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S M Lippman

Publications and source records attributed to S M Lippman.

At least 19 recordsLinked to original sources
PubMed2006

15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor gamma.

An inverse relationship exists between the expression of 15-lipoxygenase-2 (15-LOX-2) and peroxisome proliferator-activated receptor gamma (PPARgamma) in normal prostate epithelial cells (PrECs) compared with their expression in prostate carcinoma cells (PC-3). The reason for this difference, however, is unknown. We hypothesized that this inverse expression partly involves the 15-LOX-2 promoter and 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), a product of 15-LOX-2 that binds to PPARgamma. We identified an active steroid nuclear receptor half-site present in the 15-LOX-2 promoter fragment F-5 (-618/+177) that can interact with PPARgamma. After forced expression of wild-type PPARgamma, 15-(S)-HETE (1 microM) decreased F-5 reporter activity in PrECs whereas forced expression of 15-LOX-2 resulted in 15-(S)-HETE production which enhanced F-5 activity in PC-3. In contrast, the expression of dominant-negative PPARgamma reversed the transcriptional activation of F-5 by enhancing it 202-fold in PrEC or suppressing it in PC-3; the effect in PC-3 was positively increased 150-fold in the presence of 15-(S)-HETE (1 microM). Peroxisome proliferator-activated receptor gamma interacted with 15-LOX-2 promoter sequences in pulldown experiments using biotinylated 15-LOX-2 (-560/-596 bp) oligonucleotides. In gelshift analyses PPARgamma and orphan receptor RORalpha were shown to interact with the F-5 fragment in PC-3 cells. These data suggest that crosstalk mechanisms exist between the 15-LOX-2 gene and PPARgamma to counterbalance expression and help explain the inverse relationship of these genes in normal versus cancer cells.

5' Untranslated Regions↗
PubMed2006

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta (PPAR-b/d) overexpression suppresses the activity of PPAR-gamma (PPAR-g) and PPAR-alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-b/d-null cells, and it is not known whether an interaction between PPAR-b/d and PPAR-g exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-b/d. We tested (a) whether PPAR-b/d expression modulates PPAR-g activity in experimental models of the loss and gain of PPAR-b/d function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-b/d and PPAR-g. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-g activity, (b) PPAR-b/d expression suppressed PPAR-g activity in models of both loss and gain of PPAR-b/d function, (c) 15-LOX-1 activated PPAR-g by downregulating PPAR-b/d, and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-b/d suppression of PPAR-g. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-b/d and PPAR-g.

Adenoviridae↗
PubMed2002

Clinical and economic impact of multiple gated acquisition scan monitoring during anthracycline therapy.

The clinical and economic impacts of monitoring cardiac function in patients given doxorubicin have yet to be determined, especially in relation to patient age, cumulative doxorubicin dose, and the relative efficacies of doxorubicin-based vs alternative regimens. We developed a decision analysis model that includes these factors to estimate the incremental survival benefit and cost-effectiveness of using multiple gated acquisition scans to measure left-ventricular ejection fraction before and during doxorubicin chemotherapy. Probability distributions for the incidences of abnormal left-ventricular ejection fraction findings and congestive heart failure were derived from a retrospective review of 227 consecutive cases at The University of Michigan Medical Center and published findings. Multiple gated acquisition-scan monitoring minimally improved the probability of 5-year survival (<1.5% in the base--case scenario). For patients who received up to 350 mg m(-2) of doxorubicin, multiple gated acquisition-scan screening had an incremental cost of $425 402 per life saved for patients between the ages of 15--39. This incremental cost markedly decreased to $138 191, for patients between the ages of 40--59, and to $86 829 for patients older than 60 years. The small gain in 5-year survival probability secondary to multiple gated acquisition scan monitoring doubled for all age groups when the average cumulative dose for doxorubicin reached 500 mg m(-2). Variations in the cure rate differences between the doxorubicin and alternative regimens had insignificant effects on the improvement in 5-year survival rates from multiple gated acquisition-scan screening. The use of multiple gated acquisition scans for pretreatment screening appears to be more cost-effective for patients who are 40 years or older, when cumulative doxorubicin dose is 350 mg m(-2) or less.

Adolescent↗
PubMed2001

Lung cancer chemoprevention: an integrated approach.

Lung cancer is the leading cause of cancer deaths in the United States and the world, with grim incidence and mortality figures underscoring the need for new approaches, such as chemoprevention, for controlling this disease. There have been definitive, randomized, controlled lung-cancer chemoprevention trials in the three chemoprevention trial settings: primary (healthy high-risk [eg, smokers]), secondary (premalignant lesions), and tertiary (prevention of second primary tumors in previously treated patients), all of which produced negative (either neutral or harmful) primary end point results. These trials established that lung cancer was not prevented by alpha-tocopherol, beta-carotene, retinol, retinyl palmitate, N-acetylcysteine, or isotretinoin in smokers. Provocative leads of the definitive trials include the possible activity of isotretinoin in never and former smokers and that of alpha-tocopherol in prostate cancer prevention. A major area of lung cancer research is molecular epidemiologic study of highest smoking-related risk based on the interactions between tobacco carcinogens, genetic polymorphisms involved in activating and detoxifying these carcinogens, and host-cell efficiency in monitoring and repairing tobacco carcinogen-DNA damage. The future of lung cancer chemoprevention will rely heavily on molecular studies of carcinogenesis and drug mechanisms to develop novel chemopreventive targets and drugs, risk markers, and surrogate end point biomarkers; new preclinical drug-testing models; novel imaging techniques for monitoring agent activity; and molecular epidemiologic risk models for identifying the highest-risk current and former smokers.

Carcinogens↗
PubMed2001

Lipoxygenase modulation to reverse carcinogenesis.

New studies of the relationship between polyunsaturated fatty acid metabolismand carcinogenesis have led to novel molecular targets for cancer chemoprevention research. These targets include procarcinogenic lipoxygenases (LOXs), including 5-, 8-, and 12-LOX, and anticarcinogenic LOXs, including 15-LOX-1 and possibly 15-LOX-2. Recent studies indicate that 15-LOX-1 is down-regulated in colorectal cancer cells and that the ability of nonsteroidal anti-inflammatory drugs, a class of clinically active cancer chemopreventive agents, to induce apoptosis and growth inhibition in these cells was dependent on the induction of 15-LOX-1 and its metabolic product 13-S-hydroxyoctadecadienoic acid. Consistent with the colorectal studies, 15-LOX very recently has shown anticarcinogenic activity in esophageal and prostatic carcinogenesis. Inhibitors of other LOXs (e.g., 5-LOX) have preclinical anticarcinogenic activity and are being developed for clinical chemoprevention study. These and other LOX data led us to propose that the various LOX pathways exist in a dynamic balance that shifts during carcinogenesis toward 5-, 8-, and 12-LOX (and cyclooxygenase-2) and away from 15-LOX. A novel approach for cancer chemoprevention would involve LOX modulators, i.e., agents that can induce the anticarcinogenic and/or inhibit the procarcinogenic LOXs, thereby shifting the balance of LOX activities from procarcinogenic to anticarcinogenic metabolism of polyunsaturated fatty acids.

Animals↗
PubMed2001

Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial.

PURPOSE: Retinoids and interferons (IFNs) have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites. Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. We designed the present phase II adjuvant trial to prevent recurrence or second primary tumors (SPTs) using 13-cRA, IFN-alpha, and alpha-tocopherol in locally advanced-stage head and neck cancer. PATIENTS AND METHODS: After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m(2)/d, orally, daily), IFN-alpha (3 x 10(6) IU/m(2), subcutaneous injection, three times a week), and alpha-tocopherol (1,200 IU/d, orally, daily) for 12 months, with a dose modification. Screening for recurrence or SPTs was performed every 3 months. RESULTS: Tumors of 11 (24%) of the 45 treated patients were stage III, and 34 (76%) were stage IV. Thirty-eight (86%) of 44 patients completed the full 12-month treatment (doses modified as needed). Toxicity generally was consistent with previous IFN and 13-cRA reports and included mild to moderate mucocutaneous and flu-like symptoms; occasional significant fatigue (grade 3 in 7% of patients), mild to moderate hypertriglyceridemia in 30% of patients who continued treatment along with antilipid therapy, and mild hematologic side effects. Six patients did not complete the planned treatment because of intolerable toxicity or social problems. At a median 24-months of follow-up, our clinical end point rates were 9% for local/regional recurrence (four patients), 5% for local/regional recurrence and distant metastases (two patients), and 2% for SPT (one patient), which was acute promyelocytic leukemia (ie, not of the upper aerodigestive tract). Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively. CONCLUSION: The novel biologic agent combination of IFN-alpha, 13-cRA, and alpha-tocopherol was generally well tolerated and promising as adjuvant therapy for locally advanced squamous cell carcinoma of the head and neck. We are currently conducting a phase III randomized study of this combination (v no treatment) to confirm these phase II study results.

Adult↗
PubMed2001

Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression.

In previous studies, we have found that expression of 15-lipoxygenase-1 (15-LOX-1) and its main product, 13-S-hydroxyoctadecadienoic acid, are decreased in human colorectal cancers and that nonsteroidal anti-inflammatory drugs (NSAIDs) can therapeutically induce 15-LOX-1 expression to trigger apoptosis in human colorectal cancer cells. NSAIDs similarly induce apoptosis in esophageal cancer cells, although the mechanisms of these effects remain to be defined. In the present study, we tested whether 15-LOX-1 is down-regulated in human esophageal cancers using paired normal and tumor human surgical samples and whether NSAIDs can up-regulate 15-LOX-1 to restore apoptosis in esophageal cancer cells. We found that: (a) 15-LOX-1 was down-regulated in human esophageal carcinomas; (b) NSAIDs induced 15-LOX-1 expression during apoptosis in esophageal cancer cells; and (c) 15-LOX-1 inhibition suppressed NSAID-induced apoptosis, which was restored by 13-S-hydroxyoctadecadienoic acid but not by its parent compound, linoleic acid. These findings demonstrate that 15-LOX-1 is down-regulated in human esophageal carcinomas and that NSAIDs induce apoptosis in esophageal cancer cells via up-regulation of 15-LOX-1. They also support the concept that the loss of the proapoptotic role of 15-LOX-1 in epithelial cancers is not limited to human colorectal cancers.

Adenocarcinoma↗
PubMed2001

Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis.

Retinoids are essential for normal skin growth, differentiation, and apoptosis and are active pharmacologically in the prevention and treatment of skin cancers and other lesions. Retinoid effects are mediated mainly by retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which act as transcription factors to alter gene expression. Using in situ hybridization, we analyzed the expression of RARs and RXRs in normal sun-exposed skin (n = 85), squamous cell carcinoma (SCC; n = 28), and actinic keratosis [AK (a precursor to SCC); n = 38]. The expressions of five receptors (RAR-alpha and -gamma and RXR-alpha, -beta, and -gamma) were moderate to very strong in normal skin, with higher expressions in spinous and granular layers than in the basal layer. RAR-beta expression was weak or absent in normal and lesion samples. All five receptors expressed in the skin were suppressed progressively from normal skin to premalignant skin (AK) to invasive skin SCC. Specific receptor decreases in lesions relative to normal skin ranged from 75% (RXR-beta) to 96% (RAR-alpha) in SCC and from 37% (RAR-gamma) to 68% (RXR-beta) in AK. The degree of suppression of RXR-alpha and RAR-gamma, the two predominant retinoid receptors in skin, was relatively less for RXR-alpha (58% versus 86%; P = 0.015) and relatively greater for RAR-gamma (37% versus 89%; P = 0.0001) between AK and SCC, suggesting that suppression of RXR-alpha may be an earlier event and expression of RAR-gamma may be a later event of multistep squamous skin carcinogenesis. Our results indicate that suppressed expression of retinoid receptors occurs early (in AK) and is associated with progression of squamous skin carcinogenesis to SCC.

Aged↗
PubMed2001

Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer.

BACKGROUND: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. METHODS: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. CONCLUSIONS: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

Adult↗
PubMed2001

Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: In the current study the authors assessed the antitumor activity (including response rate, duration of response, and survival) and toxicity profile (including anorexia, fatigue, emesis, and peripheral neuropathy) of a combination of paclitaxel, ifosfamide, and carboplatin (TIC) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). The trial hypothesis was that the TIC therapeutic index would be as high as that of paclitaxel, ifosfamide, and cisplatin (TIP) in this setting, but with less toxicity. METHODS: Patients with recurrent or metastatic SCCHN were treated with 175 mg/m(2) of paclitaxel as a 3-hour infusion on Day 1, 1000 mg/m(2) of ifosfamide as a 2-hour infusion on Days 1-3, 600 mg/m(2) of mesna on Days 1-3, and carboplatin (area under the concentration-time curve of 6) as a 30-minute infusion on Day 1; the regimen was repeated every 3-4 weeks. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine before paclitaxel infusion. Prophylactic hematopoietic growth factors were not given. RESULTS: Among 56 patients entered onto the study, 55 patients were analyzed for survival rates (locoregional recurrence alone in 56% of patients and distant metastasis with or without locoregional recurrence in 44% of patients). Fifty-four patients were evaluable for tumor response and toxicity. A total of 32 patients (59%) had disease that responded to treatment; the complete response rate was 17% (9 of 54 patients). The median duration of the responses was 3.7 months (95% confidence interval [95% CI], 3.4-7.8 months) and that of complete responses was 9.7 months (95% CI, 7.4 months to date of last follow-up). The median duration of follow-up care in all patients was 13.5 months. The median survival time for all patients was 9.1 months (95% CI, 7.9-12.2 months). The regimen was well tolerated. Neutropenic fever developed in 30% of the patients; 1 patient died of neutropenia and sepsis. Other toxic effects included Grade 2-3 anorexia in 13% of patients, Grade 2-3 weight loss in 11% of patients, Grade 2-3 fatigue in 27% of patients, Grade 2-3 nausea/emesis in 13% of patients, and Grade 2-3 peripheral neuropathy in 9% of patients (toxicity grading based on the National Cancer Institute's Common Toxicity Criteria). Red blood cell and platelet transfusions were required in 13% and 7% of patients, respectively. CONCLUSIONS: The TIC regimen had high antitumor activity in patients with recurrent or metastatic SCCHN, with a 59% major response rate (17% complete response rate with relatively durable complete responses). Neutropenic fever developed in 30% of the patients, the incidence of which might have been decreased by prophylactic antibiotics or hematopoietic growth factor support. Other toxic effects included significantly lower rates and less severe instances of anorexia, emesis, fatigue, and peripheral neuropathy than those reported with the previously studied TIP regimen. The TIC regimen currently is being studied as an induction chemotherapy regimen in previously untreated patients with locally advanced SCCHN. The activity of TIC (a novel paclitaxel and ifosfamide-based regimen) in patients with recurrent or metastatic SCCHN should be confirmed in a Phase III randomized trial.

Adult↗
PubMed2001

Differential expression of cyclooxygenase-2 and its regulation by tumor necrosis factor-alpha in normal and malignant prostate cells.

Cyclooxygenase (COX)-2 expression is elevated in some malignancies; however, information is scarce regarding COX-2 contributions to the development of prostate cancer and its regulation by inflammatory cytokines. The present study compared and contrasted the expression levels and subcellular distribution patterns of COX-1 and COX-2 in normal prostate [prostate epithelial cell (PrEC), prostate smooth muscle (PrSM), and prostate stromal (PrSt)] primary cell cultures and prostatic carcinoma cell lines (PC-3, LNCaP, and DU145). The basal COX-2 mRNA and protein levels were high in normal PrEC and low in tumor cells, unlike many other normal cells and tumor cells. Because COX-2 levels were low in prostate smooth muscle cells, prostate stromal cells, and tumor cells, we also examined whether COX-1 and COX-2 gene expression was elevated in response to tumor necrosis factor-alpha (TNF-alpha), a strong inducer of COX-2 expression. Northern blot analysis and reverse transcription-PCR demonstrated different patterns and kinetics of expression for COX-1 and COX-2 among normal cells and tumor cells in response to TNF-alpha. In particular, COX-2 protein levels increased, and the subcellular distribution formed a distinct perinuclear ring in the normal cells at 4 h after TNF-alpha exposure. The COX-2 protein levels also increased in cancer cells, but the subcellular distribution was less organized; COX-2 protein appeared diffuse in some cells and accumulated as focal deposits in the cytoplasm of other cells. TNF-alpha induction of COX-2 and prostaglandin E2 correlated inversely with induction of apoptosis. We conclude that COX-2 expression may be important to PrEC cell function. Although it is low in stromal and tumor cells, COX-2 expression is induced by TNF-alpha in these cells, and this responsiveness may play an important role in prostate cancer progression.

Apoptosis↗
PubMed2001

The role of neck dissection after chemoradiotherapy for oropharyngeal cancer with advanced nodal disease.

OBJECTIVE: To analyze and compare the effectiveness of sequential platinum-based chemotherapy and radiotherapy with and without selective neck dissection in patients with N2a and greater stage node-positive squamous cell carcinoma of the oropharynx. DESIGN: Nonrandomized controlled trial. SETTING: Tertiary referral center. PATIENTS: Sixty-six patients with squamous cell carcinoma of the oropharynx staged N2a or greater. INTERVENTIONS: Platinum-based induction chemotherapy followed by definitive radiation therapy; and selective neck dissections 6 to 10 weeks following the completion of radiation therapy in patients with radiographic evidence suggesting residual neck disease. MAIN OUTCOME MEASURES: Locoregional recurrence and disease-free survival. RESULTS: Of 66 patients, 24 (36%) had complete responses in the primary local tumor (oropharynx) and regional disease (neck nodes), as assessed clinically and radiographically. These patients had lower rates of locoregional recurrence than did patients showing no or partial responses, but the differences were not significant (P>.05). Of 18 patients undergoing neck dissection, 10 (56%) had pathological evidence of residual tumor. Patients showing a complete response of regional and neck disease had significantly improved disease-specific and overall survival (P = .01 for both) compared with patients showing no or partial responses of their neck disease. Patients with no or partial responses who underwent neck dissections had significantly improved overall survival compared with similar patients who did not undergo neck dissections (P = .002). CONCLUSIONS: Even in patients with bulky nodal disease, a complete response in the neck to sequential chemotherapy and radiotherapy may indicate that neck surgery is not necessary for good locoregional control and improved disease-free survival. Neck dissection is recommended for patients with no or partial radiographic responses.

Adult↗
PubMed2001

SELECT: the next prostate cancer prevention trial. Selenum and Vitamin E Cancer Prevention Trial.

PURPOSE: Growing evidence implies that selenium and vitamin E may decrease the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a randomized prospective double-blind study designed to determine whether selenium and vitamin E decrease the risk of prostate cancer in healthy men. MATERIALS AND METHODS: The preclinical and epidemiological evidence regarding chemoprevention with selenium and vitamin E were reviewed. Secondary analyses from randomized trials of the 2 agents were included in the current analysis. Data from these analyses as well as evidence from the Prostate Cancer Prevention Trial were used to develop the SELECT schema. RESULTS: Preclinical, epidemiological and phase III data imply that selenium and vitamin E have potential efficacy for prostate cancer prevention. The experience of the Prostate Cancer Prevention Trial shows the interest and dedication of healthy men to long-term studies of cancer prevention. A total of 32,400 men are planned to be randomized in SELECT. CONCLUSIONS: SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment in the study is planned to begin in 2001 with final results anticipated in 2013.

Double-Blind Method↗
PubMed2001

Executive Summary of the National Cancer Institute Workshop: Highlights and recommendations.

Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.

Anticarcinogenic Agents↗
PubMed2001

Design considerations for efficient prostate cancer chemoprevention trials.

Prostate cancer, even with its substantial public health impact of 180,400 new cases and 31,900 deaths estimated for 2000, still has a very low annual incidence (0.27% for men 34.4 years and older), which makes designing and conducting efficient prostate cancer prevention trials a challenge. Definitive prevention trials with cancer endpoints, such as the Breast Cancer Prevention Trial (BCPT), Prostate Cancer Prevention Trial (PCPT), and Selenium and Vitamin E Cancer Prevention Trial (SELECT), require long trial duration (up to 12 years) and large sample size (up to 32,400 subjects) to accomplish their objectives. This article discusses design concepts for potential prostate cancer prevention trials that require fewer years, subjects, and resources to complete. Design elements, such as high-risk populations, randomization, surrogate endpoints, including quality-of-life endpoints, masking/blinding, and various clinical/statistical designs (including 1-way layout, all-versus-none, factorial, and adaptive designs), are discussed, along with the ultimate goal of gaining US Food and Drug Administration approval for prostate-cancer preventive agents that can improve public health by reducing prostate cancer incidence and mortality.

Anticarcinogenic Agents↗
PubMed2001

Molecular epidemiologic studies within the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

OBJECTIVE: To conduct timely epidemiologic investigations of molecular/genetic markers that may contribute to the development of prostate, lung, colorectal, or other cancers within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), and to evaluate interactions between these markers and the study interventions. METHODS: The epidemiologic studies within SELECT will be based on 32,400 men aged 55 years or older (age 50 or older for the African-American men) enrolled into an intergroup, randomized, placebo-controlled, double-blind, phase III prevention trial of supplemental selenium and vitamin E developed and funded by the National Cancer Institute, and coordinated by the Southwest Oncology Group. During the 12-year study period approximately 1500-2000 cases of prostate cancer, 800 lung cancers, and 500 colon cancers are estimated to be diagnosed, based on data from the ongoing Prostate Cancer Prevention Trial of finasteride. A modified fasting blood sample will be processed to collect plasma for analysis of micronutrients, hormones, cytokines, and other proteins. Buffy-coat derived white blood cells collected at baseline will be used for isolation of DNA and establishment of immortalized cell lines. Red blood cells will be stored for analysis of hemoglobin adducts and other components. RESULTS: Specific results anticipated from these molecular studies will provide information on factors hypothesized to contribute to prostate cancer risk and that may modify the efficacy of either trial supplement, including: steroid sex hormones and several polymorphic genes that encode proteins affecting androgenic stimulation of the prostate, including the androgen receptor, steroid 5alpha-reductase type II, CYP17, and beta-hydroxysteroid dehydrogenase; polymorphisms of DNA repair genes and carcinogen metabolism genes, including those involved in the activation of chemical carcinogens to reactive intermediates (e.g., CYP1A1) or the detoxification of reactive intermediates (e.g., glutathione S-transferase M1); DNA and protein adducts; and insulin-like growth factors and leptin. CONCLUSION: SELECT offers an excellent opportunity to conduct molecular epidemiologic investigations to assess gene-environment interactions and their role in prostate, lung, and colon carcinogenesis.

Colorectal Neoplasms↗