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Biomedical subjects

W K Hong

Publications and source records attributed to W K Hong.

At least 73 records · Page 4Linked to original sources
PubMed2000

Insulin-like growth factor binding protein-6 inhibits the growth of human bronchial epithelial cells and increases in abundance with all-trans-retinoic acid treatment.

Retinoids are potent inhibitors of human bronchial epithelial (HBE) cell growth. Retinoids initiate signaling through activation of nuclear receptors, but the signal transduction pathways that mediate growth inhibition have not been defined. In this study, we investigated the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-6 as a potential mediator of retinoid actions. IGFBP-6 is a secreted glycoprotein that inhibits the bioavailability of IGFs, which are potent mitogens of HBE cells. IGFBP-6 was detected by immunohistochemical staining in the basal epithelial layer of human bronchial organ cultures, and all-trans-retinoic acid (t-RA) treatment increased the intensity of IGFBP-6 immunostaining. In primary cultures of HBE cells treated with t-RA, IGFBP-6 messenger RNA and protein levels increased within 6 and 24 h, respectively, and IGFBP-6 was detected in the conditioned media at 48 h. The effect of IGFBP-6 on HBE cell growth was investigated with a recombinant adenoviral vector, Ad5CMV-BP6, which expresses IGFBP-6 under the control of a cytomegalovirus promoter. IGFBP-6 overexpression induced a proliferative arrest of HBE cells with no evidence of apoptosis. These findings provide the first evidence that IGFBP-6 is expressed in the bronchial epithelium and that IGFBP-6 may contribute to the biologic effects of retinoids on HBE cells.

Adenoviridae↗
PubMed2000

Retinoic acid receptor-beta as a prognostic indicator in stage I non-small-cell lung cancer.

PURPOSE: Retinoids are pivotal in the growth and differentiation of certain epithelial tissues, interacting with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors. RAR-beta mRNA is undetectable by in situ hybridization (ISH) in 50% of non-small-cell lung cancers (NSCLC). RAR-beta may suppress tumorigenicity. Therefore, we hypothesized that loss of expression of RAR-beta gene in stage I NSCLC is a prognostic factor of a poor clinical outcome. PATIENTS AND METHODS: We retrospectively analyzed RAR-beta mRNA levels (by ISH using a digoxigenin-labeled antisense riboprobe) in specimens from 185 consecutive patients with completely resected clinical/radiographic stage I NSCLC for whom clinical follow-up data were available. RESULTS: One hundred fifty-six patients who met the criteria of pathologic stage I NSCLC and positivity for RXR-alpha mRNA (used as a control to assess RNA degradation) and who had adequate follow-up could be evaluated. RAR-beta mRNA expression was undetectable in 51 patients, weakly positive in 64 patients, and strongly positive in 41 patients. Overall survival of the 41 patients with strongly positive RAR-beta was significantly worse than for the 115 patients with weak or absent RAR-beta (P =.045). CONCLUSION: Unexpectedly, strong RAR-beta expression was associated with a significantly worse outcome of early-stage NSCLC. The mechanisms underlying this clinically and biologically important finding should be further explored.

Adult↗
PubMed2000

Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer.

PURPOSE: To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS: Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Adenoviruses, Human↗
PubMed2000

Prognostic implication of microsatellite alteration profiles in early-stage non-small cell lung cancer.

Development of non-small cell lung cancer (NSCLC) is a result of multiple accumulated genetic abnormalities. Profiles of genetic abnormalities may determine tumor behavior and impact on patient outcome. We used microsatellite markers at 3p14, 9p21, and 10q24 to analyze tumor samples from 91 patients with pathologically confirmed stage I NSCLC for microsatellite alterations. Loss of heterozygosity at any single locus was not significantly associated with length of survival. However, patients whose tumors had microsatellite instability (MI) at 10q24 had shortened disease-specific survival. Among 31 such patients, 32% (10 of 31 patients) had died of the disease within 5 years after surgery compared with 16% (9 of 58 patients) without MI at 10q24 (P = 0.07). Interestingly, in the adenocarcinoma subtype, 71% (5 of 7 patients) of the patients with MI at 10q24 succumbed to the disease as compared with only 12% (3 of 26) of the adenocarcinoma patients without such MI (P < 0.001), suggesting the presence of distinct mechanisms in tumorigenesis among different subtypes of lung cancer. It has been noticed that certain microsatellite alteration profiles provide additional values for risk assessment. Of 23 patients who had MI at 10q24 and an alteration at 3p14, 39% (9 of 23 patients) died of the disease within 5 years as compared with only 15% (10 of 66 patients) of the patients without such a profile (P = 0.02). Strikingly, among the 22 patients with no alteration at any loci tested or with loss of heterozygosity at 10q24 and retention of at least one of the other two loci, none died of lung cancer within 5 years after surgery, whereas 28% (19 of 67 patients) of the patients outside these profiles did so (P = 0.01). Our results support the hypothesis that microsatellite alterations can be used as biomarkers for the genetic classification of pathological stage I NSCLC, which may in turn influence treatment decisions dependent on an accurate forecast of patient survival time.

Adenocarcinoma↗
PubMed2000

Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma.

Because routine histopathological examination of primary non-small cell lung cancer does not predict disease outcome, we correlated disease outcome with the expression level of multiple genes that regulate distinct steps of the metastatic process in 60 formalin-fixed, paraffin-embedded, archival specimens of stage I lung carcinoma from patients undergoing curative surgery at the M. D. Anderson Cancer Center. The expression of E-cadherin (related to cell cohesion), type IV collagenase [matrix metalloproteinase (MMP)-2 and MMP-9, related to invasion], and three angiogenic molecules, basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and interleukin 8, were examined by a colorimetric in situ mRNA hybridization technique. The expression levels of the individual genes analyzed by a Cox univariate analysis were not prognostic. In contrast, the ratio between expression of type IV collagenases (mean of the expression of MMP-2 and MMP-9) and E-cadherin, the MMP:E-cadherin ratio (measured at the periphery of each tumor), was significantly higher in patients with recurrent disease than in patients who remained disease free (P = 0.00003). Longer overall survival and reduced disease recurrence rates were significantly associated with a lower MMP:E-cadherin ratio (<2) by a Kaplan-Meier survival analysis (P = 0.0002 and P = 0.0001, respectively). Multiple covariate analyses of overall and disease-free survival also concluded that the MMP:E-cadherin ratio was a significant prognostic factor when corrected for age (P = 0.0001). Determination of this gene expression ratio in individual human lung cancers might therefore be used to direct tailored treatment for individual patients with resectable lung cancer.

Adult↗
PubMed2000

Identification of receptor-selective retinoids that are potent inhibitors of the growth of human head and neck squamous cell carcinoma cells.

Retinoids modulate the growth and differentiation of cancer cells presumably by activating gene transcription via the nuclear retinoic acid receptor (RAR) alpha, beta, and gamma and retinoid X receptor (RXR) alpha, beta, and gamma. We analyzed the effects of 38 RAR-selective and RXR-selective retinoids on the proliferation of 10 human head and neck squamous cell carcinoma (HNSCC) cell lines. All of these cell lines expressed constitutively all of the receptor subtypes except RARbeta, which was detected in only two of them. Most of the RAR-selective retinoids inhibited the growth of HNSCC cells to varying degrees, whereas the RXR-selective retinoids showed very weak or no inhibitory effects. Three RAR antagonists suppressed growth inhibition by RAR-selective agonists, as well as by RAR/RXR panagonists such as 9-cis-retinoic acid. Combinations of RXR-selective and RAR-selective retinoids exhibited additive growth-inhibitory effects. Furthermore, we found that CD437, the most potent growth-inhibitory retinoid induced apoptosis and up-regulated the expression of several apoptosis-related genes in HNSCC cells. These results indicate that: (a) retinoid receptors are involved in the growth-inhibitory effects of retinoids; (b) RXR-RAR heterodimers rather than RXR-RXR homodimer are the major mediators of growth inhibition by retinoids in HNSCC cells; and (c) induction of apoptosis can account for one mechanism by which retinoids such as CD437 inhibit the growth of HNSCC cells. Finally, these studies identified several synthetic retinoids, which are much more effective than the natural RAs and can be good candidates for chemoprevention and therapy of head and neck cancers.

Apoptosis↗
PubMed2000

Predicting cancer development in oral leukoplakia: ten years of translational research.

Our 10-year translational study of the oral premalignant lesion (OPL) model has advanced the basic understanding of carcinogenesis. Although retinoids have established activity in this model, a substantial percentage of our OPL patients progress to cancer, especially after treatment is stopped. On the basis of our 10-year OPL study, we have developed the first comprehensive tool for assessing cancer risk of OPL patients. This cancer risk assessment tool incorporates medical/demographic variables, epidemiological factors, and cellular and molecular biomarkers. Between 1988 and 1991, 70 advanced OPL patients were enrolled in a chemoprevention trial of induction with high dose isotretinoin (1.5 mg/kg/day for 3 months) followed by 9 months of maintenance treatment with either low dose isotretinoin (0.5 mg/kg/day) or beta-carotene (30 mg/d; total treatment duration, 1 year). We assessed the relationship between cancer risk factors and time to cancer development by means of exploratory data analysis, logrank test, Cox proportional hazard model, and recursive partitioning. With a median follow-up of 7 years, 22 of our 70 patients (31.4%) developed cancers in the upper aerodigestive tract following treatment. The overall cancer incidence was 5.7% per year. The most predictive factors of cancer risk are OPL histology, cancer history, and three of the five biomarkers we assessed (chromosomal polysomy, p53 protein expression, and loss of heterozygosity at chromosome 3p or 9p). In the multivariable Cox model, histology (P = 0.0003) and the combined biomarker score of chromosomal polysomy, p53, and loss of heterozygosity (P = 0.0008) are the strongest predictors for cancer development. Retinoic acid receptor beta and micronuclei were not associated with increased cancer risk. We have demonstrated a successful strategy of comprehensive cancer risk assessment in OPL patients. Combining conventional medical/demographic variables and a panel of three biomarkers can identify high risk patients in our sample. This result will need to be validated by future studies. With the identification of high risk individuals, more efficient chemoprevention trials and molecular targeting studies can be designed.

Alcohol Drinking↗
PubMed2000

Reduced expression levels of nucleotide excision repair genes in lung cancer: a case-control analysis.

Epidemiological studies have indicated that reduced DNA repair capacity and increased DNA adduct levels are associated with increased risk of lung cancer. Nucleotide excision repair (NER) is the major pathway in humans for repairing DNA adducts induced by smoking-related carcinogens, such as benzo[a]pyrene diol epoxide. We hypothesized that genetically determined baseline expression level of genes involved in NER is associated with risk of lung cancer. In a pilot case-control study, we measured the relative expression levels of five NER genes [ERCC1, XPB/ERCC3, XPG/ERCC5, CSB/ERCC6 and XPC (ERCC, excision repair cross-complementing; CSB, Cockayne's syndrome complementary group B)] in phytohemagglutinin-stimulated peripheral lymphocytes obtained from 75 lung cancer patients and 95 controls using a newly developed multiplex RT-PCR assay. Cases and controls were matched on age, sex, ethnicity and tobacco use. The expression level of the beta-actin gene was used as an internal control for the relative quantitation. We observed a 12.2 and 12.5% decrease in the baseline expression levels of XPG/ERCC5 and CSB/ERCC6, respectively, in cases compared with controls. These differences were statistically significant (P < 0.01) when the median expression level in the controls was used as the cut-off point, the lung cancer patients were significantly more likely than the controls to have reduced expression levels of XPG/ERCC5 [odds ratio (OR), 2.32; 95% confidence interval (CI), 1.22-4.43] and CSB/ERCC6 (OR, 2.49; 95% CI, 1.28-4.84). There was also a dose-response relationship between reduced expression levels and increased lung cancer risk (trend test: P < 0.01). Our results suggest that individuals whose expression levels of XPG/ERCC5 and CSB/ERCC6 are reduced may be at higher risk of lung cancer.

Actins↗
PubMed2000

Expression of vascular endothelial growth factor and microvessel density in head and neck tumorigenesis.

Angiogenesis is a fundamental process in tumor growth and metastasis, and its significance and that of vascular endothelial growth factor (VEGF) expression as prognostic indicators have been documented for various types of human tumors. However, the mechanisms responsible for angiogenesis in head and neck squamous cell carcinoma are not well defined. To examine the relationship between angiogenesis and the phenotypic progressions of head and neck tumorigenesis, we used immunohistochemistry to analyze VEGF expression and microvessel density in 70 paraffin-embedded specimens that contained adjacent normal epithelium, premalignant lesions, or both from 57 patients with head and neck squamous cell carcinoma. Ten samples of normal oral mucosa were obtained from people who did not smoke or drink alcohol and included in the analysis as normal controls. Microvessel density was evaluated by averaging 10 microscopic fields (x400) in a defined area of each specimen. The degree of VEGF expression was assessed on a cell-by-cell basis in 10 microscopic fields (x200) in a defined area on a scale ranging from 0 (no expression) to 3+ (highest level of expression). In addition, the weighted mean index of VEGF expression was calculated. The mean +/- SD weighted mean index of VEGF expression in normal control epithelium (1.10 +/- 0.38, n = 10) was higher than it was in adjacent normal epithelium (0.82 +/- 0.27, n = 13; P = 0.04). VEGF expression decreased as samples ranged from normal adjacent epithelium to hyperplasia (0.78 +/- 0.28, n = 21), mild dysplasia (0.70 +/- 0.29, n = 28), moderate dysplasia (0.67 +/- 0.29, n = 11), severe dysplasia (0.51 +/- 0.39, n = 6), and squamous cell carcinoma (0.20 +/- 0.27, n = 70; overall P = 0.0001). VEGF expression was two times lower in cases with nodal disease (0.17 +/- 0.26, n = 29) than it was in nonnodal disease (0.32 +/- 0.29, n = 16; P = 0.02). Microvessel density showed no significant difference from adjacent normal epithelium premalignant lesions to cancer. In tumor, no correlation was seen between VEGF expression or microvessel density and differentiation, primary tumor site, T stage, or smoking status. These findings indicate that VEGF expression is down-regulated during head and neck tumorigenesis. However, further studies are required to better understand the mechanism of VEGF down-regulation in head and neck tumorigenesis.

Adult↗
PubMed2000

Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck: current status and future directions.

Patients with advanced squamous cell head and neck cancer have a dismal long-term survival rate not only because of metastatic disease, but also primarily because of failure in local disease control. The role of chemotherapy in recurrent or metastatic head and neck cancer has largely been palliative. Several chemotherapy agents, including docetaxel, paclitaxel, and ifosfamide, have been extensively studied, either alone or in combination regimens, for the treatment of recurrent or metastatic disease. These have resulted in response rates that are similar or higher than those obtained with the gold standard combination, cisplatin/ fluorouracil. Single-agent and combination studies of vinorelbine and gemcitabine have demonstrated modest activity in recurrent or metastatic disease. Phase III trials are planned that will compare taxane-based regimens with cisplatin and 5-fluorouracil in recurrent or metastatic head and neck cancer. Meanwhile, new drug and compound development, including monoclonal antagonists to the epidermal growth factor receptor, farnesyl transferase inhibitors, and oncolytic viruses are being tested in this setting.

Antineoplastic Agents↗
PubMed2000

N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium.

Lung cancer remains the number one cause of cancer-related deaths in the United States. To reduce the mortality associated with this disease, individuals at risk must be identified prior to the development of lung cancer, and effective prevention strategies must be developed. One such strategy is to use retinoids like N-(4-hydroxyphenyl)retinamide (4-HPR), which has been found to possess chemopreventive activities in preclinical studies. In this study, 139 smokers were registered and 82 were randomized onto a double-blinded, placebo-controlled chemoprevention trial of 4-HPR administered p.o. (200 mg once daily). Of these, 70 participants were eligible for response evaluation. Biopsies were obtained at six predetermined sites in the bronchial tree from participants before and at the completion of 6 months of treatment. 4-HPR treatment had no measurable effect on histopathology (squamous metaplasia and dysplasia) in the bronchial epithelium of current smokers. 4-HPR was detected (104.5+/-64.0 ng/ml, mean +/- SD) in the serum of participants, supporting its potential bioavailability. Serum retinol levels decreased markedly (44% of placebo-treated patients) as a consequence of 4-HPR treatment. Notably, the mRNA level of retinoic acid receptor beta, which is typically increased by retinoid treatment, did not change in the bronchial epithelium of 4-HPR-treated participants. Clonal populations of bronchial epithelial cells were detected by analysis of loss of heterozygosity at putative tumor suppressor loci on chromosomes 3p, 9p, and 17p, and these changes were not altered by 4-HPR treatment. In conclusion, at this dose and schedule, 4-HPR was not effective in reversing squamous metaplasia, dysplasia, or genetic and phenotypic abnormalities in the bronchial epithelium of smokers.

Adult↗
PubMed2000

C-CAM1, a candidate tumor suppressor gene, is abnormally expressed in primary lung cancers.

Previous studies have shown that the expression of the cell-cell adhesion molecule (C-CAM1), located at chromosome 19, is down-regulated in several types of human cancers, including prostate and breast cancers. Two major isoforms of C-CAM1, the long or L-form C-CAM1 and the short or S-form C-CAM1, are derived from the C-CAM1 gene through alternative splicing. Tumor cells transfected with L-form C-CAM1, which contains a cytoplasmic domain, display significantly lower growth rates and less tumorigenicity in both in vitro and in vivo models compared with untransfected tumor cells, suggesting that L-form C-CAM1 may be a tumor suppressor. The transfection of the cytoplasmic domain of L-form C-CAM1 could also cause suppression of tumor growth, further supporting the role of L-form C-CAM1 in tumorigenesis. In contrast to reports of most of the tumor types tested, Ohwada et al. (Am. J. Respir. Cell Mol. Biol., 11: 214-220, 1994) reported that C-CAM1 was not down-regulated or even up-regulated in lung cancer. Because the cytoplasmic domain of L-form C-CAM1 is critical for the tumor suppressor function of C-CAM1, we hypothesized that switching of the isoform rather than down- regulation of C-CAM1 gene expression occurs during lung tumorigenesis. To test this hypothesis, we analyzed pairs of tumor tissue and corresponding normal-appearing lung tissue from 51 patients with non-small cell lung cancer (NSCLC) and 43 cell lines to determine expression profiles of L-form C-CAM1 and S-form C-CAM1 using reverse transcription-PCR. We found that L-form C-CAM1 was the predominant form (75%; 38 of 51) in normal-appearing lung tissue, whereas most (84%; 43 of 51) of the primary NSCLC tissue samples expressed predominantly S-form C-CAM1 (P < 0.0001). Similarly, 19 (79%) of the 24 NSCLC cell lines and 17 (85%) of the 20 small cell lung cancer cell lines expressed predominantly S-form C-CAM1. The frequent alteration of the C-CAM1 expression pattern suggests that C-CAM1 has an important role in lung tumorigenesis.

Adenosine Triphosphatases↗
PubMed2000

Dietary intake of isothiocyanates: evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk.

Isothiocyanates (ITCs) are nonnutrient compounds in cruciferous vegetables with anticarcinogenic properties. One proposed mechanism for their protective action is through down-regulation of cytochrome P-450 biotransformation enzyme levels and induction of phase II detoxifying enzymes. Because ITCs also serve as a substrate for GSTs, we evaluated dietary intake of ITCs and GSTM1 and GSTT1 genotype information in a lung cancer case-control study. There were 503 newly diagnosed lung cancer cases (264 men and 239 women) identified from The University of Texas M. D. Anderson Cancer Center and 465 controls (252 men and 213 women) recruited from enrollees in a local managed care organization. Subjects had an in-person interview including a semiquantitative food frequency questionnaire, and blood samples were obtained for genotyping. Cases reported significantly lower ITC intake per day compared with controls (P = 0.009). There was no main effect associated with the GSTM1 null genotype [odds ratio (OR) = 1.09]. However, there was a statistically significant OR of 1.41 associated with the GSTT1 null genotype. On stratified analysis, low ITC intake and the GSTM1 null genotype were associated with increased lung cancer risk in current smokers, with an OR of 2.22 [confidence interval (CI) = 1.20-4.10). For current smokers with the GSTT1 null genotype, the OR with low ITC intake was 3.19 (CI = 1.54-6.62). The comparable OR in the presence of both null genotypes was 5.45 (CI = 1.72-17.22). These effects were not demonstrable for former smokers by GSTM1 genotype, although the risk for low ITC intake and GSTT1 null genotype was 1.79 (CI = 0.95-3.37). Thus, current smokers who are homozygous null for the GST null genotype and who consume less carcinogenic blocking compounds are at higher lung cancer risk. Some of the inconsistencies reported in the role of GST genotypes in lung cancer risk could be due to unexpected confounding from dietary factors.

Aged↗
PubMed2000

Effect of 13-cis-retinoic acid on serum prostate-specific antigen levels in patients with recurrent prostate cancer after radical prostatectomy.

The objective of this study was to determine whether there is any beneficial effect of oral 13-cis-retinoic acid (isotretinoin) on prostate cancer, using serum prostate-specific antigen (PSA) levels as a surrogate end point in patients with a rising serum PSA after radical prostatectomy. In the first phase, the effect of the drug on the serum PSA level was tested in 14 control patients with normal prostates. Our goal was to exclude any effect of isotretinoin on PSA secretion and metabolism and thus to validate any observed effect on PSA as indicative of anticancer activity. In the second phase, patients with rising PSA levels after radical prostatectomy and no evidence of metastatic disease were treated with oral isotretinoin at a daily dose of 1.0 mg/kg. Serum PSA levels were checked monthly for the first 4 months after initiation of treatment and every 3 months thereafter. No significant changes in serum PSA levels after 3 months of isotretinoin treatment were recorded in the control group (P = 1.000). Three of 11 postprostatectomy patients (27%) had a PSA reduction of 28%, 15%, and 6.6% after initiation of treatment that lasted for a period of 2-3 months. In two of these three patients, the PSA levels subsequently rose exponentially. Another patient displayed a stabilization of the serum PSA curve for 3 months after an initial sharp rise. No grade 3 or 4 toxicity was recorded in this group of patients. Isotretinoin had a modest, transient effect on the serum PSA level in 4 of 11 (36%) patients with a rising serum PSA after radical prostatectomy. We conclude that this drug is unlikely to be of major therapeutic benefit in prostate cancer patients when used as a single agent. However, its modest effect argues for the exploration of other, more potent retinoids for prostate cancer therapy.

Adult↗
PubMed2000

Prevention of lung cancer. The new millennium.

Lung cancer is the leading cause of cancer-related death worldwide and in the United States surpassing breast, prostate, and colon cancer. Treatment of this disease over the past 2 decades has advanced incrementally as survival rates have improved only slightly. Alternate approaches to this deadly disease include an emphasis on prevention such as smoking cessation. Chemoprevention has introduced a new arena of treatment options for early intervention in lung carcinogenesis. The use of molecularly targeted therapeutic and biologic agents constitutes novel strategies for lung cancer prevention in the new millennium.

Carotenoids↗
PubMed1999

Frequent loss of imprinting at the IGF2 and H19 genes in head and neck squamous carcinoma.

Genomic imprinting is an inherited epigenetic phenomenon that results in parental-origin-specific gene expression in somatic cells. Relaxation or loss of this feature in certain genes has been demonstrated in several pediatric and adult neoplasms, suggesting an association with tumorigenesis. We analysed 64 primary untreated head and neck squamous carcinoma for the loss of imprinting in the IGF2 and H19 genes to determine the implications of this alteration in the development and progression of these tumors. Forty-nine (77%) of the 64 tumors were informative for imprinting analyses of these genes. IGF2 and H19 were imprinted in all normal squamous epithelium examined. Twelve (37.5%) of 32 tumors informative for H19 and 11 (40.7%) of 27 tumors informative for IGF2 manifested loss of imprinting. Ten tumors were informative for both genes, of which four maintained the constitutional imprinting and six showed loss of imprinting at either H19 or IGF2. These data suggest that loss of imprinting at the IGF2 and H19 loci play a role in the oncogenesis of head and neck carcinoma.

Adult↗
PubMed1999

Gender differences in p53 mutational status in small cell lung cancer.

Mutations in the p53 tumor suppressor gene have been demonstrated to be one of the most frequent genetic abnormalities in human cancers. Previous studies have shown that the frequency of p53 mutations is significantly higher in small cell lung cancer than in non-small cell lung cancer. However, this conclusion was based in large part on data derived from tumor cell lines and from studies with relatively small sample sizes and biased gender populations. To determine the mutational frequency in the p53 tumor suppressor gene and a potential difference in gender, we analyzed primary small cell lung cancer tumors from 65 patients (37 males and 28 females) for p53 mutations between exons 5 and 9. Mutations were found in 37 of 65 tumors (57%) within the region of p53 analyzed. Interestingly, none of the tumors from females contained more than one mutation, whereas four of the tumors from males contained more than one mutation. The most common mutation in this population was an adenosine-to-guanine transition (27%), followed by guanine-to-thymidine transversion (17%) and guanine-to-adenosine transition (12%). The gender difference in p53 mutational rate identified in this study suggests that a higher proportion of female tumors may develop through pathways not involving p53 mutations.

Adult↗