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J A Crowell

Publications and source records attributed to J A Crowell.

At least 37 records · Page 2Linked to original sources
PubMed1999

Chemoprevention of prostate cancer: concepts and strategies.

Chemoprevention is the administration of agents to prevent induction and inhibit or delay progression of cancers. For prostate, as for other cancer targets, successful chemopreventive strategies require well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer for evaluating chemopreventive efficacy. Agent requirements are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the observed chemopreventive activity. On this basis, promising chemopreventive drugs in prostate include retinoids, antiandrogens, antiestrogens, steroid aromatase inhibitors, 5alpha-reductase inhibitors, vitamins D and E, selenium, lycopene, and 2-difluoromethylornithine. Phase II trials are critical for evaluating chemopreventive efficacy. Cohorts in these trials should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen as endpoints. Many cohorts proposed for phase II trials are patients with previous cancers or premalignant lesions. For such patients, trials should be conducted within the context of standard treatment. Two cohorts currently used in phase II prostate cancer chemoprevention trials are patients with PIN and patients scheduled for prostate cancer surgery. Biomarkers should fit expected biological mechanisms, be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. Protocols for adequately sampling tissue are essential. Changes in PIN provide prostate biomarkers with the ability to be quantified and a high correlation to cancer. PIN measurements include nuclear polymorphism, nucleolar size and number of nucleoli/nuclei, and DNA ploidy. Other potentially useful biomarkers are associated with cellular proliferation kinetics (e.g. PCNA and apoptosis), differentiation (e.g. blood group antigens, vimentin), genetic damage (e.g. LOH on chromosome 8), signal transduction (e.g. TGFalpha, TGFbeta, IGF-I, c-erbB-2 expression), angiogenesis, and biochemical changes (e.g. PSA levels).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Lipoxygenase inhibitors as potential cancer chemopreventives.

Mounting evidence suggests that lipoxygenase (LO)-catalyzed products have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO metabolites have been found in lung, prostate, breast, colon, and skin cancer cells, as well as in cells from patients with both acute and chronic leukemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumor cell adhesion, and regulation of apoptotic cell death. Agents that block LO-catalyzed activity may be effective in preventing cancer by interfering with signaling events needed for tumor growth. In fact, in a few studies, LO inhibitors have prevented carcinogen-induced lung adenomas and rat mammary gland cancers. During the past 10 years, pharmacological agents that specifically inhibit the LO-mediated signaling pathways are now commercially available to treat inflammatory diseases such as asthma, arthritis, and psoriasis. These well-characterized agents, representing two general drug effect mechanisms, are considered good candidates for clinical chemoprevention studies. One mechanism is inhibition of LO activity (5-LO and associated enzymes, or 12-LO); the second is leukotriene receptor antagonism. Although the receptor antagonists have high potential in treating asthma and other diseases where drug effects are clearly mediated by the leukotriene receptors, enzyme activity inhibitors may be better candidates for chemopreventive intervention, because inhibition of these enzymes directly reduces fatty acid metabolite production, with concomitant damping of the associated inflammatory, proliferative, and metastatic activities that contribute to carcinogenesis. However, because receptor antagonists have aerosol formulations and possible antiproliferative activity, they may also have potential, particularly in the lung, where topical application of such formulations is feasible.

Animals↗
PubMed1998

Determination of phenethylamine, a phenethyl isothiocyanate marker, in dog plasma using solid-phase extraction and gas chromatography-mass spectrometry with chemical ionization.

Phenethyl isothiocyanate is unstable in aqueous media and at low pH, and rapidly degrades to phenethylamine. Concentrations of phenethylamine, a phenethyl isothiocyanate marker, in dog plasma, were determined utilizing solid-phase extraction and gas chromatography-mass spectrometry with chemical ionization using acetone as the reagent gas. Deuterated d5-amphetamine was used as an internal standard. After extraction, phenethylamine and d5-amphetamine were derivatized using MBHFBA. Ions monitored for d5-amphetamine were m/z 337 and 338; and for phenethylamine were m/z 318 and 319. Precision and accuracy were studied using control solutions prepared in naive dog plasma (80 and 300 ng/ml). Intra-day variability was determined using six replicates of each control solution analyzed on a single day. The relative standard deviation for the 80 ng/ml control was 12.9% and for the 300 ng/ml it was 12.1%. Relative accuracy was 10.9% for the low control and -4.1% for the high control. Inter-day variability was determined over a 6-day period. For the 80 and 300 ng/ml control solutions, the relative standard deviations were 15.8 and 9.1%, respectively, and relative accuracy values were 10.1 and -5.2%, respectively. Standard curves were prepared in naive dog plasma and were linear over the range of phenethylamine assayed (10-500 ng/ml). The results of this study indicate that the proposed method is simple, precise, accurate and sensitive enough for analysis of large numbers of plasma samples.

Animals↗
PubMed1998

Depth information and perceived self-motion during simulated gaze rotations.

When presented with random-dot displays with little depth information, observers cannot determine their direction of self-motion accurately in the presence of rotational flow without appropriate extra-retinal information (Royden CS et al. Vis Res 1994;34:3197-214.). On theoretical grounds, one might expect improved performance when depth information is added to the display (van den Berg AV and Brenner E. Nature 1994;371:700-2). We examined this possibility by having observers indicate perceived self-motion paths when the amount of depth information was varied. When stereoscopic cues and a variety of monocular depth cues were added, observers still misperceived the depicted self-motion when the rotational flow in the display was not accompanied by an appropriate extra-retinal, eye-velocity signal. Specifically, they perceived curved self-motion paths with the curvature in the direction of the simulated eye rotation. The distance to the response marker was crucial to the objective measurement of this misperception. When the marker distance was small, the observers' settings were reasonably accurate despite the misperception of the depicted self-motion. When the marker distance was large, the settings exhibited the errors reported previously by Royden CS et al. Vis Res 1994;34-3197-3214. The path judgement errors observers make during simulated gaze rotations appear to be the result of misattributing path-independent rotation to self-motion along a circular path with path-dependent rotation. An analysis of the information an observer could use to avoid such errors reveals that the addition of depth information is of little use.

Cues↗
PubMed1998

Optical, receptoral, and retinal constraints on foveal and peripheral vision in the human neonate.

We examined the properties of the foveal, parafoveal, and near peripheral cone lattice in human neonates. To estimate the ability of these lattices to transmit the information used in contrast sensitivity and visual acuity tasks, we constructed ideal-observer models with the optics and photoreceptors of the neonatal eye at retinal eccentricities of 0, 5, and 10 degrees. For ideal-observer models limited by photon noise, the eye's optics, and cone properties, contrast sensitivity was higher in the parafovea and near periphery than in the fovea. However, receptor pooling probably occurs in the neonate's parafovea and near periphery as it does in mature eyes. When we add a receptor-pooling stage to the models of the parafovea and near periphery, ideal acuity is similar in the fovea, parafovea, and near periphery. Comparisons of ideal and real sensitivity indicate that optical and receptoral immaturities impose a significant constraint on neonatal contrast sensitivity and acuity, but that immaturities in later processing stages must also limit visual performance.

Contrast Sensitivity↗
PubMed1998

Preclinical drug development paradigms for chemopreventives.

Preclinical screening studies and animal efficacy testing models currently are used by the National Cancer Institute's chemoprevention drug discovery program to assess and identify chemical agents and natural products that may have the potential to prevent human cancer. Identification of potential cancer preventing agents begins by subjecting each compound to a sequential series of short-term, in vitro prescreens of mechanistic, biochemical assays to provide quantitative data to help establish an early indication of chemopreventive efficacy and to assist in prioritizing agents for further evaluation in longer-term, in vitro transformation bioassays and whole animal models. Promising chemical agents or combinations of agents that work through different inhibitory mechanisms subsequently are tested in well-established, chemically induced, animal tumor models, which include models of the lung, bladder, mammaries, prostate, and skin. These preclinical bioassays afford a strategic framework for evaluating agents according to defined criteria, and not only provide evidence of agent efficacy, but also serve to generate valuable dose-response, toxicity, and pharmacokinetic data required prior to phase I clinical safety testing. Based on preclinical efficacy and toxicity screening studies, only the most successful agents considered to have potential as human chemopreventives progress into clinical chemoprevention trials.

Animals↗
PubMed1998

Visual self-motion perception during head turns.

Extra-retinal information is critical in the interpretation of visual input during self-motion. Turning our eyes and head to track objects displaces the retinal image but does not affect our ability to navigate because we use extra-retinal information to compensate for these displacements. We showed observers animated displays depicting their forward motion through a scene. They perceived the simulated self-motion accurately while smoothly shifting the gaze by turning the head, but not when the same gaze shift was simulated in the display; this indicates that the visual system also uses extra-retinal information during head turns. Additional experiments compared self-motion judgments during active and passive head turns, passive rotations of the body and rotations of the body with head fixed in space. We found that accurate perception during active head turns is mediated by contributions from three extra-retinal cues: vestibular canal stimulation, neck proprioception and an efference copy of the motor command to turn the head.

Cues↗
PubMed1998

Aromatase inhibitors as potential cancer chemopreventives.

Epidemiological and experimental evidence strongly supports a role for estrogens in the development and growth of breast tumors. A role for estrogen in prostate neoplasia has also been postulated. Therefore, one chemopreventive strategy for breast and prostate cancers is to decrease estrogen production. This can be accomplished by inhibiting aromatase, the enzyme that catalyzes the final, rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is of clinical interest for cancer therapy, and selective, potent aromatase inhibitors have been developed. Several of these agents have demonstrated chemopreventive efficacy in animal models. The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to serve as potential chemopreventive agents are the subjects of this review. After background information regarding aromatase is presented, the data for each inhibitor are summarized separately. The discussion focuses on those inhibitors that are clinically available or in clinical trials, including: aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane, exemestane, and atamestane. On the basis of results from preclinical studies, aromatase inhibitors may be promising agents for clinical trials in populations at high risk for developing estrogen-dependent cancers. Total suppression of aromatase may have adverse effects, as is evident in postmenopausal women (increased osteoporosis, cardiovascular disease, and urogenital atrophy). However, on the basis of preclinical studies of chemopreventive efficacy and chemotherapeutic applications of aromatase inhibitors showing dose-response efficacy, it may be possible to obtain chemopreventive effects without total suppression of aromatase and circulating estrogen levels. Suppressing local estrogen production may be an alternative strategy, as suggested by the discovery of a unique transcriptional promoter of aromatase gene expression, I.4, in breast adipose tissue. The development of drugs that target this promoter region may be possible.

Aromatase↗
PubMed1998

Development of new cancer chemoprevention agents: role of pharmacokinetic/pharmacodynamic and intermediate endpoint biomarker monitoring.

Recently, several promising strategies have been advanced for improving the efficiency of new agent development. These include pharmacokinetic/pharmacodynamic (PK/PD) and intermediate endpoint biomarker (IEB) monitoring. Here, we review their essential role as practical tools for guiding the evaluation of agents for cancer chemoprevention (CP) and provide examples of CP agents that utilize these approaches. Several important categories of IEBs are delineated, including histologically based (intraepithelial neoplasias and nuclear morphometry). The use of select IEBs combined with a Bayesian method for clinical trial monitoring for rapid identification of ineffective or promising agents is discussed. The similarities between IEB and TDM are described. Finally, we present future tools for enhanced monitoring of CP agents that will impact on laboratory medicine and are also applicable to many other drug classes, e.g., laser capture microdissection and cDNA chip microarrays that assess gene expression patterns of precancerous and cancerous lesions.

Anti-Inflammatory Agents↗
PubMed1997

NIST/NCI Micronutrients Measurement Quality Assurance Program: measurement repeatabilities and reproducibilities for fat-soluble vitamin-related compounds in human sera.

The NIST/NCI Micronutrient Measurement Quality Assurance Program has conducted 33 interlaboratory comparison exercises for fat-soluble vitamin-related compounds in human sera over the past 12 years. Periodic reanalysis of lyophilized serum samples prepared from more than 70 different sera has enabled estimation of the short- and long-term measurement characteristics. Median- and interquartile-range-based statistics adequately estimate the distribution of results from laboratories that are in analytical control from total distributions that include a significant minority of outlier data. Short-term interlaboratory reproducibility standard deviations (SDs) are predictable functions of analyte concentration, with an asymptotic limit at low analyte concentration and a linear relationship at high concentrations. Long-term trends in the interlaboratory reproducibility can be estimated by standardizing the short-term SD at the observed analyte concentration to an expected SD at a given physiologically significant analyte concentration. The "average" laboratory's same-day analytical repeatability SD is about one-third of the estimated interlaboratory reproducibility; repeatability for longer periods between analyses is, on average, on better than the reproducibility. While a few exceptional laboratories have maintained excellent repeatability over the entire decade, long-term study measurements generated within a single laboratory are not generally more internally consistent than results from multiple laboratories. Enhanced and more consistently implemented intralaboratory quality control and quality assurance methods are required to further improve and maintain interlaboratory measurement comparability.

Humans↗
PubMed1997

Chronic toxicity studies of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione, a potential chemopreventive agent.

The synthetic compound Oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione, is related to the 1,2-dithiolthiones naturally found in cruciferous vegetables, the consumption of which has been epidemiologically associated with reduced frequency of colorectal cancers. Oltipraz has shown chemopreventive efficacy in numerous laboratory epithelial cancer models and is a potential chemopreventive, antimutagenic compound that specifically induces Phase II enzymes. Thirteen-week and 1-year toxicity studies in rats and dogs were performed to characterize the toxicities of the compound at high dosages and to support potential further development as a chemopreventive agent in clinical trials. Administration to rats by gavage for 13 weeks at dosages of 5 and 50 mg/kg/day and for 52 weeks at dosages of 10, 30, and 60 mg/kg/day produced effects on the liver and on clinical chemistry and hematology parameters. Absolute and relative liver weight increases correlated with diffuse hypertrophy in the mid- and high-dose males and centrilobular hypertrophy in the high-dose females. Granularity of hepatocyte cytoplasm was also observed. These anatomical findings were associated with dose-associated slight increases in albumin, total protein, and cholesterol in the males and a moderate increase in cholesterol only in the females. In addition, slight decreases in erythrocyte count, hemoglobin, and hematocrit and reticulocyte elevations occurred. The no effect dose was considered 10 mg/kg/day. Administration by capsule to dogs at dosages of 10 and 100 mg/kg/day for 13 weeks and of 5, 15, and 60 mg/kg/day for 52 weeks also produced effects on the same endpoints noted in the rodent studies. In the 13-week study, precipitate was observed in the bile canaliculi, and gonadal atrophy and increased pituitary weights occurred in the males. Cholesterol and alkaline phosphatase activity were slightly elevated in both studies. Decreased hematology parameters in the 13-week study also occurred. The no effect dose was considered to be 5 mg/kg/day. Oltipraz is being carefully evaluated in clinical trials as a potential antimutagenic compound.

Administration, Oral↗
PubMed1997

Testing the Perrone and Stone (1994) model of heading estimation.

Human observers cannot judge heading accurately in the presence of simulated gaze rotations under many conditions [Royden et al. (1994). Vision Research, 34, 3197-3214]. They make errors in the direction of rotation with magnitudes proportional to the rotation rate. Two hypotheses have been advanced to explain this phenomenon. The extra-retinal-signal hypothesis states that the observer's estimate of gaze rotation is always based on an extra-retinal signal such as an efference copy. In the absence of such a signal, the observer assumes that no rotation has taken place and responds accordingly. The retinal-image hypothesis states that visual input dominates when the extra-retinal signal is small or absent; under this hypothesis, errors with simulated rotations are the consequence of faulty visual mechanisms. Perrone and Stone [(1994). Vision Research, 34, 2917-2938] proposed a model that purports to account for these errors using retinal-image information (optic flow) alone; its assumptions make it inefficient under some conditions. The most important of these assumptions is that the fixated target is stationary with respect to the world (the gaze-stabilization constraint). I compared the model's performance to human data from two experiments of Royden et al. [(1994). Vision Research, 34, 3197-3214]. One experiment simulated translation while tracking a target attached to the scene (gaze-stabilized), while the other simulated translation while tracking a target that was not attached (gaze-unstabilized). The incorporation of the gaze-stabilization constraint leads to a predicted asymmetry for the errors in the gaze-unstabilized experiment that is not observed in human data. I conclude that the model as it stands is not consistent with human behavior. It is possible, however, that the predicted asymmetry is masked in human data by a counteracting asymmetry in a hypothetical processing stage subsequent to the heading estimation that extrapolates the observer's future path of self-motion.

Eye Movements↗
PubMed1997

Farnesyl protein transferase inhibitors as potential cancer chemopreventives.

Among the most important targets for chemopreventive intervention and drug development are deregulated signal transduction pathways. Ras proteins serve as central connectors between signals generated at the plasma membrane and nuclear effectors; thus, disrupting the Ras signaling pathway could have significant potential as a cancer chemopreventive strategy. Target organs for Ras-based chemopreventive strategies include those associated with activating ras mutations (e.g., colorectum, pancreas, and lung) and those carrying aberrations in upstream element(s), such as growth factors and their receptors. Ras proteins require posttranslational modification with a farnesyl moiety for both normal and oncogenic activity. Inhibitors of the enzyme that catalyzes this reaction, farnesyl protein transferase (FPT) should, therefore, inhibit Ras-dependent proliferative activity in cancerous and precancerous lesions (J. B. Gibbs et al., Cell, 77: 175-178, 1994). Because growth factor networks are redundant, selective inhibition of signaling pathways activated in precancerous and cancerous cells should be possible. Requirements for Ras farnesylation inhibitors include: specificity for FPT compared with other prenyl transferases; specificity for FPT compared with other farnesyl PPi-utilizing enzymes; ability to specifically inhibit processing of mutant K-ras (the most commonly mutated ras gene in human cancers); high potency; selective activity in intact cells; activity in vivo; and lack of toxicity. Numerous FPT inhibitors have been identified through random screening of natural products and by rational design of analogues of the two substrates, farnesyl PPi and the COOH-terminal CAAX motif of Ras tetrapeptides. A possible testing strategy for developing FPT inhibitors as chemopreventive agents includes the following steps: (a) determine FPT inhibitory activity in vitro; (b) evaluate selectivity (relative to other protein prenyl transferases and FPT-utilizing enzymes); (c) determine inhibition of Ras-mediated effects in intact cells; (d) determine inhibition of Ras-mediated effects in vivo (e.g., in nude mouse tumor xenografts); and (e) determine chemopreventive efficacy in vivo (e.g., in carcinogen-induced A/J mouse lung, rat colon, or hamster pancreas).

Alkyl and Aryl Transferases↗
PubMed1997

Progress in clinical chemoprevention.

Chemoprevention has four goals: (1) inhibition of carcinogens, (2) logical intervention for persons at genetic risk for cancer, (3) treatment of precancerous lesions, and (4) confirmation and translation of leads from dietary epidemiology into intervention strategies. The National Cancer Institute has described a multidisciplinary, cancer science-based program for chemopreventive drug development that addresses these objectives, and has collaborated with the US Food and Drug Administration to provide consensus guidance for applying this approach. A critical component is the identification and characterization of intermediate biomarkers of cancer and their validation as surrogate end points for cancer incidence in clinical chemoprevention trials. More than 40 agents in the program are currently on the clinical development path (preclinical toxicology and phase I clinical safety studies or phase II/III efficacy trials), with the major effort in phase II studies to identify and characterize intermediate biomarkers. The continually advancing knowledge of molecular and tissue-based carcinogenesis mechanisms will provide leads to new chemopreventive agents with increased specificity for carcinogenesis-related activities and, hence, reduced toxicity by virtue of minimal effects on normal cell and tissue functions. Results from the Human Genome Project will help identify and evaluate the potential for chemopreventive intervention in cohorts at genetic risk and will provide specific target lesions for intervention strategies.

Anticarcinogenic Agents↗
PubMed1996

A genetic selection for Caenorhabditis elegans synaptic transmission mutants.

We have isolated 165 Caenorhabditis elegans mutants, representing 21 genes, that are resistant to inhibitors of cholinesterase (Ric mutants). Since mutations in 20 of the genes appear not to affect acetylcholine reception, we suggest that reduced acetylcholine release contributes to the Ric phenotype of most Ric mutants. Mutations in 15 of the genes lead to defects in a gamma-aminobutyric acid-dependent behavior; these genes are likely to encode proteins with general, rather than cholinergic-specific, roles in synaptic transmission. Ten of the genes have been cloned. Seven encode homologs of proteins that function in the synaptic vesicle cycle: two encode cholinergic-specific proteins, while five encode general presynaptic proteins. Two other Ric genes encode homologs of G-protein signaling molecules. Our assessment of synaptic function in Ric mutants, combined with the homologies of some Ric mutants to presynaptic proteins, suggests that the analysis of Ric genes will continue to yield insights into the regulation and functioning of synapses.

Acetylcholine↗
PubMed1996

New agents for cancer chemoprevention.

Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid], calcium, Beta carotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylornithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.

Animals↗
PubMed1996

Strategy and planning for chemopreventive drug development: clinical development plans II.

This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs.

Animals↗