Showing papers by "Michael B. Sporn published in 1978"

Retinoids block phenotypic cell transformation produced by sarcoma growth factor.

Abstract: MURINE SARCOMA VIRUS (MSV)-transformed cells lack available receptors for epidermal growth factor (EGF)1,2. We have shown that this altered phenotype is the result of the endogenous production of growth factors by the MSV-trans-formed cells themselves. The major activity, isolated and purified from transformed cells, has been found in a 12,000-molecular weight peak and competed with EOF in an EGF-receptor-binding assay3. This growth factor, called sarcoma growth factor (SGF), stimulates cell division, causes normal cells to grow in soft agar and produces rapid, reversible morphological transformation of cells in monolayer culture3. There is no evidence that SGF acts as a complete carcinogen, producing permanent cell transformation; its properties resemble classical chemical promoters of carcinogenesis, like 12-O-tetradecanoylphorbol-13-acetate (TPA)4–6, the highly active component of croton oil. Whereas TPA is an exogenous plant derivative acting on an animal or a cell, SGF is an endogenous, virally induced growth promoter. In this respect it is interesting that retinoids (vitamin A and synthetic analogues)7 block the action in vivo of exogenous and endogenous promoters, preventing carcinogens from producing new tumours, but do not reverse the growth of many established tumours7–10. Retinoids prevent cancer of the lung7,11, skin9, bladder12 and mammary gland13 in experimental animals, block cell transformation induced by chemicals14 and radiation14,15 in culture, and reverse the anchorage-independent growth of transformed mouse fibroblasts16. If SGF is part of the natural tumour-promoting system and retinoids are part of the natural defence against that system, then one should be able to demonstrate a direct antagonism in cell culture. This, report establishes that this happens.

Inhibitory Effect of 13-cis-Retinoic Acid on Urinary Bladder Carcinogenesis Induced in C57BL/6 Mice by N-Butyl-N-(4-hydroxybutyl)nitrosamine

Abstract: The effect of 13-cis-retinoic acid on the induction of urinary bladder carcinoma by N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) was studied in male C57BL/6 mice. Animals received a total dose of either 90 or 140 mg of OH-BBN via gastric intubations of 7.5 or 10.0 mg of OH-BBN 2 times each week for 6 or 7 weeks, respectively. Seven days after the last OH-BBN intubation, animals were fed laboratory chow diet supplemented with either 200 mg of 13-cis-retinoic acid per kg or its placebo. Animals were killed at 6 months after the first carcinogen intubation. Highly invasive squamous and transitional cell carcinomas of the urothelium were found at autopsy. In the majority of these carcinomas, invasion of the bladder muscle wall by tumor cells had occurred. At the two dose levels of OH-BBN, feeding of 13-cis-retinoic acid reduced the incidence of both carcinomas and noninvasive papillomas, as well as the extent of neoplastic development in the urinary bladder. In mice receiving the lower dose of OH-BBN, the feeding of 13-cis-retinoic acid prevented the appearance of both squamous and transitional cell carcinomas with a reduction in incidence from 33 to 0% (p less than 0.01). The results of this study indicate that 13-cis-retinoic acid reduced not only the severity of highly invasive urinary bladder carcinomas but also the incidence of such cancers.

Pathology of esophageal neoplasms and associated proliferative lesions induced in rats by N-methyl-N-benzylnitrosamine.

Abstract: Multiple squamous cell neoplasms of the esophagus were induced in 24 inbred F344 rats by sc injection of N-methyl-N-benzylnitrosamine at a dose level of 2.5 mg/kg weekly for 20 weeks. All of these rats also developed papillomas, 67% developed pedunculated papillary carcinomas, and 63% developed carcinomas that invaded the wall. Of 191 total neoplasms, 66% were papillomas, 17% were papillary carcinomas, and 17% were carcinomas that invaded the wall. The neoplasms were well differentiated with various degrees of keratinization. Anaplastic areas were found in most lesions, but were more common in carcinomas. Neoplasms that invaded the wall were sessile, with prominent intraluminal growth, or infiltrating, with predominant intramural growth. Penetration through the wall was observed, but neither metastases nor invasion of adjacent tissues was found. In addition to neoplasms, atypical endophytic proliferation of basal and spinous cells was observed in some of these rats. Proliferative or neoplastic changes were not observed outside the upper gastrointestinal tract.

Assay of Retinoids in Biological Samples by Reverse-Phase High-Pressure Liquid Chromatography

Abstract: A separation procedure for retinoids based on reversephase high-pressure liquid chromatography with solvent mixtures of acetonitrile and water is described. The method may be applied to the screening of synthetic retinoids, which have potential for use in the prevention of cancer. It is easily adapted to a variety of biological samples and can be applied to other conventional retinold assays in liver and plasma, detecting as little as 1 nmol retinyl esters and less than 0.3 nmol retinol per g tissue. The one-step chromatography results in separation and simultaneous determination of many of the synthetic retinoids and all of the natural retinoids, including the retinyl esters that are separated into their major fatty acid components. The method has been applied to the analysis of retinoid levels in the liver and intestine of vitamin Adeficient hamsters following a p.o. dose (0.5 mg/day for 2 days) of retinyl acetate or of a synthetic vitamin A analog and is predictive of the degree to which various synthetic retinoids can be converted to retinol and stored in the liver as retinyl esters. Because of its speed, excellent recoveries, and high resolution, the method offers significant advantages over previous, more lengthy procedures.

Dose Response to Intrarectal Administration of N-Methyl-N-nitrosourea and Histopathologic Evaluation of the Effect of Two Retinoids on Colon Lesions Induced in Rats

Abstract: Male F344 rats, 8 weeks of age, were given 16 intrarectal administrations of N-methyl-N-nitrosourea (NMU) at one of three dose levels over a period of 8 weeks. Five days after the final NMU instillation, rats were placed on one of three diets: chow with gelatin beadlets, chow with beadlets containing 0.024% 13-cis-retinoic acid, or chow and beadlets with 0.006% of the trimethylmethoxy phenyl analog of retinoic acid ethylamide. Groups of 20-40 rats were killed at 22-26 weeks after the first carcinogen treatment. The number of rats with colon carcinoma and the number of tumors per rat were dose related. In addition, "blind" histopathologic evaluation of four predesignate colon locations revealed a dose-related incidence of microscopic preinvasive and invasive colon carcinomas. The feeding of diets containing these two retinoids did not significantly alter the incidence of these parameters of carcinogenesis or the mean histopathologic score at predesignated colon locations for preinvasive or invasive neoplastic lesions. Over 90% of the colon neoplasms induced were invasive tubulopapillary adenocarcinomas. The diameters of the tumors correlated significantly with degrees of invasion of the colons. Only 1 tumor (a signet ring carcinoma) metastasized to the peritoneal cavity. Only 2 of 300 rats treated with NMU had tumors at sites other than the colon.

Biological Activity and Metabolism of the Retinoid Axerophthene (Vitamin A Hydrocarbon)

Abstract: Biological properties of axerophthene, the hydrocarbon analog of retinol, have been studied both in vitro and in vivo . In tracheal organ culture axerophthene reversed keratinization caused by deficiency of retinoid in the culture medium; its potency was of the same order of magnitude as that of retinyl acetate. Axerophthene supported growth in hamsters fed vitamin A-deficient diets although less effectively than did retinyl acetate. Axerophthene was considerably less toxic than was retinyl acetate when administered repeatedly in high doses to rats. Administration of an equivalent p.o. dose of axerophthene caused much less deposition of retinyl palmitate in the liver than did the same dose of retinyl acetate, while a greater level of total retinoid was found in the mammary gland after administration of axerophthene.

Chemoprevention of cancer

Abstract: In this short article, we review the conceptual basis for chemoprevention of cancer, the proven clinical efficacy of this concept, and current trends to develop new chemopreventive agents based on understanding of their mechanisms of action. Four classes of new agents, namely selective inhibitors of cyclooxygenase-2, selective estrogen receptor modulators, rexinoids (retinoids that bind selectively to the receptors known as RXRs) and ligands for the peroxisome proliferator-activated receptor-gamma are discussed in detail. The importance of developing totally new classes of chemopreventive agents is stressed, with particular emphasis on the potential usefulness of new synthetic triterpenoids derived from naturally occurring molecules.