HPR enhanced the effect of gamma-irradiation in three bladder cancer cell lines. To investigate the role of p53 in mediating the radiosensitizing effect of 4-HPR, we also examined mutations in exons 5-9 by using direct sequencing and the levels of p53 expression by using RT-PCR and Western blot, before and after treatment with 4-HPR in these bladder cancer cell lines. Two cell lines had low expression of GADD45, and a dose-dependent increase in GADD45 expression induced by 4-HPR was found in bladder cancer cell lines without p53 mutations in exons 5-9. A combination of gamma-irradiation and 4-HPR showed a significantly greater effect in enhancing GADD45 expression than either agent used alone. The results indicate that the combined treatment with 4-HPR and gamma-irradiation has a stronger effect on GADD45 expression than the treatment with either agent alone, which suggests that the two agents may have an additive/synergistic effect. However, a normal p53 function appears to be necessary for the dose-dependent induction of GADD45 by 4-HPR. Once our results are verified and replicated by other investigators, 4-HPR may have a potential clinical implication in effectively treating bladder cancer in combination with low-gamma-irradiation therapy.

Antineoplastic Agents↗