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R C Moon

Publications and source records attributed to R C Moon.

At least 37 records · Page 2Linked to original sources
PubMed1992

Intermediate endpoint biomarkers for chemoprevention.

The understanding of intermediate endpoint biomarker expression in relation to the sequential events in bladder tumorigenesis establishes a useful approach for evaluating chemopreventive agents. Biomarkers may be genotypic or phenotypic and function as biomarkers of susceptibility, exposure, effect, or disease. This paper reviews several years of research on biomarkers and their use in monitoring chemoprevention therapy. In initial animal experiments, mice were dosed with N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) while co-administering N-(4-hydroxyphenyl)retinamide (4-HPR). 4-HPR did not statistically reduce tumor incidence, but did affect tumor differentiation and, consequently, nuclear size and DNA ploidy. These results suggest that nuclear size and ploidy may function as intermediate endpoint biomarkers of effect for oncogenesis and that epigenetic as well as genetic mechanisms may be primary in the oncogenic process. Early biomarkers of effect which occur prior to genetic effects or chromosome aberration may portend a higher probability of being modulated by differentiating agents such as retinoids. In vitro studies demonstrated that RPMI-7666 cells cultured with a phorbol ester tumor promoter (12-O-tetradecanoyl-phorbol-13-acetate) could be redifferentiated with 13-cis-retinoic acid and dimethyl sulfoxide (DMSO). F-actin, a cytoskeletal biomarker with a presumed function in the epigenetic mechanisms of carcinogenesis, could also be normalized in HL-60 cells treated with 4-HPR or DMSO. A clinical evaluation of F-actin in patients with varying degrees of risk confirmed the value of F-actin as a differentiating biomarker useful for bladder cancer risk assessment. The clarification of when the phenotypic changes of F-actin occur in the oncogenic process was achieved when a variety of biochemical changes were mapped in the patients with bladder cancer. These studies confirmed that G-actin, a reciprocal form of F-actin, is increased relatively early in bladder cancer oncogenesis when multiple biomarkers are quantitated in the field, adjacent area, and the tumor. Comparison of each individual biomarker's expression from field, adjacent to tumor, and tumor, and subsequent cluster analysis of these biomarkers, indicated that the possible sequence of phenotypic expression of biomarkers in bladder cancer oncogenesis is from G-actin, to p300 antigen, to epidermal growth factor receptor (EGFR), to p185 (neu oncogene product), to DNA aneuploidy and, finally, to visual morphology.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Chemoprevention of experimental bladder cancer.

The chemopreventive efficacy of several compounds was evaluated in the N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer model using C57BL/6 x DBA/2F1 (BDF) male mice. Compounds were administered in a defined semipurified diet (AIN-76-A) either as single agents or in combination. As single agents and at the doses employed, 2-alpha-difluoromethylornithine (DFMO), piroxicam, oltipraz, and sodium molybdate effectively inhibited the incidence of transitional cell carcinoma (TCC). 4-Hydroxyphenyl retinamide (4-HPR) was ineffective. Body weight gain and survival was not affected by the doses of agents used. Combinations of two agents which increased efficacy were 4-HPR+DFMO, DFMO+piroxicam, 4-HPR+oltipraz, and DFMO+oltipraz. Three-agent combinations which showed enhanced efficacy against TCC induction were 4-HPR+Na molybdate+DFMO, 4-HPR+DFMO+piroxicam, and 4-HPR+DFMO+oltipraz. Although the three-agent combinations were, for the most part, no more effective than the two-agent combinations at the doses employed, all combination regimens significantly reduced bladder cancer incidence even when single agent administration did not.

Animals↗
PubMed1992

Secretion of vitamin A and retinol-binding protein into plasma is depressed in rats by N-(4-hydroxyphenyl)retinamide (fenretinide).

In clinical trials the cancer preventive drug N-(4-hydroxyphenyl)retinamide (HPR) markedly lowers plasma concentrations of retinol and retinol-binding protein (RBP). Five hours after injection of HPR (51 mumol/kg), serum concentrations of retinol and RBP were 33 and 42% lower, respectively, than control values in rats. Because the mean transit time for retinol disappearance from serum of HPR-treated rats (1.9 h) was similar to that for radiolabeled retinol in control rats in previous studies, plasma retinol turnover is apparently not accelerated by HPR treatment. To study the effects of HPR on the secretion of the retinol-RBP complex from liver, control or HPR-treated rats were injected with chylomicrons containing [3H]vitamin A and [14C]triglycerides. Both labels were rapidly cleared from plasma in the two groups. In control rats [3H]retinol concentrations began to increase in plasma after 30 min due to liver secretion of retinol bound to RBP. In HPR-treated rats, secretion was apparently inhibited because the amount of [3H]retinol bound to RBP at 4.66 h was only 2.6% of the control level. We conclude that HPR partially blocks the secretion of the retinol-RBP complex from liver and other tissues, and thus depresses plasma concentrations of vitamin A and RBP.

Animals↗
PubMed1992

Enhancement of biological activity by conjugation reactions.

Conjugation reactions, such as the formation of sulfates, glucuronides and amino acid derivatives of biologically active compounds, are classically considered as detoxication processes. In essence, common nonpolar compounds are rendered less active by the formation of water-soluble metabolites, which then can readily be excreted in the urine. In the past decade, however, it has become clear that some natural metabolites become more active rather than less so by the formation of such conjugates. Several compounds in this special group will be considered in this article; namely, glucuronide and hydroxyphenylamide conjugates of retinoic acid, glutathione and cysteine conjugates of halogenated hydrocarbons, glucuronide conjugates of various xenobiotics and polyglutamates of folic acid and its inhibitors. The metabolism, biological activity and toxicity of the parent molecule is profoundly affected in complex ways by such reactions. Thus, the historical concept of conjugation reactions as general detoxication processes is no longer tenable.

Animals↗
PubMed1992

Animal models for chemoprevention of respiratory cancer.

Of the several models for lung carcinogenesis, two appear appropriate for chemoprevention studies based upon dose response, tumor type, and tumor localization. One model utilizes the direct-acting carcinogen methylnitrosourea (MNU), and the other utilizes a carcinogen (diethylnitrosamine) requiring metabolic activation. Tumors appear rapidly in both models (within 6 months), and the model systems are responsive to modulation by several classes of potential chemopreventive agents. For example, the retinoid N-(4-hydroxyphenyl) retinamide reduces the incidence of lung adenosquamous carcinoma, but retinol or beta-carotene are ineffective when administered alone. However, concomitant administration of these compounds reduces the incidence of non-neoplastic dysplasias as well as adenosquamous carcinomas of the lung. In the MNU system, retinoids in general have been ineffective in reducing the incidence of tracheobronchial squamous-cell carcinomas.

Animals↗
PubMed1992

Retinoid glucuronides do not interact with retinoid binding proteins.

Retinoid glucuronides have recently been described as water soluble, biologically active retinoids. In mouse mammary gland organ cultures retinoyl glucuronide, a retinoic acid counterpart, inhibited hormone induced differentiation. In this report we examined whether the effects of retinoyl and retinyl glucuronides are mediated by specific retinoid binding protein in mammary glands in organ culture. Results indicated that neither retinoyl nor retinyl glucuronide competed for cytosolic retinoic acid or retinol binding proteins respectively. These results indicate that either the effects of retinoid glucuronides are independent of retinoid binding proteins or they have to be metabolized to an active component which may in turn bind to retinoid binding protein for the glucuronide action.

Animals↗
PubMed1992

Retinoids as chemopreventive agents for breast cancer.

Although several retinoids have been evaluated for prevention of mammary carcinogenesis in rats and mice, retinyl acetate (RA) and N-(4-hydroxyphenyl)retinamide (4-HPR) proved most effective. In rats, dietary administration of the retinoids reduced the incidence and number, and increased the latency of N-methyl-N-nitrosourea (MNU)-induced mammary cancers. 4-HPR reduced the number of hyperplastic alveolar nodules (HAN) in MTV- mice and the number of tumors in MTV+ mice. Other studies indicate that the synergistic effect of retinoid administration and hormonal deprivation is more efficacious in prevention of MNU-induced mammary cancer than either modality alone. Furthermore, retinoids alone and the combination of retinoid and tamoxifen inhibit the appearance of mammary cancers following the surgical removal of the first cancer as well as inhibit the growth of established cancers. Again, the combined modality was the most effective. Retinoids also exert an antiproliferative effect upon the mammary epithelium in vivo, which is represented morphologically by a bare duct system with little branching, end buds, and few, if any, alveoli. In organ culture, retinoids inhibit mammary end bud differentiation and proliferation induced by insulin and prolactin or carcinogens.

Animals↗
PubMed1991

Inhibition of rat mammary gland chemical carcinogenesis by dietary dehydroepiandrosterone or a fluorinated analogue of dehydroepiandrosterone.

The chemopreventive efficacy of p.o. administered dehydroepiandrosterone (DHEA), DHEA plus N-(4-hydroxyphenyl)retinamide (4-HPR), or 16 alpha-fluoro-5-androsten-17-one (DHEA analogue 8354) was examined in rats treated with N-methyl-N-nitrosourea (MNU; 50 mg/kg body weight, i.v.) at 50 days of age. Semipurified diet (AIN-76A) containing each steroid alone, or DHEA plus 4-HPR, was administered during initiation (-1 week to +1 week post-MNU), promotion/progression (+1 week post-MNU to termination), or both phases (-1 week post-MNU to termination) of the carcinogenic process. Neither DHEA nor DHEA analogue 8354 (0.2%, w/w) significantly affected the initiation of mammary cancer when administered alone; however, DHEA (0.2%, w/w) plus 4-HPR (1 mmol/kg diet) significantly reduced cancer multiplicity (26%) when given during initiation. All three treatments were strongly effective when given during promotion/progression, significantly reducing mammary cancer multiplicity by 77% (DHEA), 84% (DHEA/4-HPR), and 66% (DHEA analogue 8354), relative to carcinogen controls. Cancer incidence was significantly inhibited by DHEA (33% inhibition) and DHEA/4-HPR (24% reduction) during promotion/progression. However, the most effective chemopreventive treatment encompassed both phases of carcinogenesis. Thus, under these conditions, DHEA (0.2% or 0.1%, w/w) reduced cancer incidence (52% and 32% reductions, respectively) and multiplicity (91% and 86% reductions, respectively). Further reduction in mammary cancer incidence was observed in animals that received DHEA (both doses) plus 4-HPR (1 and 0.5 mmol/kg diet, respectively). DHEA analogue 8354 (0.2% or 0.1%, w/w) given for the duration of the study reduced only cancer multiplicity (61% and 56% reductions, respectively). Tumor-related mortality was significantly lower in rats that received long-term treatment with DHEA or DHEA/4-HPR, when compared with carcinogen controls. Except for a slight, but significant, postcarcinogen decrease in the mean body weights of rats treated concomitantly with DHEA (plus or minus 4-HPR) and MNU, additional gross manifestations of steroid-induced toxicity were not observed.

Androstenes↗
PubMed1991

Distribution of fenretinide in the mammary gland of breast cancer patients.

Fenretinide has been used orally as a chemopreventive retinoid in a trial for women at risk of developing contralateral breast cancer. The levels of fenretinide and its metabolites were measured in the breast tissue obtained at surgery from women in the trial. Fenretinide was concentrated by breast tissue. Two major metabolites were detected in the tissue extract, one co-eluting with N-(4-methoxyphenyl)retinamide (4-MPR), and the other, more polar, eluting at 17 min under the conditions used. This metabolite remains unidentified. Division of the breast tissue into epithelial cells and fat fractions revealed that fenretinide and the metabolite at the 17 min peak were concentrated in the epithelial cells, whereas 4-MPR was principally localised in the fat compartment. Thus fat may serve as a storage compartment for the retinoid.

Adipose Tissue↗
PubMed1991

Effects of retinoid glucuronides on mammary gland development in organ culture.

Retinoyl beta-glucuronide (RAG) and retinyl beta-glucuronide (ROG) inhibit prolactin-induced morphological developments in cultured mouse mammary gland, and are equally effective in depressing prolactin and steroid hormone-induced DNA synthesis in the same tissue. Retinol is essentially inactive by both assay methods. Although RAG and ROG show little or no toxicity in several cell and animal models, some possibly toxic manifestations were seen at higher concentrations in cultured mammary tissue. Nonetheless, because of the strong correlation between the actions of chemopreventive agents in culture mouse mammary glands and their effectiveness in vivo, the retinoid glucuronides may well prove to be useful cancer chemopreventive agents.

Animals↗
PubMed1990

Respiratory carcinogenesis of nitroaromatics.

The carcinogenic potential of 1-nitropyrene, a major mutagenic constituent of diesel-exhaust particles, was investigated using a hamster respiratory-carcinogenesis model. The specific aims of the investigation were to assess the activity of 1-nitropyrene as a complete carcinogen (Study 1) and as a cocarcinogen (Study 2) when administered in combination with the known environmental carcinogen benzo[a]pyrene. Preparations of 1-nitropyrene and benzo[a]pyrene adsorbed onto an equal mass of carbon carrier particles (Stokes diameter 2 to 5 microns, greater than 70 percent) were used for the intratracheal administration. Evaluation of 1-nitropyrene as a complete carcinogen involved exposing male Syrian golden hamsters to 1 or 2 mg of 1-nitropyrene either once or twice each week. A once-per-week instillation of 2 mg of benzo[a]pyrene served as a positive control. Two groups of animals received sterile saline only (saline controls) or carbon particles suspended in saline (particle controls). In addition, a group of untreated hamsters served as shelf controls. Evaluation of 1-nitropyrene as a cocarcinogen involved treating animals once each week with either 1 or 2 mg of 1-nitropyrene with or without concomitant exposure to 0.25 mg of benzo[a]pyrene. The studies were terminated after 92 weeks of treatment. In both studies, hamsters receiving 1-nitropyrene showed a dose-related decrease in survival and body-weight gain. In general, animals in Study 2 showed better survival than those in Study 1. A high intercurrent mortality was observed in the control groups of Study 1. In order to adjust for intercurrent mortality, tumor incidences were analyzed after modeling (using Cox regression) the effect of treatment in all animals for the period they were alive. A broad spectrum of neoplastic and nonneoplastic lesions was observed in the lungs and tracheas of all hamsters except shelf controls. Because of the histologic complexity of these lesions, the slides were coded, and the tissues were evaluated by an unbiased pathologist. The tumor types included papillomas, adenomas, adenocarcinomas, and squamous cell carcinomas, the latter being the most prevalent type in benzo[a]pyrene-treated animals. In view of the low incidence of tumors in 1-nitropyrene-treated hamsters, the tumor incidences in various experimental groups were compared regardless of the tumor type, location, and multiplicity. A small, but significant, increase in tumor incidence, with a dose-response trend, was observed only in Study 2 hamsters receiving 1-nitropyrene once weekly. In contrast, treatment with benzo[a]pyrene adsorbed onto carbon particles induced benign and malignant tumors virtually in all animals that survived more than 50 weeks of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1989

Chemopreventive efficacy of combined retinoid and tamoxifen treatment following surgical excision of a primary mammary cancer in female rats.

Dietary N-(4-hydroxyphenyl)retinamide (4-HPR; 3 mmol/kg diet) and s.c. injections of the antiestrogen, tamoxifen (Tx; 10 micrograms or 20 micrograms per rat, thrice weekly) were used together as adjunct chemopreventive therapy in groups of 39-40 female, Sprague-Dawley rats that each received an i.v. injection (50 mg/kg b.w.) of the mammary gland carcinogen N-methyl-N-nitrosourea (MNU). Treatment was started immediately following the surgical excision of the first (primary) mammary carcinoma from each MNU-treated rat and was continued for 180 days. When compared to the effect of treatment with 4-HPR or Tx (30 micrograms/wk) alone, the combination treatments significantly enhanced terminal survival and reduced nonrecurrent mammary cancer incidence and multiplicity. Data showing the incidence of rats bearing the first through fifth additional cancers to appear following surgical resection of a primary lesion demonstrate that combined treatment with 4-HPR/Tx was immediately and consistently more efficacious than either agent per se in suppressing subsequent tumor appearance. This effect was apparently related to the dose of Tx. These results suggest that combined treatment with 4-HPR/Tx is superior to that of either agent alone in blocking progression of incipient neoplastic lesions at both early and later stages of the process.

Animals↗
PubMed1989

Chemoprevention of experimental carcinogenesis in animals.

Retinoids are well-established chemopreventive agents for experimental carcinogenesis of many target organs including mammary glands, urinary bladder, lung, skin, liver, pancreas, colon, and esophagus. Modification of the basic retinoid structure has produced analogs with enhanced target organ specificity, increased inhibitory activity, and reduced toxicity. N-(4-hydroxyphenyl)retinamide (4-HPR) currently appears to be the most efficacious retinoid against carcinogen-induced breast, urinary bladder, and lung cancer in rodents. Retinoids are most effective when administered shortly after the carcinogen treatment; however, the treatment can be delayed significantly while maintaining its chemopreventive effect. Under various experimental conditions combining retinoid treatment with other modifiers of growth enhances its chemopreventive activity; for example retinoid plus hormonal modulation can provide better protection against mammary cancer than either treatment alone. More recently chemopreventive activity of various other classes of agents, such as thiols, phenols, antioxidants, inhibitors of prostaglandin synthesis, etc., have been investigated in experimental mammary, urinary bladder, and lung cancer models.

Animals↗
PubMed1989

Therapeutic effect of N-(4-hydroxyphenyl)retinamide on N-methyl-N-nitrosourea-induced rat mammary cancer.

Virgin Sprague--Dawley rats received a single i.v. injection of 40 mg N-methyl-N-nitrosourea (MNU)/kg body wt. at 50 days of age. After the first palpable mammary tumor reached 10 mm in size, the animals were sequentially allocated to one of 4 groups: (I) placebo diet, (II) 10 micrograms tamoxifen s.c. 3 times per week, (III) 3 mmol N-(4-hydroxyphenyl)retinamide (4-HPR)/kg diet, or (IV) both (II) and (III). Weekly measurements of initial tumors and subsequent tumors were made throughout the study. 4-HPR administration resulted in a complete regression (non-palpable state) of the first mammary tumor in 6 animals (22%) and partial regression or nonprogression in 5 others (19%). Tamoxifen alone induced only partial response in 9 animals (33%). 4-HPR and tamoxifen resulted in 19% total and 26% partial response. The data suggests therapeutic value of 4-HPR in MNU-induced rat mammary carcinoma.

Adenocarcinoma↗
PubMed1989

Suppression of rat mammary cancer development by N-(4-hydroxyphenyl)retinamide (4-HPR) following surgical removal of first palpable tumor.

A study was conducted to determine whether N-(4-hydroxyphenyl)retinamide (4-HPR) affects the development of new mammary tumors subsequent to the surgical removal of the first palpable tumor. Sprague-Dawley female rats were injected i.v. with 35 mg N-methyl-N-nitrosourea (MNU) per killogram body weight at 50 days of age. The first palpable tumor was removed when 0.3-0.5 cm in diameter, and the animals placed on diets containing either 1, 2 or 3 mmol 4-HPR/kg diet. Placebo diet without 4-HPR served as control. Some animals were killed at the time of surgical removal of the first tumor and whole mounts of the mammary glands were prepared. Moreover, five animals per group were bled at 1, 3 and 6 months after commencing the 4-HPR diet and the levels of 4-HPR and N-(4-methoxyphenyl)retinamide (4-MPR) were determined. 4-HPR decreased tumor multiplicity in a dose-related manner, but cancer formation was only inhibited at the 2 and 3 mmol levels of 4-HPR. Whole mounts of mammary glands of rats treated with MNU demonstrated the presence of nonpalpable microscopic tumors in addition to the palpable tumor which was excised. Plasma levels of 4-HPR and 4-MPR increased with increasing dietary dose levels, but a linear relationship was not evident. However, the increase in plasma 4-HPR was directly correlated with an increased survival of the tumor-bearing animals. The results indicate that 4-HPR effectively inhibits the appearance of subsequent mammary tumors following excision of the first palpable tumor, and thus may be suitable for use as a chemopreventive agent in patients at increased risk for breast disease.

Administration, Oral↗