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V E Steele

Publications and source records attributed to V E Steele.

At least 37 records · Page 2Linked to original sources
PubMed2000

Potential use of lipoxygenase inhibitors for cancer chemoprevention.

Increasing evidence suggests that lipoxygenase (LO)-catalysed metabolites have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO products have been found in breast tumours, colon cancers, lung, skin and prostate cancers, as well as in cells from patients with both acute and chronic leukaemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumour cell adhesion and regulation of apoptotic cell death. Agents that block LO catalytic activity may be effective in preventing cancer by interfering with signalling events needed for tumour growth. In the past ten years, pharmaceuticals agents that specifically inhibit the 5-LO metabolic pathway have been developed to treat inflammatory diseases such as asthma, arthritis and psoriasis. Some of these compounds possess anti-oxidant properties and may be effective in preventing cancer by blocking free radical-induced genetic damage or by preventing the metabolic activation of carcinogens. Other compounds may work by negatively modulating DNA synthesis. Pharmacological profiles of potential chemopreventive agents are compiled from enzyme assays, in vitro testing (e.g., cell proliferation inhibition in human cancer cells) and in vivo animal carcinogenesis models (e.g., N-methyl-N-nitrosourea-induced rat mammary cancer, benzo(a)pyrene-induced lung tumours in strain A/J mice and hormone-induced prostate tumours in rats). In this way, compounds are identified for chemoprevention trials in human subjects. Based on currently available data, it is expected that the prevention of lung and prostate cancer will be initially studied in human trials of LO inhibitors.

Animals↗
PubMed2000

Lack of chemopreventive efficacy of DL-selenomethionine in colon carcinogenesis.

Epidemiologic observations and laboratory research have suggested that dietary selenium reduces the risk of colon cancer. Selenium-enriched brewer's yeast as a dietary supplement reduces the incidence of and mortality from cancer of the colon in humans. It is not clear whether the observed inhibitory effect is due to selenomethionine, or to other forms of selenium, or to a mixture of the selenium compounds present in selenium-enriched brewer's yeast. Therefore, bioassay described in this study examined the chemopreventive efficacy of 10 and 15 ppm selenomethionine, equivalent to 3.6 and 5.4 ppm as selenium, against azoxymethane (AOM)-induced colon carcinogenesis. At five weeks of age, groups of male F344 rats were fed diets containing 0 (control diet), 10 or 15 ppm selenomethionine. At seven and eight weeks of age, all rats except those in vehicle-treated groups received s.c. injections of AOM at a dose rate of 15 mg/kg body wt. The rats were maintained on their respective diets for 52 weeks and were then sacrificed. Colon tumors were processed and evaluated histopathologically. Colon tumor incidence and multiplicity were analyzed statistically. No obvious toxic effects were observed following dietary administration of 10 or 15 ppm selenomethionine as indicated by body weight gain. Administration of 10 or 15 ppm selenomethionine had no significant effect on colon tumor incidence and multiplicity. This study suggests that i) selenomethionine lacks chemopreventive efficacy against AOM-induced colon carcinogenesis and ii) other forms of selenium or a mixture of selenium compounds present in selenium-enriched brewer's yeast need to be evaluated for their chemopreventive efficacy.

Adenocarcinoma↗
PubMed2000

Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.

We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.

Animals↗
PubMed1999

Termination of piroxicam treatment and the occurrence of azoxymethane-induced colon cancer in rats.

Piroxicam has been shown to prevent azoxymethane (AOM)-induced colon cancer when administered during the promotion/ progression phase. The requirement for continued treatment with piroxicam in order to maintain prevention of colon cancer was investigated. Male F344 rats were administered 15 mg/kg AOM at 7 and 8 weeks of age and started to receive piroxicam (200 mg/kg) in their diet at 11 weeks after the second dose of AOM. Piroxicam was removed from the diet of some of the rats at weeks 19 and 28 and the animals were held until week 47. Other rats continued to receive piroxicam until sacrificed at week 47. Treatment with piroxicam from week 11-47 reduced the yield of colon tumors. When treatment was terminated at week 19 or 28 the yield of tumors at week 47 was not reduced. Within 1 week of the start of piroxicam treatment, the number of aberrant crypt foci (ACF)/animal was decreased. Termination of treatment resulted in the recurrence of ACF. Apoptosis in adenomas was increased when piroxicam treatment was continued to week 47 but not when treatment was terminated earlier at week 19 or 28. The proliferating cell nuclear antigen-labeling index in adenomas was not affected by piroxicam even when treatment was from week 11 to 47. In summary, termination of treatment resulted in the occurrence of ACF and colon cancer indicating that prevention by piroxicam was reversible. Furthermore, enhancement of apoptosis and not decreased cell proliferation correlated with prevention of colon cancer.

Adenocarcinoma↗
PubMed1999

Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process.

Epidemiological and model studies with laboratory animals have provided evidence that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer. Sulindac, a nonsteroidal anti-inflammatory drug, has been shown to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats when administered continuously before, during, and after carcinogen treatment (initiation and postinitiation periods) or when given continuously beginning 14 weeks after carcinogen administration (promotion/ progression stage). The present study was designed to investigate the chemopreventive efficacy of sulindac sulfone (exisulind), the sulfone metabolite of sulindac, when administered during the promotion/progression stage of colon carcinogenesis in comparison to the effect during the initiation and postinitiation periods. We have also studied the modulating effect of exisulind on colonic tumor apoptosis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0%, 0.06%, and 0.12% exisulind. At 7 weeks of age, groups of animals were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 weeks). Animals intended for the promotion/progression study and receiving 0% exisulind were switched to an experimental diet containing 0.12% exisulind at 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, 50 weeks after the second AOM injection. Colon tumors were evaluated histopathologically for tumor type. Administration of 0.06% and 0.12% exisulind during the initiation and postinitiation periods significantly inhibited the incidence and multiplicity of invasive and/or noninvasive adenocarcinomas of the colon. The inhibition of colon tumorigenesis by exisulind was associated with a significant retardation of body weight gain shortly after sulfone administration and increased apoptosis in the colon tumors. In contrast, administration of the higher dose (0.12%) of exisulind during the promotion/progression stage had only minimal effects on colon tumorigenesis and apoptosis in the colon tumors, suggesting that early administration, but not late administration, may be required for chemopreventive efficacy of this drug.

Adenocarcinoma↗
PubMed1999

Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone.

Two in vivo bioassays were conducted to evaluate the efficacy of dehydroepiandrosterone (DHEA) as an inhibitor of prostate carcinogenesis in rats. Prostate adenocarcinomas were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In the first experiment, DHEA (1000 or 2000 mg/kg diet) was administered continuously to rats beginning 1 week before MNU exposure. In the second experiment, continuous administration of DHEA (2000 mg/kg diet) was begun either 1 week before, 20 weeks after, or 40 weeks after MNU exposure. Controls received basal diet without added DHEA. Studies were terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. In the first study, continuous dietary administration of DHEA beginning 1 week before MNU resulted in a dose-related inhibition of prostate cancer induction. In the second experiment, comparable reductions in prostate cancer incidence were observed in groups exposed to DHEA beginning 1 week before, 20 weeks after, and 40 weeks after carcinogen exposure. These data demonstrate that nontoxic doses of DHEA confer significant protection against prostate carcinogenesis in rats. The efficacy of delayed administration of DHEA suggests that the compound confers protection against later stages of prostate cancer induction and can suppress the progression of existing preneoplastic lesions to invasive disease.

Adenocarcinoma↗
PubMed1999

Chemoprevention of rat prostate carcinogenesis by 9-cis-retinoic acid.

A chemoprevention study was conducted to evaluate the activity of 9-cis-retinoic acid (9-cis-RA) as an inhibitor of prostate carcinogenesis in male Wistar-Unilever (HsdCpb:Wu) rats. After pretreatment with a sequential regimen of cyproterone acetate (50 mg/kg/day for 21 days) and testosterone propionate (100 mg/kg/day for 3 days), groups of 40 rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU; 30 mg/kg body weight). Beginning 2 weeks after carcinogen administration, rats received chronic exposure to testosterone administered in s.c. implanted silastic capsules. The study was terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. Continuous dietary administration of 9-cis-RA at 100 mg/kg diet or 50 mg/kg diet beginning 1 week before MNU administration reduced cancer incidence in the dorsolateral + anterior prostate from 65% in dietary controls to 18 and 20%, respectively (P < 0.001 for both comparisons). Similarly, these dose levels of 9-cis-RA reduced the incidence of cancer in all accessory sex glands from 79% in dietary controls to 48 and 33% (P < 0.01 for both comparisons), respectively. Chronic dietary administration of 9-cis-RA induced no gross or organ-specific toxicity in any animal and did not suppress group mean body weight gain. The potent anticarcinogenic activity of 9-cis-RA in the rat prostate, when considered with its apparent lack of toxicity in rodents, suggests that this and other ligands for the retinoid X receptor merit consideration for evaluation in clinical prostate cancer chemoprevention trials.

Alitretinoin↗
PubMed1999

Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer.

Curcumin, derived from the rhizome of Curcuma longa L. and having both antioxidant and anti-inflammatory properties, inhibits chemically induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or postinitiation stages. This study was designed to investigate the chemopreventive action of curcumin when it is administered (late in the premalignant stage) during the promotion/progression stage of colon carcinogenesis in male F344 rats. We also studied the modulating effect of this agent on apoptosis in the tumors. At 5 weeks of age, groups of male F344 rats were fed a control diet containing no curcumin and an experimental AIN-76A diet with 0.2% synthetically derived curcumin (purity, 99.9%). At 7 and 8 weeks of age, rats intended for carcinogen treatment were given s.c. injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight per week. Animals destined for the promotion/progression study received the AIN-76A control diet for 14 weeks after the second AOM treatment and were then switched to diets containing 0.2 and 0.6% curcumin. Premalignant lesions in the colon would have developed by week 14 following AOM treatment. They continued to receive their respective diets until 52 weeks after carcinogen treatment and were then sacrificed. The results confirmed our earlier study in that administration of 0.2% curcumin during both the initiation and postinitiation periods significantly inhibited colon tumorigenesis. In addition, administration of 0.2% and of 0.6% of the synthetic curcumin in the diet during the promotion/progression stage significantly suppressed the incidence and multiplicity of noninvasive adenocarcinomas and also strongly inhibited the multiplicity of invasive adenocarcinomas of the colon. The inhibition of adenocarcinomas of the colon was, in fact, dose dependent. Administration of curcumin to the rats during the initiation and postinitiation stages and throughout the promotion/progression stage increased apoptosis in the colon tumors as compared to colon tumors in the groups receiving AOM and the control diet. Thus, chemopreventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase (starting late in premalignant stage) of colon carcinogenesis.

Animals↗
PubMed1999

Effect of reduced body weight gain on the evaluation of chemopreventive agents in the methylnitrosourea-induced mammary cancer model.

These studies examined whether the small to moderate reductions in body weight gain (< or = 15%) affect mammary carcinogenesis. Beginning 1 week prior to methylnitrosourea (MNU) administration (experiment 1), rats received diets supplemented with 4-hydroxyphenylretinamide (4-HPR) (782 mg/kg of diet) and retinyl acetate (328 mg/kg of diet) or underwent food restrictions. Rats were administered an i.v. dose of MNU (50 mg/kg body wt) at 50 days of age. Although the final body weights were similarly depressed by 4-HPR (8%) and by retinyl acetate (11%) from rats fed ad libitum, the kinetics of inhibition were quite different. Whereas 4-HPR caused an acute decrease in body weight at the time it was administered, the effect of retinyl acetate was more chronic. At 110 days after the administration of MNU, the average number of mammary cancers per rat was 4.9 for rats fed ad libitum, 1.3 for rats fed 4-HPR, 3.1 when body weights were matched to 4-HPR-treated rats, 1.9 for retinyl acetate and 3.2 when body weights were matched to retinyl acetate. Experiment II was performed to determine the minimal degree of acute body weight gain reduction that would alter MNU-induced mammary carcinogenesis. Body weight gain depressions of 3, 6, 9, 12 and 15% were initiated at 43 days of age by dietary restrictions and MNU was administered at 50 days of age. At 120 days after MNU, the percentage decreases in mammary cancer multiplicity in the various groups were 14, 15, 41, 44 and 55%, respectively. These data demonstrate that moderate reductions (9-15%) in body weight gain, in particular when occurring during the initiation and early promotion stages can greatly affect cancer multiplicity.

Animals↗
PubMed1999

Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci.

We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.

Adenocarcinoma↗
PubMed1999

Prevention by aspirin and its combination with alpha-difluoromethylornithine of azoxymethane-induced tumors, aberrant crypt foci and prostaglandin E2 levels in rat colon.

The dose-response relationship in male F344 rats was determined for the ability of aspirin administered in the diet to prevent azoxymethane (AOM)-induced colon cancer and aberrant crypt foci (ACF) and to reduce prostaglandin E2 (PGE2) levels. Starting at either 7 or 22 weeks of age, the rats received aspirin. All rats received two doses of AOM (15 mg/kg each on days 7 and 14) and were killed on day 36. The lowest concentrations of aspirin to prevent ACF or reduce PGE2 levels were 600 and 400 mg/kg, respectively. To evaluate the prevention of tumors, rats received either 0 or 400 mg/kg aspirin for a total of 39 weeks with AOM (30 mg/kg) administered 7 days after the start of treatment. Aspirin had no effect on the yield of colon tumors. In a second experiment, rats started to receive 0, 200, 600 or 1800 mg/kg aspirin or 1000 mg/kg alpha-difluoromethylornithine (DFMO) +/- aspirin. Eight and 15 days later, all the rats received 15 mg/kg AOM. Eleven weeks later, animals that were receiving the control diet started to receive 0, 200, 600 or 1800 mg/kg aspirin; 1000 or 3000 mg/kg DFMO; or 1000 mg/kg DFMO + 200 or 600 mg/kg aspirin. The animals were killed 32 weeks later. DFMO effectively reduced the yield of colon tumors when administered starting either before or after AOM while aspirin was much weaker. The combination of aspirin + DFMO administered after AOM was synergistic. Both aspirin and DFMO decreased the Mitotic Index, while apoptosis was increased only by DFMO. Our results demonstrated that aspirin and DFMO could prevent colon cancer when administered after AOM. Furthermore, aspirin reduced ACF, PGE2 levels and mitosis at concentrations that did not prevent cancer. In contrast, the ability to enhance apoptosis did correlate with the prevention of cancer.

Animals↗
PubMed1999

Progress in cancer chemoprevention.

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).

Animals↗
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

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.

Animals↗
PubMed1998

Use of Druckrey analysis to quantitatively evaluate the chemopreventive efficacy of N-difluoromethylornithine (DFMO), a prototype proliferation inhibitor.

Druckrey analysis of the results of skin painting TG.AC transgenic mice with three different doses of benzo[a]pyrene was used to obtain quantitative estimates of the in vivo cancer chemopreventive efficacy of N-difluoromethylornithine. The percent decrease in mean rate of subvisible tumor development during the tumor latent period produced by 2000 ppm and 4000 ppm DFMO in the diet was 39% and 50%, respectively. Druckrey analysis was also successfully applied to transformations of published data on human cigarette smokers. The time before onset of lung cancer in 2% of smokers was prolonged 17 weeks for every cigarette per day not smoked. The Druckrey model, of substantiated validity because of the results in human smokers, provides a rapid quantitative screening method applicable to large numbers of candidate chemopreventive agents.

Animals↗
PubMed1998

Modulation of methylnitrosourea-induced breast cancer in Sprague Dawley rats by dehydroepiandrosterone: dose-dependent inhibition, effects of limited exposure, effects on peroxisomal enzymes, and lack of effects on levels of Ha-Ras mutations.

Dehydroepiandrosterone (DHEA), the major steroid precursor of androgens and estrogens produced in peripheral tissues in primates, is an effective chemopreventive agent in the N-methyl-N-nitrosourea (MNU)-induced rat mammary tumor model. Dietary DHEA (5-600 ppm; 600 mg/kg diet) was administered beginning 1 week before MNU and administered continually throughout the duration of the experiment. The highest dose of DHEA (600 ppm) significantly decreased tumor incidence from 95 to 45% and increased tumor latency and decreased tumor multiplicity from 4.1 to 0.5 tumors/rat. Lower doses of DHEA (5, 24, and 120 ppm) were also effective, decreasing tumor multiplicity by 28, 40, and 55%, respectively, increasing tumor latency in a dose-dependent manner but only minimally affecting final tumor incidence. DHEA in the diet caused a dose-dependent increase in serum levels of DHEA. The 120-ppm dietary dose of DHEA resulted in serum levels of DHEA of approximately 42 pmol/ml levels, similar to those seen in young humans. When we examined whole mounts of mammary glands derived from rats exposed to higher levels of DHEA (600 ppm), we observed a striking increase in lobular development. The doses of DHEA used in these studies (< or =600 ppm) had minimal effects on the induction of fatty acid CoA synthetase, a peroxisome-associated enzyme. In contrast, a dose of 2000 ppm substantially increased levels of peroxisome-associated fatty acid CoA synthetase. The varied and striking efficacy of DHEA was achieved in the absence of any significant effect on body weight gain in the treated rats. Furthermore, tumors from rats treated with MNU alone or rats treated with MNU plus DHEA were examined for the presence of mutations in the Ha-Ras oncogene. There was a slight decrease in the percentage of tumors bearing Ha-Ras mutations in tumors derived from MNU-control rats as contrasted with tumors from MNU-DHEA (120 and 600 ppm)-treated rats. Based on the striking chemopreventive efficacy of continual exposure to DHEA, we examined the effects of more limited exposure to DHEA. Rats were treated with DHEA for a period of 7 weeks immediately before and after MNU injection. Rats were then placed on the control diet for the ensuing 15 weeks. Even this limited exposure to DHEA for a period of 7 weeks profoundly decreased final tumor incidence and multiplicity. Additionally, we examined the effects of intermittent dosing with DHEA. Rats were treated alternatively at 3-week intervals either with diet containing DHEA or with control diet. It was found that this intermittent dosing with DHEA also substantially inhibited the formation of mammary tumors.

Animals↗