Biomedical subjects

James Ranger-Moore

Publications and source records attributed to James Ranger-Moore.

At least 19 recordsLinked to original sources

PubMed2007

Combination of 4-HPR and oral contraceptive in monkey model of chemoprevention of ovarian cancer.

4-(N-hydroxyphenyl) retinamide (4-HPR) and the oral contraceptives (OCP) are currently being used alone, and in combination, for the prevention of ovarian cancer. However, the mechanism of their effects has not been studied. Non-human primate models are ideal for studying the role of these and other drugs for cancer chemoprevention because of the genetic similarity between primates and humans in respect to hormone regulation and menstrual cycle. 4-HPR and OCP were administered to sixteen female adult Macacca mulatta (Rhesus macaques) for three months alone and in combination. Laparotomy was performed before and after treatment, and ovarian biopsies were obtained to evaluate the expression of retinoid and hormone receptors, and apoptosis. ER alpha was undetectable, but ER beta, PR, RXR alpha, and RXR gamma were constitutively expressed in the ovaries. 4-HPR induced RXR alpha and RXR gamma expression at a low level and, OCP induced expression of ER beta. However, the combination of 4-HPR with OCP had a larger effect on expression of retinoid receptors. Apoptosis was detected in the 4-HPR group (equivalent dose: 200 mg/day).

Animals↗

PubMed2006

Reproducibility and expression of skin biomarkers in sun-damaged skin and actinic keratoses.

OBJECTIVES: To explore p53 and proliferating cell nuclear antigen (PCNA) expression and polyamine content as biomarkers in skin cancer chemoprevention trials, we evaluated their expression in early stages of UV-induced squamous cell tumorigenesis. METHODS: Biopsies were collected from three groups: 78 subjects with sun damage on forearms, 33 with actinic keratosis (AK) on forearms, and 32 with previous squamous cell carcinoma. Participants with sun damage were randomized to sunscreen or no sunscreen. RESULTS: We found significant differences in p53 and polyamines in forearms from the sun-damaged group (11.5 +/- 1.2% for p53, 65.5 +/- 1.9 nmol/g for putrescine, and 187.7 +/- 3.3 nmol/g for spermidine) compared with the group with sun damage plus AK (20.9 +/- 2.3% for p53, P = 0.0001; 81.7 +/- 3.9 nmol/g for putrescine, P = 0.0001; 209.4 +/- 8.2 nmol/g for spermidine, P < 0.06). PCNA was not different. When lesion histology was considered, there was a stepwise significant increase in p53 in biopsies without characteristics of AK compared with early AK (P = 0.02) and AK (P = 0.0006) and a similar pattern for PCNA with the only significant difference between early AK and AK. There was a stepwise increase in putrescine and spermidine in normal, sun-damaged forearm, forearm from subjects with AK, and the AK lesion itself (P < 0.0001). No significant differences in p53 or polyamines were seen in 3-month biopsies or, as a result of sunscreen use, although PCNA in the sun-damaged group not using sunscreen decreased significantly. CONCLUSIONS: p53 expression and polyamines in skin were elevated in early stages of skin tumorigenesis and were not affected by sunscreen, adding validity to their use as biomarkers in skin cancer chemoprevention trials.

Adult↗

PubMed2006

The role of Rac1 in maintaining malignant phenotype of mouse skin tumor cells.

We have previously developed an in vitro tumor progression model with mouse skin keratinocytes to study the molecular targets that mediate the tumor cell's progression from a benign to a malignant phenotype. The malignantly transformed cells were found to have elevated MAP kinase signaling and increases in AP-1, NFkappaB and cAMP response element (CRE) transcription factors activities compared to their benign counter-part. In this study, we showed that Rac1, a member of the Rho superfamily of small GTPases, functions as a key signaling molecule that mediates these malignant phenotypes. We used a doxycycline inducible system to express dominant negative Rac1 (N17 Rac1) in the squamous cell carcinomas producing 6M90 cell line. Conditional expression of the N17 Rac1 was able to decrease multiple markers of malignancy including: growth rate, colony formation, migration, invasion and most importantly, in vivo tumor growth. In addition, these phenotypic changes were accompanied by decreases in mitogenic signals, which include ERK1/2, JNK, and PI-3 kinase/Akt activation. Transactivation mediated by AP-1, NFkappaB, and CRE were also attenuated by expression of dominant negative Rac1. These observations led us to conclude that Rac1 signaling is required for the malignant phenotypes of the squamous cell carcinoma cells.

Animals↗

PubMed2006

Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study.

Immunoglobulin secretion onto mucosal surfaces is a major component of the mucosal immune system. We hypothesized that chronic gastrointestinal (GI) disturbances associated with autistic disorder (AD) may be due to an underlying deficiency in mucosal immunity, and that orally administered immunoglobulin would be effective in alleviating chronic GI dysfunction in these individuals. In this pilot study, twelve male subjects diagnosed with AD were evaluated using a GI severity index (GSI) while receiving daily dosing with encapsulated human immunoglobulin. Following eight weeks of treatment, 50% of the subjects met prespecified criteria for response in GI signs and symptoms and showed significant behavioral improvement as assessed by the Autism Behavior Checklist and parent and physician rated Clinical Global Impression of Improvement.

Administration, Oral↗

PubMed2006

Effects of repeated green tea catechin administration on human cytochrome P450 activity.

PURPOSE: Preclinical studies suggested that green tea or green tea catechins can modulate the activities of drug-metabolizing enzymes. We conducted this clinical study to determine the effect of repeated green tea catechin administration on human cytochrome P450 (CYP) enzyme activities. METHODS: Forty-two healthy volunteers underwent a 4-week washout period by refraining from tea or tea-related products. At the end of the washout period, study participants received a cocktail of CYP metabolic probe drugs, including caffeine, dextromethorphan, losartan, and buspirone for assessing the activity of CYP1A2, CYP2D6, CYP2C9, and CYP3A4, respectively. Blood and urine samples before and 8 h after probe drug administration were collected to determine parent drug and metabolite concentrations for measurements of baseline CYP enzyme activities. Following the baseline evaluation, study participants underwent 4 weeks of green tea catechin intervention at a dose that contains 800 mg epigallocatechin gallate (EGCG) daily. The green tea catechin product was taken on an empty stomach to optimize the p.o. bioavailability of EGCG. The EGCG dose given in this study exceeded the amounts provided by average green tea consumption. Upon completion of the green tea catechin intervention, the postintervention CYP enzyme activities were evaluated as described above. RESULTS: There are large between-subject variations in CYP enzyme activities in healthy individuals. Four weeks of green tea catechin intervention did not alter the phenotypic indices of CYP1A2, CYP12D6, and CYP12C9, but resulted in a 20% increase (P = 0.01) in the area under the plasma buspirone concentration-time profile, suggesting a small reduction in CYP3A4 activity. CONCLUSIONS: We conclude that repeated green tea catechin administration is not likely to result in clinically significant effects on the disposition of drugs metabolized by CYP enzymes.

Administration, Oral↗

PubMed2006

Risk group, skin lesion history, and sun sensitivity reliability in squamous cell skin cancer progression.

In studies of skin cancer, participants are often classified into risk groups based on self-reported history of sun exposure or skin characteristics. We sought to determine the reliability of self-reported skin characteristics among participants of a study to evaluate markers for nonmelanoma skin cancer (NMSC). Multiple questionnaires and screening protocols were administered over a 3-month period to individuals from three risk groups: existing sun damage on forearms but no visible actinic keratoses (n = 91), visible actinic keratoses (n = 38), and history of resected squamous cell skin cancer in the last 12 months (n = 35). We assessed consistency of risk group assignment between telephone screen and study dermatologist assignment, self-reported sun sensitivity (telephone recruitment form versus participant completed profile), and self-reported history of NMSC skin lesions (telephone recruitment form versus health history). There was substantial agreement between probable risk group and final assignment (kappa = 0.76; 95% confidence interval, 0.65-0.85) and agreement did not differ by gender. Agreement for self-reported sun sensitivity was moderate (kappa weighted = 0.46; 95% confidence interval, 0.36-0.56) with higher agreement for women. For self-reported NMSC lesion history between two interviews, 24 days apart, kappa estimates ranged from 0.66 to 0.78 and were higher for women than men. Overall, there was evidence for substantial reproducibility related to risk group assignment and self-reported history of NMSC, with self-reported sun sensitivity being less reliable. In all comparisons, women had higher kappa values than men. These results suggest that self-reported measures of skin cancer risk are reasonably reliable for use in screening subjects into studies.

Adult↗

PubMed2006

Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model.

A number of human melanomas show hyperactivation of the Ras pathway due to mutations of the molecule or alteration of upstream or downstream effectors. In this study, we evaluated the effect of blocking the two Ras downstream pathways phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase on melanoma development and regression in the TPRas mouse model. The inhibition of these two signaling cascades by topically applied Ly294002 and U0126 significantly delayed melanoma development and significantly decreased the tumor incidence, particularly when the drugs were applied in combination. Treatment with the inhibitors of established melanomas resulted in complete remission in 33% of mice and partial regression in 46% of mice when drugs were delivered in combination. These responses correlated with increased apoptosis and decreased proliferation both in vitro and in vivo and reduced tumor angiogenesis. In conclusion, this study strongly supports the role of the phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways in the development and maintenance of Ras-dependent melanomas and supports the notion that specific inhibition of these effectors may represent a very promising avenue for the treatment and prevention of the disease.

Animals↗

PubMed2006

Fruit and vegetable consumption of older Mexican-American women is associated with their acculturation level.

Little is known about the association between acculturation and fruit and vegetable (FV) consumption among older Mexican-American (MA) women. Environmental and lifestyles changes experienced by immigrants to the United States may markedly affect their diet and health and increase their risk for chronic diseases. Our objectives were to: 1) describe FV consumption by ethnicity, acculturation, and sociodemographic characteristics, and 2) compare effects of acculturation and sociodemographic variables on FV intake in a population of older MA and non-Hispanic White (NHW) women from the Well-Integrat-ed Screening and Evaluation for Women Across the Nation (WISEWOMAN) Study. This report examines baseline FV intake of 346 underinsured women aged 50-76 years, assessed through 24-hour dietary recalls. Acculturation was measured with a five-item Likert-type scale. Twenty percent of more acculturated MA women, 24% of less acculturated MA women, and 36% of White women consumed > or = 5 servings of FV servings per day. Fruit and vegetable (FV) intake was associated with acculturation, education, and smoking status. Being more acculturated was associated with lower consumption of FVs among MAs, while having a higher education and no smoking was associated with higher intakes of FV servings among NHWs. Public health efforts to improve the intake of FVs among MA women should be sensitive to their acculturation status.

Acculturation↗

PubMed2006

Carcinogenesis and the hypothesis of phylogenetic reversion.

Chemoprevention must target early molecular events involved in malignant transformation. The sequence of events leading from a normally functioning interphase cell to an uncontrolled tumor cell is only partially understood, impeding systematic design of chemopreventive agents. The respective roles of mutagenic and epigenetic mechanisms have not been definitively established. Also, traditional models do not appear to incorporate cellular response to events leading to carcinogenesis. A perspective on system response offered by complexity science elucidates the roles of feedback and control in maintaining functional stability during carcinogenesis. Carcinogenesis is seen as a process of epigenetic redifferentiation resulting in a cell behaving like an archetypal karyocyte free of growth restraints (phylogenetic reversion). Genes that evolved during the development of multicellular organisms, restraining uncontrolled growth and regulating intercell communication may be systematically silenced during carcinogenesis. The formation of heterochromatin, which results in epigenetic silencing by hypermethylation in CpG-dense islands, finds expression in the nuclear chromatin pattern. Karyometry is an integrating biomarker of chromatin pattern information that accommodates the possibility of multiple, differently ordered pathways and provides exquisite sensitivity, allowing detection of very early transformation events. Its use can monitor the impact of chemopreventive agents on the earliest events in progression to cancer.

Animals↗

PubMed2005

Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals.

PURPOSE: Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. Its consumption has been associated with decreased risk of certain types of cancers in humans. The oral bioavailability of the major green tea constituents, green tea catechins, is low, resulting in systemic catechin levels in humans many fold less than the effective concentrations determined in in vitro systems. We conducted this clinical study to test the hypothesis that the oral bioavailability of green tea catechins can be enhanced when consumed in the absence of food. EXPERIMENTAL DESIGNS: Thirty healthy volunteers were randomly assigned to one of the following doses of Polyphenon E (a decaffeinated and defined green tea catechin mixture): 400, 800, or 1,200 mg, based on the epigallocatechin gallate content (10 subjects per dose group). After an overnight fast, study participants took a single dose of Polyphenon E with or without a light breakfast, which consisted of one or two 4-oz muffins and a glass of water. Following a 1-week wash-out period, subjects were crossed over to take the same dose of Polyphenon E under the opposite fasting/fed condition. Tea catechin concentrations in plasma and urine samples collected after dosing were determined by high-pressure liquid chromatography analysis. RESULTS: Consistent with previous reports, epigallocatechin gallate and epicatechin gallate were present in plasma mostly as the free form, whereas epicatechin and epigallocatechin were mostly present as the glucuronide and sulfate conjugates. There was >3.5-fold increase in the average maximum plasma concentration of free epigallocatechin gallate when Polyphenon E was taken in the fasting condition than when taken with food. The dosing condition led to a similar change in plasma-free epigallocatechin and epicatechin gallate levels. Taking Polyphenon E in the fasting state did not have a significant effect on the plasma levels of total (free and conjugated) epigallocatechin, but resulted in lower plasma levels of total epicatechin. Urinary epigallocatechin gallate and epicatechin gallate levels were very low or undetectable following Polyphenon E administration with either dosing condition. Taking Polyphenon E under the fasting state resulted in a significant decrease in the urinary recovery of total epigallocatechin and epicatechin. Polyphenon E administered as a single dose over the dose range studied was generally well-tolerated by the study participants. Mild and transient nausea was noted in some of the study participants and was seen most often at the highest study agent dose (1,200 mg epigallocatechin gallate) and in the fasting condition. CONCLUSIONS: We conclude that greater oral bioavailability of free catechins can be achieved by taking the Polyphenon E capsules on an empty stomach after an overnight fast. Polyphenon E up to a dose that contains 800 mg epigallocatechin gallate is well-tolerated when taken under the fasting condition. This dosing condition is also expected to optimize the biological effects of tea catechins.

Abdominal Pain↗

PubMed2005

Determining suitable internal standards for mRNA quantification of increasing cancer progression in human breast cells by real-time reverse transcriptase polymerase chain reaction.

Real-time reverse transcriptase polymerase chain reaction is recognized as a highly sensitive and specific method for quantification of mRNA expression. SYBR green I dye simplifies the experimental design but introduces the need for specific controls to maintain high specificity. Due to this increased sensitivity, standards that may have been acceptable for normalization of less sensitive methods have been shown to vary considerably among cell lines, tissues, proliferative states, treatments, and developmental conditions and by degree of cancer progression. It has become evident that determination of suitable normalization standards is a requirement for the use of this method as it is applied toward any new experimental model. We have assessed the suitability of a number of commonly used standards for the normalization of mRNAs among a set of human breast cancer cell lines of increasing metastatic potential and have determined that 18S rRNA and beta-actin (ACTB) mRNA are both suitable for this purpose, with each having some limitations. 18S rRNA varies less among the cell lines but has a higher degree of random variability, while ACTB mRNA varies more among cell lines but has a lower degree of random variation.

Actins↗

PubMed2005

Differential inhibition of UVB-induced AP-1 and NF-kappaB transactivation by components of the jun bZIP domain.

Potential targets for chemoprevention of nonmelanoma skin cancer include UV-induced nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) activation in keratinocytes. Inhibition of both these ultraviolet light B (UVB)-induced transcription factors has been shown with the dominant-negative c-jun mutant, TAM67; however, its mechanism of action has not yet been determined. Here we demonstrated that transient transfection of a mouse keratinocyte cell line (308) with a dominant-negative phosphorylation mutant of c-Jun before exposure to 250 J/m(2) UVB inhibits transactivation mediated by both AP-1 and NF-kappaB transcription factors to levels below those of UVB exposed controls. Through the utilization of immunoprecipitation techniques, protein-protein interactions between NF-kappaB family members IkappaBalpha, IkappaBbeta, p50, and p65 (Rel-A) were identified with an Xpress tagged dominant-negative c-Jun (TAM67) protein. Expression of the leucine zipper domain of the TAM67 protein inhibited UVB-induced NF-kappaB transactivation but not AP-1 transactivation. Expression of the bZIP domain of the TAM67 protein was able to inhibit transactivation mediated by both transcription factors. These data demonstrate that TAM67 is able to inhibit two significant UVB-induced molecular targets AP-1 and NF-kappaB, and that the inhibition of these two transcription factor families is potentially due to protein-protein interactions between different regions of the dominant-negative c-Jun protein.

Animals↗

PubMed2005

Exploratory study of ovarian intraepithelial neoplasia.

PURPOSE: This was an exploratory study to test two hypotheses related to potential epithelial precursors to ovarian cancer: (a) histologically normal ovarian surface epithelium exhibited changes in the nuclear chromatin pattern, which indicate an ovarian abnormality, and (b) such changes were detectable in the ovarian surface epithelium of cancer-free subjects who were at high risk for ovarian cancer. EXPERIMENTAL DESIGN: Ovaries were carefully collected to avoid damage to the surface epithelium. Five-micron-thick histologic sections were cut and stained with H&E. High-resolution images were recorded from the ovarian surface epithelium and from the underlying stroma of ovaries from normal women (10 cases), women at high risk of developing ovarian cancer (7 cases), and histologically normal areas adjacent to ovarian cancer (3 cases). Karyometric features and measurements of nuclear abnormality were computed for 3,390 epithelial nuclei. Discriminant function analyses and unsupervised learning algorithms were employed to define deviations from normal and to identify the subpopulations of nuclei exhibiting these changes. RESULTS: Epithelium from ovaries harboring a malignant lesion had changes in the nuclear chromatin pattern consistent with a second phenotype, which were not visually detected with histopathologic surveillance. This phenotype was also present in the ovaries obtained from women at increased risk of ovarian cancer, suggesting that it may represent a premalignant abnormality. These changes were statistically significant. CONCLUSION: The observed changes in karyometric features were sufficiently distinct to warrant further study as both diagnostic and prognostic biomarkers for early detection and prevention of ovarian cancer.

Carcinoma in Situ↗

PubMed2005

Second order discriminant analysis in chemopreventive efficacy measurement.

OBJECTIVE: To describe the use of second order discriminant analysis as a classification methodology along with the underlying assumptions and sampling requirements, with special emphasis on the use of this analysis in chemopreventive efficacy studies. STUDY DESIGN: The discriminant function score distributions derived in an analysis of 2 diagnostic groups may show such overlap that a statistically significant difference in mean values cannot be shown and, more important, that a useful case-based classification cannot be attained. By using the discriminant function score distributions from each case, it is frequently possible to derive a second order discriminant function based on case-specific characteristics, rather than characteristics of nuclei, thereby attaining improved case classification. RESULTS: Second order discriminant analysis has proven very useful in the documentation of case-level efficacy in chemopreventive trials. In a study of orally administered vitamin A, a first order discriminant analysis did not achieve a statistically significant difference in the score distributions for nuclei, but a second order discriminant analysis allowed a correct recognition of intervention effects in 85% of submitted cases. In a chemopreventive study of triamcinolone, a similarly inadequate discrimination based on discriminant function scores for nuclei resulted. After a second order discriminant analysis, a reduction in solar-actinic damage could be shown in 14/15, or 93%, of treated cases. CONCLUSION: Second order discriminant analysis can be highly effective when the discriminating information offered at the nuclear level is inadequate due to high dispersion and small differences in mean values of discriminant function scores for the diagnostic groups. Second order analysis utilizes case-specific characteristics of the discriminant function score distributions to document diagnostic group separation and/or efficacy of chemopreventive intervention by a reduction in case discriminant function scores.

Administration, Oral↗

PubMed2005

Karyometry in rectal mucosa of patients with previous colorectal adenomas.

OBJECTIVE: To determine whether karyometric measurements taken in biopsies from histologically normal-appearing rectal mucosa could serve as a biomarker for the risk of recurrence of polyps. MATERIALS AND METHODS: Biopsies were taken from the rectal mucosa of cases with a prior history of colonic polyps at the baseline of the study. In 57 cases recurrent polyps occurred (R cases); in 72 cases no recurrent disease was found at the end of the study (NR cases). From each biopsy 100 nuclei were recorded at high resolution. After segmentation, feature extraction and selection of a discriminating subset of features, a number of discriminant functions were derived. Also, measures of nuclear abnormality were computed. RESULTS: The differences in karyometricfeature values for nuclei from biopsies of cases with recurrent or nonrecurrent disease were very small and not notably expressed in the majority of nuclei. It was possible by focusing on nuclei showing clear deviations from normal to derive a discriminant function that exhibited a shift for the NR and R data sets. The distributions of discriminant function scores were then subjected to a second-order discriminant analysis to separate cases according to recurrence status. This function showed a statistically highly significant correlation with recurrence. At one extreme of its score distribution were 11 of 57 cases that had a recurrence, and at the other extreme were 8-10 of 72 cases that had no recurrence. The distributions of nuclear abnormality values for these subsets of cases were drastically different, with an average value of 1.72 for the group that may be at high risk for another recurrence and 1.02 for the group possibly at low risk. All cases with a prior history of colonic polyps showed a nuclear abnormality deviating from normal. CONCLUSION: Measurement of a sample of 100 nuclei from the rectal mucosa will suggest, for approximately 10% of cases, that a high risk for recurrence of adenomatous polyps exists and, for a slightly lower proportion, confirm that the nuclei deviate only slightly from those from individuals with no history of colonic polyps. For the majority of cases with a prior history of adenoma, the nuclei in the biopsy show a notable deviation from normal, but the deviation is practically the same for cases that had a recurrence and those that did not. However, a tentative discriminant function (DF I,3) derived from the characteristics of the extreme cases correctly classified approximately 64% of nonrecurrent and 83% of recurrent cases using a Bayesian decision boundary.

Adenomatous Polyposis Coli↗

PubMed2005

Karyometry of infiltrating breast lesions.

OBJECTIVE: To characterize nuclei from well-differentiated, moderately differentiated and poorly differentiated lesions of invasive breast cancer by karyometry and to test the hypothesis that these diagnostic categories form homogeneous sets. STUDY DESIGN: Histopathologic sections from 6 cases of well-differentiated, 11 cases of moderately differentiated and 17 cases of poorly differentiated ductal carcinomas were digitally recorded. From each case 100 nuclei were segmented and analyzed by karyometry. A discriminant analysis was performed, and nuclear and lesion signatures were computed. The nonsupervised learning algorithm P-index was applied. A progression curve per diagnostic category based on mean nuclear abnormality and a discriminant function score was derived. RESULTS: The well-differentiated lesions formed a homogeneous set, but both the moderately and poorly differentiated lesions showed 2 significantly different subpopulations with nuclei of substantially different nuclear abnormality and progression. CONCLUSION: The visual histopathologic diagnostic assessment of these lesions was based on an evaluation of both tissue architectural criteria and nuclear criteria. Here, only the pattern of nuclear chromatin was evaluated. Cases belonging to the same diagnostic category as assessed by their differentiation may be further characterized by the extent to which the nuclei deviate from normal. There was substantial case-to-case heterogeneity in these invasive lesions.

Breast Neoplasms↗

PubMed2005

The evolution of scanning microphotometry: a historical review.

This article traces the evolution of scanning microphotometry from its beginning, with an emphasis on the developing technologies that have made feasible the rapid and detailed capture of high-resolution image information. Consideration is given to future directions that may prove fruitful to clinical practice.

History, 20th Century↗

PubMed2004

Safety and efficacy of dose-intensive oral vitamin A in subjects with sun-damaged skin.

PURPOSE: Previously, we reported the results of a Phase III, placebo-controlled trial in 2297 randomized participants with moderately severe actinic keratoses wherein 25000 IU/day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50000 or 75000 IU/day would be both safe and more efficacious in skin cancer chemoprevention. EXPERIMENTAL DESIGN: One hundred and twenty-nine participants with severely sun-damaged skin on their lateral forearms were randomized to receive placebo or 25000, 50000, or 75000 IU/day vitamin A for 12 months. The primary study end points were the clinical and laboratory safety of vitamin A, and the secondary end points included quantitative, karyometric image analysis and assessment of retinoid and rexinoid receptors in sun-damaged skin. RESULTS: There were no significant differences in expected clinical and laboratory toxicities between the groups of participants randomized to placebo, 25000 IU/day, 50000 IU/day, and 75000 IU/day. Karyometric features were computed from the basal cell layer of skin biopsies, and a total of 22600 nuclei from 113 participants were examined, showing statistically significant, dose-response effects for vitamin A at the 25000 and 50000 IU/day doses. These karyometric changes correlated with increases in retinoic acid receptor alpha, retinoic acid receptor beta, and retinoid X receptor alpha at the 50000 IU/day vitamin A dose. CONCLUSIONS: The vitamin A doses of 50000 and 75000 IU/day for 1 year proved safe and equally more efficacious than the 25000 IU/day dose and can be recommended for future skin cancer chemoprevention studies.

Administration, Oral↗