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Biomedical subjects

Frank L Meyskens

Publications and source records attributed to Frank L Meyskens.

At least 19 recordsLinked to original sources
PubMed2006

Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer--a plan to move forward.

This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

Biomarkers, Tumor↗
PubMed2005

Can a marker be a surrogate for development of cancer, and would we know it if it exists?

Carcinogenesis proceeds through a very long preclinical period. Our collective hope is that multiple opportunities exist for chemoprevention to arrest or reverse progression towards malignancy. In the hope of faster progress with fewer subjects and lower total cost, much effort is being expended on the search for reliable biomarkers to predict the likelihood of developing cancer and/or to signal the effectiveness of chemopreventive therapy. Considerable attention is paid to identifying those markers that can act as surrogate markers for cancer development, since favorable modulation of the surrogate end-point biomarker (SEBM) may demonstrate effectiveness of a putative preventive treatment. However, the complexity of the biology challenges our ability to measure the effectiveness of attempts to arrest or reverse carcinogenesis, other than through costly and time-consuming prospective trials with disease state as the endpoint. Despite much work, to date no prehistologic biological or molecular intermediate marker has been validated for sporadic cancers. Several factors accounting for the difficulties encountered in SEBM development are reviewed. Discussion is focused on the common thread of the complexity of the underlying biological changes in carcinogenesis limiting the effectiveness of any single biomarker. Additionally, the incidence of sporadic cancers is also low, further limiting the positive predictive value of any putative prognostic marker. Recent successes in development of chemopreventive agents show the concept is valid and worth pursuing, but the current strategies to develop biochemical and genetic markers to identify surrogate biomarkers is flawed, and need to be reassessed in light of the difficulties faced over the last 20 years.

Anticarcinogenic Agents↗
PubMed2005

Principles of cancer prevention.

OBJECTIVE: To summarize the scientific principles underlying cancer prevention. DATA SOURCES: Articles, text books, personal communications, and experience. CONCLUSION: The scientific basis of cancer prevention is complex and involves experimental and epidemiologic approaches and clinical trials. IMPLICATIONS FOR NURSING PRACTICE: As more information becomes available regarding proven and potential cancer-prevention strategies, oncology nurses are regularly called upon to guide patients and others in making choices regarding preventative options. It is important for oncology nurses to stay abreast of this growing body of knowledge.

Clinical Nursing Research↗
PubMed2005

Redox regulation by intrinsic species and extrinsic nutrients in normal and cancer cells.

Cells in multicellular organisms are exposed to both endogenous oxidative stresses generated metabolically and to oxidative stresses that originate from neighboring cells and from other tissues. To protect themselves from oxidative stress, cells are equipped with reducing buffer systems (glutathione/GSH and thioredoxin/thioredoxin reductase) and have developed several enzymatic mechanisms against oxidants that include catalase, superoxide dismutase, and glutathione peroxidase. Other major extrinsic defenses (from the diet) include ascorbic acid, beta-carotene and other carotenoids, and selenium. Recent evidence indicates that in addition to their antioxidant function, several of these redox species and systems are involved in regulation of biological processes, including cellular signaling, transcription factor activity, and apoptosis in normal and cancer cells. The survival and overall well-being of the cell is dependent upon the balance between the activity and the intracellular levels of these antioxidants as well as their interaction with various regulatory factors, including Ref-1, nuclear factor-kappaB, and activating protein-1.

Antioxidants↗
PubMed2005

Diet and cancer: the disconnect between epidemiology and randomized clinical trials.

Dietary epidemiology has been highly successful in identifying the responsible agent in many diseases, including scurvy, pellagra, blindness, and spinal bifida. Case-control, cohort, and ecologic observational studies have consistently associated increased consumption of fruits and vegetables with a decreased risk for a wide variety of epithelial cancers and, in many cases, specific dietary components seem to decrease the risk for a wide array of epithelial cancers. Over time, there has been enthusiasm for one or another compounds, such as beta-carotene in the past and folate currently. Despite the success of translating similar epidemiologic observations to clinical benefit in other areas of medicine via the crucible of the randomized clinical trial, this strategy has not been nearly as successful for cancer. We propose that the inability of nutritional epidemiology to identify effective chemopreventive strategies is not just a problem of quantitation, but rather that the discipline is usually qualitatively incapable of identifying a dietary compound(s) that will be efficacious. One needs to consider the following basic questions in trying to understand why nutritional epidemiology has not been translated into progress in cancer prevention: Why do fruits and vegetable show a consistent protective effect against many epithelial cancers in epidemiologic studies? Once a specific dietary compound is identified as protective in observational studies, why do most subsequent observational studies confirm the effect? Why are dietary epidemiology observations frequently not confirmed by the randomized clinical trial? We call the identified problems "fishing with only one bait" and the "four-legged stool problem." The considerations identified in this analysis offer a number of possible solutions to puzzling findings: (a) Fruits and vegetables consistently show a protective effect against cancer in observational studies because they represent the entire "biological action package." (b) Dietary compounds show a protective effect in observational studies, but not in clinical trials, because this is an inevitable consequence of one compound being falsely identified as the active agent in a system in which multiple agents or multiple interacting regulatory molecules underlie the biological effect. The consequences are serious for trying to use epidemiology to identify effective nutritional compounds. The major conclusion has to be as follows: Supplementation with single dietary compounds is rarely going to be as effective as epidemiologic studies suggest; it is the biological action package that determines efficacy. Options for how we should move forward will be discussed. Dietary observational epidemiology is complex and involves many biases and confounders. We need to be more critical in the design of large randomized trials based on observational epidemiology or analysis. Rules of evidence are frequently ignored or misunderstood although the limitations of observational epidemiology are analogous to the problems associated with discovery-based research and biomarker identification. We need to be much more self-critical in the important and critical assessment of dietary compounds and their role in cancer prevention given the very high appeal for this approach both within the lay and scientific communities.

Chemoprevention↗
PubMed2005

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor.

Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein involved in DNA base excision repair and redox regulation of many transcription factors. In different melanoma cell lines, we found that both nucleus and cytoplasm exhibited higher levels of Ref-1 compared with normal melanocytes. Similar increases of Ref-1 expression, detected by immunohistofluorescence, were also evident in nevi and malignant melanoma biopsies compared with normal skin, which were predominantly localized in the nucleus. Using recombinant adenovirus Adref-1, encoding full-length Ref-1, we transiently overexpressed APE/Ref-1 in human melanocytes, which protected these cells from UVB-induced apoptosis and increased foci formation in culture. Ref-1 overexpression also protected melanoma cells from cisplatin- or H2O2-induced apoptosis, whereas increased apoptosis was observed with Ref-1 antisense construct infection. These observations suggested that intracellular Ref-1 levels played an important role in sensitization of melanoma cells to apoptosis. Electrophoretic mobility shift assay results showed that in both cultured primary and metastatic melanomas DNA-binding activities of activator protein-1 and nuclear factor-kappaB were significantly diminished or shifted when anti-APE/Ref-1 antibody was added to deplete APE/Ref-1 from the binding complexes. Induced nuclear factor-kappaB transcriptional activities were also evident after Ref-1 overexpression. Furthermore, using three-dimensional molecular structure modeling and virtual screening, we found that resveratrol, a natural compound found in fruits and vegetables, docks into a druggable pocket of Ref-1 protein. In vitro studies revealed that resveratrol inhibited, in a dose-dependent manner, Ref-1-activated activator protein-1 DNA-binding activities as well as Ref-1 endonuclease activities and rendered melanoma cells more sensitive to dacarbazine treatment.

DNA-(Apurinic or Apyrimidinic Site) Lyase↗
PubMed2004

Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells.

The alcohol-abuse deterrent disulfiram (DSF) is shown to have a highly selective toxicity against melanoma in culture, inducing a largely apoptotic response, with much lower toxicity against several other cell lines. Melanoma cell lines derived from different stages (radial, vertical, and metastatic phase) were all sensitive to DSF treatment in vitro; melanocytes were only slightly affected. A required role of extracellular Cu is demonstrated for DSF toxicity. Low concentrations of DSF alone decreased the number of viable cells, and the addition of CuCl(2) significantly enhanced the DSF-induced cell death to less than 10% of control. Significantly, the intracellular Cu concentration of melanoma cells increased rapidly upon DSF treatment. Both the intracellular Cu uptake and the toxicity induced by DSF were blocked by co-incubation with bathocuproine disulfonic acid (BCPD, 100 muM), a non-membrane-permeable Cu chelator. Chemical studies demonstrated a complicated, extracellular redox reaction between Cu(II) and DSF, which forms the complex Cu(deDTC)(2) in high yield, accompanied by oxidative decomposition of small amounts of disulfiram. The Cu complex has somewhat higher activity against melanoma and is suggested to be the active agent in DSF-induced toxicity. The redox conversion of DSF was unique to Cu(II) and not engendered by the other common biological metal ions Fe(II or III), Mn(III), and Zn(II). The implications of this work are significant both in the possible treatment of melanoma as well as in limiting the known side-effects of DSF, which we propose may be diminished by cotreatment to decrease adventitious Cu.

Apoptosis↗
PubMed2004

The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements.

BACKGROUND: The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group. METHODS: After the intervention ended, CARET participants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self-reported cancer endpoints were confirmed by review of pathology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two-sided. RESULTS: With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to 1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped. During the post-intervention phase, females had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36), cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males. CONCLUSIONS: The previously reported adverse effects of beta-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smokers.

Adult↗
PubMed2004

Alterations in activating protein 1 composition correlate with phenotypic differentiation changes induced by resveratrol in human melanoma.

Resveratrol has demonstrated preventive and therapeutic activities in a variety of tumors. However, the mechanistic basis of its pharmacological effects on human melanoma has not been well defined. Our results demonstrated that resveratrol significantly inhibited melanoma anchorage-independent growth, and even at high doses no distinct apoptosis or cell cycle arrest was observed. It is noteworthy that c83-2c (metastatic) and wm3211 (radial growth phase) melanoma cells became more dendritic shaped with resveratrol treatment. Major histocompatibility complex (MHC) class I antigen and Fas/CD95 constitutive surface expression levels were, respectively, increased by 2.7- and 1.6-fold of control in c83-2c cells. Resveratrol reduced both activator protein-1 (AP-1) DNA binding and transcriptional activities, and supershift assay revealed that AP-1 composition was shifted from c-Jun/JunD/Fra-1 to JunD/Fra-1/Fra-2, with markedly increased JunD, Fra-1, and Fra-2 protein expression levels in the nucleus. Furthermore, we overexpressed Fra-2 in human melanoma cells by using a Fra-2 expression construct and both AP-1 transcriptional activity and 12-O-tetradecanoylphorbol-induced transcriptional transactivation were reduced significantly, whereas MHC class I antigen and Fas/CD95 levels were elevated to 2.0 and 1.8 times of control, respectively. Addition of H(2)O(2) (10 muM) partially reversed the inhibition of colony proliferation; however, no effects on either MHC class I antigen or Fas expression was evident. Although H(2)O(2) restored participation of c-Jun in AP-1 complexes, H(2)O(2) addition did not affect the induction of Fra-1 and Fra-2 by resveratrol nor the morphological changes. We propose that alterations in AP-1 transcription signaling, mediated by changes in AP-1 dimeric composition and reduced intracellular reactive oxygen species levels, substantially contribute to the phenotypic changes induced by resveratrol.

Antioxidants↗
PubMed2004

Screening for cancer: valuable or not?

Screening for cancer has become extremely common. The evidence supporting screening for breast, colon, and cervix cancer is strong, but it is unclear for skin cancer, problematic for prostate cancer, and ineffective for lung cancer. Despite the problems associated with many screening approaches for cancer, enthusiasm by the medical profession and the public remains high. The objective analysis for the major tumor types is presented in this review, but the ultimate decision on whether to be screened lies in the personal and societal arena of values.

Breast Neoplasms↗
PubMed2004

Polyamines and cancer: old molecules, new understanding.

The amino-acid-derived polyamines have long been associated with cell growth and cancer, and specific oncogenes and tumour-suppressor genes regulate polyamine metabolism. Inhibition of polyamine synthesis has proven to be generally ineffective as an anticancer strategy in clinical trials, but it is a potent cancer chemoprevention strategy in preclinical studies. Clinical trials, with well-defined goals, are now underway to evaluate the chemopreventive efficacy of inhibitors of polyamine synthesis in a range of tissues.

Anti-Inflammatory Agents, Non-Steroidal↗