Showing papers by "Scott M. Lippman published in 2004"

Prevalence of Prostate Cancer among Men with a Prostate-Specific Antigen Level ≤4.0 ng per Milliliter

Abstract: Background The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. Methods Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. Results Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per mi...

Hypermethylation of the Retinoic Acid Receptor-β2 Gene in Head and Neck Carcinogenesis

Abstract: Purpose: Retinoic acid receptor-β 2 (RAR-β 2 ) expression is suppressed in oral premalignant lesions and head and neck squamous cell carcinomas (HNSCCs). This study was conducted to determine whether RAR-β 2 gene expression in such lesions can be silenced by promoter methylation. Experimental Design: RAR-β 2 methylation was analyzed in DNA samples from 22 pairs of primary HNSCC and adjacent normal epithelium, 124 samples of oral leukoplakia, and 18 HNSCC cell lines using methylation-specific PCR. RAR-β 2 promoter was methylated in 67, 56, and 53% of HNSCC tumors, HNSCC cell lines, and microdissected oral leukoplakia specimens, respectively. RAR-β 2 hypermethylation was confirmed by sodium bisulfite-PCR combined with restriction enzyme digestion analysis and by random cloning and sequencing of bisulfite-treated DNA isolates. Results: Significantly higher RAR-β 2 hypermethylation levels were found in tumor tissue compared with adjacent normal tissue ( P = 0.002). RAR-β 2 methylation in the cell lines was correlated with loss of RAR-β 2 expression ( P = 0.013) and inversely related to the presence of mutated p53 ( P = 0.025). The demethylating agent 5-aza-2′-deoxycytidine (5-aza-CdR) restored RAR-β 2 inducibility by all- trans -retinoic acid (ATRA) in some of the cell lines, which posses a methylated RAR-β 2 promoter. In some cell lines, this effect was associated with increased growth inhibition after combined treatment with 5-aza-CdR and ATRA. Conclusions: RAR-β 2 silencing by methylation is an early event in head and neck carcinogenesis; 5-Aza-CdR can restore RAR-β 2 inducibility by ATRA in most cell lines, and the combination of 5-aza-CdR and ATRA is more effective in growth inhibition than single agents.

The influence of resection and aneuploidy on mortality in oral leukoplakia

Abstract: Background Although the standard treatment of oral leukoplakia ranges from watchful waiting to complete resection, the value of these approaches is unknown. Methods We studied the relations among resection, ploidy status, and death from cancer in 103 patients with diploid dysplastic oral leukoplakia, 20 patients with tetraploid lesions, and 27 patients with aneuploid lesions. Data on cancer-specific mortality and treatment were obtained from the Cancer Registry of Norway, Statistics Norway, and chart reviews. Results Primary oral carcinoma developed in 47 of the 150 patients with leukoplakia (31 percent) — 5 with diploid, 16 with tetraploid, and 26 with aneuploid leukoplakia — during a mean follow-up of 80 months (range, 4 to 237). The margin status of the initial leukoplakia resection had no relation to the development of oral cancer (P=0.95). Twenty-six of the 47 patients in whom cancer developed (4 with prior tetraploid and 22 with prior aneuploid lesions) had recurrences (55 percent); the recurrences ...

Randomized, Double-Blind, Placebo-Controlled Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia

Abstract: Purpose: Nonselective cyclooxygenase (COX) inhibitors have been reported to decrease the frequency of upper aerodigestive cancers. Ketorolac tromethamine oral rinse has been shown to resolve another COX-dependent process, periodontal disease, without incurring gastrointestinal side effects. This trial evaluated if a topically delivered oral rinse containing ketorolac was as safe as and more effective than oral rinse alone in reducing the area of oral leukoplakia. Experimental Design: 57 patients were randomized (2:1 ratio) in a double-blind, placebo-controlled study of ketorolac (10 ml of a 0.1% ketorolac rinse solution; n = 38) or placebo (10 ml of rinse solution; n = 19) given twice daily for 30 s over 90 days. Primary end point was evaluated visually obtaining bidimensional measurement of the size of leukoplakia lesion(s) at entry and at 90 days. Secondary end point was histological assessment of the leukoplakia as sampled by serial punch biopsy and independently reviewed by three pathologists. Results: The patients included 67% males, 11% non-Caucasian, and 86% used tobacco with no significant differences between the two arms. Both rinses were well tolerated with good compliance, and there was no significant difference in adverse events ( P = 0.27). Major response rate (complete response and partial response) was 30% for ketorolac and 32% for the placebo arm. There was no significant difference in change in histology between the two arms. Conclusion: Local delivery of a COX-containing oral rinse was well tolerated but produced no significant reduction in the extent of leukoplakia compared with the placebo. However, the favorable response rate to placebo arm remains unexplained and additional investigation of the tissue penetration with ketorolac is warranted.

The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells.

Abstract: Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors have emerged recently as promising chemotherapeutic agents. One such agent, suberoylanilide hydroxamic acid, is a potent inhibitor of HDACs that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. Because of its low toxicity, suberoylanilide hydroxamic acid is currently in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of <2% of genes in cultured cells. In this study, we show that low micromolar concentrations of suberoylanilide hydroxamic acid induce the expression of 15-lipoxygenase-1 in human colorectal cancer cells. The expression of 15-lipoxygenase-1 correlates with suberoylanilide hydroxamic acid-induced increase in 13-S-hydroxyoctadecadienoic acid levels, growth inhibition, differentiation, and apoptosis observed with these cells. Furthermore, specific inhibition of 15-lipoxygenase-1 significantly reduced the suberoylanilide hydroxamic acid-induced effects. These novel findings are the first demonstration of a mechanistic link between the induction of 15-lipoxygenase-1 by a HDAC inhibitor and apoptosis in cancer cells. This result has important implications for the study of suberoylanilide hydroxamic acid and other HDAC inhibitors in the prevention and therapy of colorectal cancer and supports future investigations of the mechanisms by which HDAC inhibitors up-regulate 15-lipoxygenase-1.

Science Peels the Onion of Selenium Effects on Prostate Carcinogenesis

Abstract: The role of the essential trace element selenium in prostate cancer was first (and last) editorialized in the Journal in 1998 in conjunction with the report of the first large prospective observational study of selenium and the risk of advanced prostate cancer (1,2). Although the principals for the 1998 study were the same as those for the observational study by Li et al. (3) in this issue of the Journal, much has changed in the basic scientific understanding of selenium. The onion, an allium vegetable that concentrates selenium, is an apt metaphor for the scientific work of peeling back the layers of molecular effects and mechanisms underlying the strong selenium epidemiology in the prostate. The past 6 years have seen the publication of seven prospective epidemiologic studies of selenium status and prostate cancer (including the study in this issue of the Journal) (2– 8), with a collective total of nearly 2000 case subjects. The studies involved low [Europe (8)], moderate [Maryland (5)], and high [Hawaii (4)] selenium status populations, and all but one found a protective effect associated with higher concentrations of selenium. Furthermore, low plasma selenium levels are associated with increases in other cancers and human diseases (9). Although the findings of the observational studies have been encouraging and consistent regarding the prostate, the most powerful evidence to date for the beneficial effect of selenium is the 49% reduction in prostate cancer incidence in the randomized, placebo-controlled Nutritional Prevention of Cancer (NPC) trial, in which selenium was administered at 200 g/day (10,11). On the basis of the NPC trial, epidemiologic studies, a randomized prevention trial in China of selenium in combination with other minerals and vitamins (12), and early preclinical data (13–17) available in 2000, selenium was included in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in 32 400 men to definitively test the role of supplementation with selenium and/or vitamin E in the prevention of prostate cancer (18). Before addressing the basic science behind the results of these selenium studies, we will highlight two important aspects of the study by Li et al. (3): selenium effects by stage of disease and selenium effects by baseline prostate-specific antigen (PSA) levels. The finding that selenium was associated with a reduced risk of advanced prostate cancer (stage C or D) is consistent with the findings of three of four other epidemiologic studies (2– 4) that assessed this variable and supports the hypothesis of Li et al.—that selenium affects tumor progression rather than premalignancy. This finding also is consistent with the observation that selenium was associated with a greater reduction in risk for men with PSA levels of greater than 4 ng/mL than for men with PSA levels of 4 ng/mL or less. These stage and PSA associations seemingly are at odds, however, with the NPC findings that the protection conferred by selenium was largely due to reduced local disease and was limited almost exclusively to men with PSA levels of 4 ng/mL or less (11). The discrepancy between the results of Li et al. (3) and those of the NPC may be due, in part, to differences in study designs (i.e., observation versus intervention) and to enormous differences in the doses and durations of

Differential Peroxisome Proliferator-Activated Receptor-γ Isoform Expression and Agonist Effects in Normal and Malignant Prostate Cells

Abstract: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is being studied intensively for its role in carcinogenesis and in mediating the effects of prostate cancer treatment and prevention drugs. Prostate cancers express abundant and higher constitutive levels of PPAR-gamma than do normal prostate cells and are growth inhibited by ligand activation of PPAR-gamma. However, little is known about the role of PPARs in tumorigenesis or in normal prostate epithelial cells (EC). We examined the expression, phosphorylation patterns, and functions of the human PPAR (hPPAR)-gamma1 and hPPAR-gamma2 isoforms in normal prostate ECs to determine if activation of the receptor is sufficient for PPAR-gamma ligand activity in prostate cells. We found that ECs did not express either PPAR-gamma1 or PPAR-gamma2 protein and were not sensitive to growth inhibition by the PPAR-gamma ligand 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)). In contrast, prostate cancer cells (PC-3), which express PPAR-gamma1 receptor isoform, are growth inhibited by PPAR-gamma ligand. Forced expression of hPPAR-gamma1 or hPPAR-gamma2 made ECs sensitive to 15d-PGJ(2) and led to reduced cellular viability. The direct repeat-1 promoter containing PPAR response elements was transactivated in ECs expressing exogenous PPAR-gamma1 or PPAR-gamma2, indicating that either isoform can be active in these cells. 15-Lipoxygenase-2, expressed at high levels in ECs, was down-regulated by transfecting PPAR-gamma expression construct (either gamma1 or gamma2 isoform) into ECs. Addition of PPAR-gamma ligand 15-hydroxyeicosatetraenoic acid in the presence of PPAR-gamma expression caused further down-regulation of 15-lipoxygenase-2. Our data illustrate that a PPAR-gamma ligand (15d-PGJ(2)) activates PPAR-gamma1 and selectively induces cell death in human prostate cancer cells but not in normal prostate ECs. These findings have important implications for the development of PPAR-gamma-targeting agents that prevent or treat prostate cancer and spare normal prostate cells.

Peroxisome Proliferator-Activated Receptor-γ Suppresses Cyclooxygenase-2 Expression in Human Prostate Cells

Abstract: Recent studies have found that cyclooxygenase-2 (COX-2) protein expression was low and inducible with cytokines in prostate cancer cells (in the absence of serum) and that, in contrast, COX-2 expression was high in normal prostate epithelial cells (EC). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) was expressed at high levels in the prostate cancer cell line PC-3 but not in ECs. In contrast to previous findings by others, PPAR-gamma ligands did not induce PPAR-gamma expression in EC or PC-3. The present study examined the relationship between PPAR-gamma and COX-2 expression patterns in EC and PC-3 in the presence and absence of serum and/or the PPAR-gamma agonist 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)). We also evaluated the effects that the forced expression of PPAR-gamma1 and PPAR-gamma2 had on COX-2 in ECs. We found that expression of PPAR-gamma and COX-2 protein was inversely correlated in ECs and PC-3. Low COX-2 expression in PC-3 was up-regulated by serum, and 15d-PGJ(2) blocked serum-induced COX-2 expression and activity in a dose-dependent manner. 15d-PGJ(2) had no effect on COX-2 expression in ECs or PPAR-gamma expression in either cell type. However, forced expression of PPAR-gamma1 or PPAR-gamma2 in ECs suppressed the high level of endogenous COX-2. This effect was not isoform specific and was augmented by 15d-PGJ(2). The present study showed that PPAR-gamma activation can be an important regulator of COX-2 in prostate cells and may be an important target for prostate cancer chemoprevention.

Can Selenium Prevent Colorectal Cancer? A Signpost From Epidemiology

Abstract: The limited epidemiology published heretofore on associations between selenium and colorectal adenomas or cancer has been mixed, inconclusive, and based predominantly on small studies. The epidemiology studies have been about evenly split between those showing a statistically significant (1–5) or suggestive (6,7) protective association and those showing a null (8–11) or suggestive harmful (12,13) association between selenium and colorectal adenomas or cancer. The strongest (and only clinical) previous support for a possible protective effect of selenium intake came from a large, randomized controlled trial of selenium in preventing nonmelanoma skin cancer (14). This trial showed a statistically significant reduction of colorectal cancer as a secondary endpoint (relative risk [RR] 0.58, 95% confidence interval [CI] 0.18 to 0.95) that attenuated after longer follow-up (RR 0.45, 95% CI 0.19 to 1.08) (15). A marginally statistically significant overall reduction in colorectal adenomas, which became stronger in association with the lowest tertile of baseline selenium, was also observed again, as a secondary endpoint in the trial (16). In this issue of the Journal, Jacobs et al. report their pooled analysis of three randomized clinical trials of dietary or nutrient interventions in preventing colorectal adenomas (17). Individuallevel data from each of the Wheat Bran Fiber (WBF) Trial (18), the Polyp Prevention Trial (PPT) (19), and the Polyp Prevention Study (PPS) (20) were statistically reanalyzed to provide a more precise estimate of the association between plasma selenium concentration and adenoma risk than would be possible from any of the three studies alone. None of the trials tested selenium as an intervention. This pooled analysis, the largest epidemiologic investigation of the role of selenium in preventing colorectal neoplasia, indicates that individuals in the highest quartile of plasma selenium concentration (median 150 ng/mL) (plasma collected at enrollment for PPT and PPS and 1 year after randomization for WBF) had 34% lower odds (OR 0.66, 95% CI 0.50 to 0.87, Ptrend .006) of developing a new adenoma throughout the follow-up, compared with those in the lowest quartile of plasma selenium (median 113 ng/mL). Plasma selenium concentrations were not statistically significantly associated with adenoma size, location, or histology in the pooled analysis. There was a trend, however, of fewer advanced adenomas ( 1 cm in diameter and/or villous histology) in persons within the highest quartile of plasma selenium. This suggestion of activity in higher–cancer risk, advanced adenomas supports the promise of selenium for reducing colorectal cancer risk. The association of selenium with colorectal cancer development (and mortality) will be assessed as a prespecified secondary endpoint of the Selenium and Vitamin E [prostate] Cancer Prevention Trial (SELECT) currently under way in more than 35 000 men (21). Although the three source studies were mutually independent and executed prior to the pooling project, they had similar designs and outcomes that strengthened the pooled analysis. All participants were at high adenoma risk after recent colonoscopic adenoma resection; each of the three trials assessed colorectal adenoma endpoints in over 85% of its patients, at year 1 and either year 3 (WBF) or year 4 (PPT and PPS) after randomization; and each intervention did not statistically significantly alter the adenoma risk. The pooled analysis also had limitations, however, which were adequately discussed by the authors and included the possibility that some events (new adenomas) detected at year 1 were not actual events but preexisting adenomas missed at the index colonoscopy, varied blood collection times, and different methodologies used to determine plasma selenium concentrations. The biologic plausibility of the pooled analysis and earlier secondary clinical data is provided by consistent animal studies showing the activity of selenium in colorectal neoplasia (22–28) and by other data that address relevant selenium mechanisms. Selenium has effects on key cellular events of tumorigenesis, such as cell proliferation and apoptosis, and the possible complex mechanisms underlying these effects are emerging in increasing numbers (28–30). Important relevant selenium mechanisms may involve gene promoter methylation and polyunsaturated fatty acid metabolism. Cancer cells commonly have aberrant methylation patterns characterized by global hypomethylation coupled with hypermethylation of CpG islands that appear to contribute importantly to tumorigenesis (31). The enzyme DNA cytosine methyltransferase 1 (DNMT1) is increased in tumor progression in association with regional hypermethylation (31). Preclinical studies suggest that selenium inhibits DNMT1 in various cell lines, including the HCT116 and HT-29 human colonic carcinoma cell lines (22,32–34). Oxidative metabolism of the n-6 polyunsaturated fatty acids arachidonic and linoleic acids contributes importantly to colonic tumorigenesis (35), and current data suggest that selenium and arachidonic and linoleic acid metabolism are linked in colonic tumorigenesis. Selenomethionine inhibited growth in four hu-

Cancer prevention and the American Society of Clinical Oncology.

Abstract: Scott M. Lippman and Bernard Levin, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Dean E. Brenner, University of Michigan, Ann Arbor, MI; Gary B. Gordon, Abbott Laboratories, Abbott Park, IL; Carolyn R. Aldige, Cancer Prevention and Research Foundation of America, Alexandria, VA; Barnett S. Kramer, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; Ernest Hawk, National Cancer Institute, Department of Health and Human Services, Bethesda, MD; Patricia A. Ganz, UCLA Schools of Medicine and Public Health, Los Angeles, CA; Mark R. Somerfield, American Society of Clinical Oncology, Alexandria, VA. These authors collaborated on this article as a Writing Committee of the ASCO Cancer Prevention Committee.

Human telomerase reverse transcriptase mRNA is highly expressed in normal breast tissues and down-regulated in ductal carcinoma in situ.

Abstract: Telomerase is a ribonuclear protein that maintains telomere length in eukaryotic cells. Activation of the human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, has been implicated in cellular immortalization and may play a critical role in carcinogenesis. Prior studies in DCIS have been small, and used polymerase chain reaction (PCR)-based methods on heterogeneous tissue extracts. In this study, we used in situ hybridization to determine the cell type and topographic expression pattern of hTERT mRNA in a large series of cased in normal breast ductal-lobular units and ductal carcinoma in situ (DCIS). A total of 120 breast samples were evaluated. High level of hTERT mRNA expression was observed in both normal breast ductal-lobular units and DCIS, which showed a very heterogeneous expression pattern. Overall, hTERT mRNA expression was significantly higher in normal cells compared to DCIS (p=0.000). These results suggest that hTERT not only plays an important role in breast cancer progression but it is also involved in regulating the cellular function of normal breast ductal-lobular units. This finding challenges the conventional view that hTERT mRNA expression is repressed in somatic cells but activated in neoplastic cells. Our results also suggest that telomerase reverse transcriptase mRNA expression may play an important role in the homeostasis of normal breast epithelial cells and neoplastic cells do not necessarily have increased level of expression of hTERT.

Prognostic factors in early stage head and neck squamous cell carcinoma (HNSCC) patients in a prospective clinical trial

Abstract: 5515 Background: HNSCC is the 5th most common cancer in the United States. A majority abuse tobacco which leads to higher relapse rates and second primary tumors (SPT). Methods: We reported results of a randomized chemoprevention study (FRK ASCO 2003) in which pts received isotretinoin or placebo. This analysis focuses on the placebo group and prognostic characteristics related to prior therapy, site of disease, stage, and smoking status. Results: From 1991 to 1999, 600 pts were enrolled into the placebo arm: stage I (n=389), II (211); primary tumor of larynx (L; 343), oral cavity (OC; 187), pharynx (P; 70); prior therapy of radiation (RT; 353), surgery (S; 158), both (86); and smoking status of current (220), former (296), never (84). The median follow-up is 6 years and 5-year survival is 0.83 (0.80, 0.87). We compared the above pts in statistical models to identify prognostic markers, which may impact recurrence, smoking-related (sm) SPT development, disease-free (DFS), and overall survival (OS). Smokin...