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Ronald Lieberman
American journal of therapeutics 10/2009; 16(6):477-9.
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Anne R Simoneau,
Eugene W Gerner,
Ray Nagle,
Argyrios Ziogas,
Sharon Fujikawa-Brooks,
Hagit Yerushalmi,
Thomas E Ahlering, Ronald Lieberman,
Christine E McLaren,
Hoda Anton-Culver,
Frank L Meyskens
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ABSTRACT: Prostate cancer is a major health issue, and prevention of prostate cancer and/or its progression will yield benefits for men. Difluoromethylornithine (DFMO) is an antiproliferative agent, inhibiting ornithine decarboxylase, the first enzyme in the polyamine pathway, and has been studied as a therapeutic and chemopreventive agent. The prostate has high levels of tissue polyamines and has shown sensitivity to DFMO both in vitro and in vivo.
Eighty-one men participated in a 1-year randomized trial of placebo or DFMO. Prostate volume determination and biopsy of the prostate for histology and polyamine content were done at baseline and after 12 months. Other biomarker variables were assessed, including total and free prostate-specific antigen and prostate-specific antigen doubling time.
Compared with baseline, men receiving DFMO had a smaller increase in prostate volume (0.14 cm(3)) than those on placebo (2.95 cm(3); P = 0.0301) at 1 year. In addition, DFMO caused a 60.8% reduction of prostate putrescine levels compared with a 139.5% increase in the placebo arm (P = 0.0014). Stratification by ornithine decarboxylase genotype showed that DFMO reduced prostate volume (P = 0.029) and putrescine levels (P = 0.0053) in the AA + GA group but not in the GG group. There were no grade 3 or 4 toxicities. There was no clinical ototoxicity, with one subclinical grade 2 hearing decline on audiogram.
In this randomized placebo-controlled trial, DFMO induced a decrease of prostate putrescine levels and rate of prostate growth. The potential of this compound for prostate cancer or hyperplasia should be further studied.
Cancer Epidemiology Biomarkers & Prevention 03/2008; 17(2):292-9. · 4.12 Impact Factor
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James R Marshall,
Wael Sakr,
David Wood,
Donna Berry,
Catherine Tangen,
Felicia Parker,
Ian Thompson,
Scott M Lippman, Ronald Lieberman,
David Alberts,
David Jarrard,
Charles Coltman,
Peter Greenwald,
Lori Minasian,
E David Crawford
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ABSTRACT: High-grade prostatic intraepithelial neoplasia (HGPIN) is generally regarded as a premalignant lesion that progresses toward prostate cancer. In light of the significant sequelae of prostate cancer treatment, prevention is desirable, and men with HGPIN would be suitable, high-risk subjects. There is in vitro, in vivo, epidemiologic, and human experimental evidence that selenium supplementation may protect against prostate cancer. This article introduces the rationale for, and progress to date, of a double-blind, randomized, placebo-controlled trial of selenium supplementation (200 mug/d in the form of selenomethionine), to prevent the development of prostate cancer among men with HGPIN. The trial, Southwest Oncology Group Protocol 9917, funded by a National Cancer Institute program supporting pivotal prevention trials has registered 537 patients and has randomized >380 to date. Subject accrual is expected to be completed by the fall of 2006, with trial completion in 2009.
Cancer Epidemiology Biomarkers & Prevention 08/2006; 15(8):1479-84. · 4.12 Impact Factor
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Philip M Arlen,
James L Gulley,
Nushin Todd, Ronald Lieberman,
Seth M Steinberg,
Steve Morin,
Anne Bastian,
Jennifer Marte,
Kwong-Yok Tsang,
Patricia Beetham,
Douglas W Grosenbach,
Jeffrey Schlom,
William Dahut
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ABSTRACT: There is no current standard treatment for patients with prostate cancer who have received hormonal therapy but have an increasing prostate specific antigen (PSA) without radiographic evidence of metastasis. This trial was designed to analyze toxicity, immunogenicity and time to treatment failure using vaccine, antiandrogen therapy or their sequential use.
A total of 42 patients were randomized to receive vaccine vs antiandrogen therapy with nilutamide. The vaccine consisted of recombinant vaccinia viruses containing the PSA and B7.1 costimulatory genes as prime vaccinations, and avipox-PSA as boosters. After 6 months patients with an increasing PSA and no metastasis may receive a combination of both treatments.
Three patients on nilutamide were removed from study secondary to grade 3 toxicities but no grade 3 toxicities were attributed to vaccine. In the vaccine arm median time to treatment failure was 9.9 months with 13 of 21 decreases in PSA velocity vs 7.6 months with 16 of 21 decreases in PSA velocity in the nilutamide arm (p =0.28). Of the patients in the nilutamide arm 8 had vaccine added at the time of PSA progression. Median time to treatment failure with combined therapy was 5.2 months, with a median duration from study entry of 15.9 months. Of the patients in the vaccine arm 12 had nilutamide added at the time of PSA progression. Median time to treatment failure with combined therapy was 13.9 months and a median of 25.9 months from initiation of therapy.
Further studies are merited to investigate the role of combining vaccine with antiandrogen therapy or vaccine followed by vaccine plus antiandrogen therapy in this patient population.
The Journal of Urology 09/2005; 174(2):539-46. · 3.75 Impact Factor
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Jeri Kim,
Peiyu Sun,
Ying-Wai Lam,
Patricia Troncoso,
Anita L Sabichi,
Richard J Babaian,
Louis L Pisters,
Curtis A Pettaway,
Christopher G Wood,
Scott M Lippman,
Timothy J McDonnell, Ronald Lieberman,
Christopher Logothetis,
Shuk-Mei Ho
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ABSTRACT: Evidence of the chemopreventive effects of the dietary antioxidants alpha-tocopherol (vitamin E) and l-selenomethionine (selenium) comes from secondary analysis of two phase III clinical trials that found treatment with these antioxidants reduced the incidence of prostate cancer. To determine the effects of selenium and vitamin E in blood and prostate tissue, we undertook a preoperative feasibility study complementary to the currently ongoing Selenium and Vitamin E Cancer Prevention Trial.
Forty-eight patients with clinically localized prostate cancer enrolled on this 2 x 2 factorial design study were randomized to take selenium, vitamin E, both, or placebo for 3 to 6 weeks before prostatectomy. Sera were collected from patients before and after dietary supplementation. Thirty-nine patients were evaluable, and 29 age-matched disease-free men served as controls. Mass profiling of lipophilic serum proteins of lower molecular weight (2-13.5 kDa) was conducted, and mass spectra data were analyzed using custom-designed software.
Weighted voting analyses showed a change in sera classification from cancerous to healthy for some patients with prostate cancer after dietary intervention. ANOVA analysis showed significantly different treatment effects on prediction strength changes among the four groups at a 95% confidence level. Eliminating an outlying value and performing post hoc analysis using Fisher's least significant difference method showed that effects in the group treated with the combination were significantly different from those of the other groups.
In sera from patients with prostate cancer, selenium and vitamin E combined induced statistically significant proteomic pattern changes associated with prostate cancer-free status.
Cancer Epidemiology Biomarkers & Prevention 08/2005; 14(7):1697-702. · 4.12 Impact Factor
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ABSTRACT: We describe the current National Cancer Institute chemoprevention agent development program and provide a summary of the intermediate end points used.
The National Cancer Institute is currently sponsoring a wide range of studies of promising chemoprevention agents in a variety of informative cohorts, eg high grade prostatic intraepithelial neoplasia, positive family history of cancer, increased prostate specific antigen with negative biopsies, prostate cancer followed expectantly, prostate cancer awaiting definitive therapy and the general population. The rationale for each agent under investigation is derived from epidemiological observations, prostate cancer treatment trials, secondary analyses of large cancer prevention studies, an understanding of cancer biology and prostate carcinogenesis, and/or experimental animal models.
Carcinogenesis is a multistep process occurring over decades which is characterized by disruption of the normal regulatory pathways controlling cellular proliferation, programmed cell death and differentiation. Administration of agents to reverse, inhibit or slow this process of malignant transformation is known as chemoprevention.
Chemoprevention represents a promising approach to reducing the morbidity and mortality of prostate cancer. A variety of agents are currently being studied in phase 2 clinical trials, some of which may warrant subsequent evaluation in phase 3 trials with definitive cancer end points. Two large phase 3 trials, the Prostate Cancer Prevention Trial and the Selenium and Vitamin E Cancer Prevention Trial, which are ongoing, are also sponsored by the National Cancer Institute.
The Journal of Urology 03/2004; 171(2 Pt 2):S68-74; discussion S75. · 3.75 Impact Factor
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Chris H Takimoto,
Kira Glover,
Xiaoke Huang,
Steven A Hayes,
Lilia Gallot,
Mary Quinn,
Borko D Jovanovic,
Alla Shapiro,
Leticia Hernandez,
Andrew Goetz,
Victor Llorens, Ronald Lieberman,
James A Crowell,
Brett A Poisson,
Raymond C Bergan
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ABSTRACT: Preclinical studies suggest that the isoflavone genistein may have prostate cancer chemopreventive activity. Genistein has been shown to alter cellular levels of protein-tyrosine phosphorylation and is present at high levels in soy. This study was designed to measure the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones, PTI G-2535 and PTI G-4660 (which contain 43% and 90% genistein, respectively), in human subjects with cancer, to evaluate toxicity and obtain pilot data on in vivo effects on protein-tyrosine phosphorylation. Cohorts of four patients were given single doses of each preparation; each dose was separated by 1 week. Sequential cohorts received genistein at 2, 4, or 8 mg/kg orally. Pharmacokinetic sampling was performed after each dose, and tyrosine phosphorylation was measured in proteins extracted from peripheral blood mononuclear cells. One of 13 patients treated developed a treatment-related rash. No other toxicities were observed. Maximal plasma concentrations (C(max)) ranged between 4.3 and 16.3 micro M for total genistein and 0.066 and 0.17 micro M for free genistein. For PTI G-2535 and PTI G-4660, half-life was 15.03 and 22.41 h, respectively, and volume of distribution was 189.9 and 653.8 liters, respectively, and there was a trend toward higher area under the concentration curve for PTI G-2535 (P = 0.07 at the 8 mg/kg dose). Treatment-related increases in tyrosine phosphorylation were observed in peripheral blood mononuclear cells. Oral administration of soy isoflavones gives plasma concentrations of genistein that have been associated with antimetastatic activity in vitro.
Cancer Epidemiology Biomarkers & Prevention 12/2003; 12(11 Pt 1):1213-21. · 4.12 Impact Factor
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Oncology (Williston Park, N.Y.) 09/2003; 17(8):1097-8, 1103-5, 1110-6. · 1.03 Impact Factor
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Ronald Lieberman
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ABSTRACT: Prostate cancer chemoprevention (CP) can be defined as the use of natural and synthetic agents that inhibit, reverse or regress precancer and delay progression to invasive cancer. During the past two decades several CP strategies have evolved. The first generation of CP trials tested the efficacy of antioxidants and vitamins including B-carotene, vitamin A, retinol, 13 cis retinoic acid, vitamins E, C and selenium. Although these trials were disappointing, provocative hypotheses were generated for selenium and vitamin E that set the stage for future prostate trials. In the 1990s, the NCI launched a second generation of large CP trials aimed at breast and prostate cancer. One of these trials is the PCPT, testing the efficacy of a 5 alpha-reductase inhibitor-finasteride to prevent prostate cancer in 18,000 men. Although PCPT is still in progress, the NCI recently launched a second large primary prostate CP trial called SELECT, testing the efficacy of selenium and vitamin E in 32,400 men. The Prostate Cancer Progress Report to the Director of NCI in 1998 challenged the research community to design more efficient CP trials for prostate cancer. In response, the NCI has evolved a third generation of CP trials. This involves pharmacologically driven translational science research including agents and their targets, biomarker endpoints, suitable clinical models for testing agents and efficient trial designs employing high risk cohorts and surrogate endpoints. In summary, a dual strategy for CP is being developed which includes public health measures and a medical intervention approach.
World Journal of Urology 06/2003; 21(1):3-8. · 2.41 Impact Factor
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Ronald Lieberman
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ABSTRACT: Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the future, a selective COX-2 inhibitor may be combined with other agent classes such as proapoptotic antioxidant micronutrients, receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators, IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense enzyme in precursors (HGPIN) and prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and secondary prevention that can be employed in both short-term developmental (translational) trials for proof of biologic activity and in intermediate sized longer-term chemoprevention trials for proof of efficacy against prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.
Cancer and metastasis reviews 02/2002; 21(3-4):297-309. · 10.57 Impact Factor
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Steven R Alberts,
Paul J Novotny,
Jeff A Sloan,
John Danella,
David G Bostwick,
Thomas J Sebo,
Michael L Blute,
Tom R Fitch,
Ralph Levitt, Ronald Lieberman,
Charles L Loprinzi
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ABSTRACT: High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a premalignant change in the prostate that indicates increased risk of the subsequent development of prostate adenocarcinoma. Prior studies have suggested that androgen deprivation therapy causes a regression of HGPIN. We therefore conducted a chemoprevention trial assessing the efficacy of flutamide in reducing the rate of prostate adenocarcinoma development in men with HGPIN. Men with biopsyproven HGPIN but no evidence of prostate adenocarcinoma were randomized in a double-blind manner to either flutamide 250 mg/d or a placebo. Treatment was continued for 1 year. Repeat biopsies were obtained at 12 and 24 months. Quality of life and toxicities related to treatment were also measured. Sixty patients were randomized and began therapy with either flutamide or placebo. At 1 year, 14% of men receiving flutamide and 10% of men receiving placebo had developed prostate adenocarcinoma. Flutamide-associated toxicities were mild to moderate in severity. Quality-of-life measures did not show any differences between the 2 groups. This study showed no evidence of benefit from flutamide as a chemoprevention agent in men with HGPIN.
American Journal of Therapeutics 13(4):291-7. · 1.49 Impact Factor
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Ronald Lieberman
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ABSTRACT: Following FDA approval and introduction into the clinic in the mid-1980s, PSA testing has become arguably the most versatile serum tumor marker in urologic oncology with clinical use for early detection (screening) of prostate cancer (PC), risk stratification for clinical staging, prognosis, intermediate biomarker for monitoring tumor recurrence, and more recently as an intermediate biomarker for assessing therapeutic response to antiandrogens, radiation therapy, and chemotherapy. PSA now routinely guides health care providers for the clinical management of PC over a wide range of clinical risk states for men at risk of PC, after local definitive therapy and after systemic therapy to prevent progression to metastatic bone disease, and to palliate men with hormone refractory prostate cancer (HRPC). To further assess the evidence that supports these clinical applications, this commentary reviews and critically evaluates the emerging body of new data focusing on several recently published seminal articles by D'Amico et al and Thompson et al, the new National Comprehensive Cancer Network 2004 recommendations for starting PSA testing at the age of 40 years old, the latest results from 2 phase 3 randomized, controlled trials of taxane-based regimens showing improved survival for men with HRPC, and the recent US FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer that helped to distill and synthesize the current state of the art and the progress toward validation of PSA metrics (eg, PSA velocity) as a surrogate end point (SE) for treatment efficacy with taxane-based regimens. Furthermore, several randomized, controlled chemoprevention trials in progress evaluating agents such as selenium and vitamin E in high-risk cohorts are well poised to confirm the validity of PSA as an SE for clinical efficacy for the prevention and progression of PC. Although there continues to be a need to validate better biomarkers before diagnosis of PC (more sensitive and specific) and after diagnosis to discern between indolent and aggressive forms of PC, it is very likely that some metric of PSA as a biomarker alone or as part of a panel of other serum proteomic markers or tissue-derived multiplex gene expression arrays will be around for years to come as a useful tool for risk stratification, early detection, prognosis, prediction, and as an SE of efficacy for prevention and treatment of PC.
American Journal of Therapeutics 11(6):501-6. · 1.49 Impact Factor
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ABSTRACT: There is currently no standard therapy for patients with prostate cancer who have progressive rise in PSA levels despite treatment with hormonal ablation and antiandrogen withdrawal (stage D0.5). One potential treatment option is the use of a different androgen receptor antagonist (ARA), such as nilutamide. We report a case of a 66-year-old gentleman with greater than a 46 month sustained response to nilutamide therapy after failing bicalutamide therapy and its subsequent withdrawal. The patient continues to have undetectable PSA levels and an excellent performance status. This case demonstrates the prolonged response to a second-line ARA in patients deemed to have androgen insensitive prostate cancer. Further investigation of the potential role of nilutamide therapy as second-line antiandrogen therapy is warranted as monotherapy and/or in combination with other promising novel approaches including PSA-based vaccines.
American Journal of Therapeutics 12(2):172-4. · 1.49 Impact Factor
