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Showing papers by "Michael B. Sporn published in 1981"


Journal ArticleDOI
19 Mar 1981-Nature
TL;DR: If dietary β-carotene is truly protective—which could be tested by controlled trials—there are a number of theoretical mechanisms whereby it might act, some of which do not directly involve its ‘provitamin A’ activity.
Abstract: Human cancer risks are inversely correlated with (a) blood retinol and (b) dietary beta-carotene. Although retinol in the blood might well be truly protective, this would be of little immediate value without discovery of the important external determinants of blood retinol which (in developed countries) do not include dietary retinol or beta-carotene. If dietary beta-carotene is truly protective--which could be tested by controlled trials--there are a number of theoretical mechanisms whereby it might act, some of which do not directly involve its 'provitamin A' activity.

1,483 citations


Journal ArticleDOI
TL;DR: Proteins potentiated by epidermal growth factor to induce a transformed phenotype in non-neoplastic rat kidney fibroblasts in cell culture have been isolated from many non-Neoplastic tissues of the adult mouse, including submaxillary gland, kidney, liver, muscle, heart, and brain.
Abstract: Proteins potentiated by epidermal growth factor (EGF) to induce a transformed phenotype in non-neoplastic rat kidney fibroblasts in cell culture have been isolated from many non-neoplastic tissues of the adult mouse, including submaxillary gland, kidney, liver, muscle, heart, and brain. They resemble previously described transforming growth factors (TGFs) isolated from neoplastic cells as follows: they are extractable by acid/ethanol and are acid-stable, low molecular weight (6000-10,000) polypeptides requiring disulfide bonds for activity; and they cause anchorage-independent growth of non-neoplastic indicator cells that will not grow in soft agar in their absence. Partial purification of these TGFs from submaxillary glands of male mice shows that they are distinct from EGF. Unlike previously described extracellular TGFs, but like certain cellular TGFs from neoplastic cells, they are potentiated by EGF in their ability to promote anchorage-independent growth. The isoelectric point of the submaxillary gland TGF protein is near neutrality. Chromatography on Bio-Gel P-30 followed by high-pressure liquid chromatography has resulted in a 22,000-fold overall purification. The most purified protein is active in inducing growth in soft agar at 1 ng/ml when assayed in the presence of EGF. The data add further evidence to the concept that neoplasia may result from a quantitative, rather than qualitative, alteration in non-neoplastic biochemical processes.

899 citations


Journal ArticleDOI
TL;DR: The term "autocrine secretion" has been proposed for this type of situation where a cell secretes a hormone-like substance for which it has external cell membrane receptors and may provide a partial explanation for some aspects of tumor cell progression.
Abstract: Transforming growth factors (TGFs) are growth-promoting polypeptides that cause phenotypic transformation and anchorage-independent growth of normal cells. They have been isolated from several human and animal carcinoma and sarcoma cells. One TGF is sarcoma growth factor (SGF) which is released by murine sarcoma virus-transformed cells. The TGFs interact with epidermal growth factor (EGF) cell membrane receptors. TGFs are not detectable in culture fluids from cells which contain high numbers of free EGF cell membrane receptors. SGF acts as a tumor promoter in cell culture systems and its effect on the transformed phenotype is blocked by retinoids (vitamin A and synthetic analogs). The production of TGFs by transformed cells and the responses of normal cells to the addition of TGFs to the culture medium raise the possibility that cells "autostimulate" their own growth by releasing factors that rebind at the cell surface. The term "autocrine secretion" has been proposed for this type of situation where a cell secretes a hormone-like substance for which it has external cell membrane receptors. The autocrine concept may provide a partial explanation for some aspects of tumor cell progression.

93 citations


Journal Article
TL;DR: The highly invasive nature of the carcinomas induced by quantitative administration of OH-BBN in B6D2F1, mice provides a useful animal model of the highly invasive variant of human transitional cell urinary bladder cancer in which to study chemoprevention by retinoids as well as other compounds.
Abstract: Highly invasive carcinomas of the urinary bladder were induced in male C57BL/6 X DBA/2 F1 (hereafter called B6D2F1) mice by gastric intubation of N-butyl-(4-hydroxybutyl)nitrosamine (OH-BBN) using a quantitative dosing schedule. Animals received either 5 or 10 mg OH-BBN per intubation, two times each week, for 9 weeks for a total dose of either 90 or 180 mg, and they were killed 6 months after the first carcinogen intubation. Seven days after the final intubation of OH-BBN, animals were fed either a placebo diet or diet supplemented with either 150 or 200 mg 13-cis-retinoic acid per kg of diet. A 41 and 43% incidence of urinary bladder cancer was observed in mice given the low and high dose of carcinogen, respectively, and fed a placebo diet. Sixty-seven % of the carcinomas induced in these animals invaded either into or through the urinary bladder wall. Varying degrees of transitional and either squamous or glandular or both squamous and glandular differentiation were observed in the carcinomas. Feeding of diet supplemented with 13-cis-retinoic acid reduced cancer incidence; the degree of reduction was proportional to the dose of retinoid administered. The highly invasive nature of the carcinomas induced by quantitative administration of OH-BBN in B6D2F1, mice provides a useful animal model of the highly invasive variant of human transitional cell urinary bladder cancer in which to study chemoprevention by retinoids as well as other compounds.

76 citations


Journal ArticleDOI
TL;DR: Plasma concentration-time curves for all-trans-retinoic acid (RA) after 0.0.015, 0.25 or 5 mg/kg, i.V., deviated from first-order kinetics in the rat, which indicated dose-dependent kinetics of RA in plasma were not due to enterohepatic recirculation of RA, since RA levels in Plasma were not lower in rats with biliary fistulas given comparable doses.

69 citations


Book ChapterDOI
01 Jan 1981
TL;DR: The role of retinol and its esters in determining normal epithelial cell differentiation has been known for over 50 years since the classical studies of Wolbach and Howe (1925) who observed the differentiated cells of various specialized epithelia throughout the body were replaced by squamous, keratinizing cells during retinoid* deficiency.
Abstract: The role of retinol and its esters in determining normal epithelial cell differentiation has been known for over 50 years since the classical studies of Wolbach and Howe (1925) who observed the differentiated cells of various specialized epithelia throughout the body were replaced by squamous, keratinizing cells during retinoid* deficiency.

50 citations


Journal Article
TL;DR: The chemopreventive activity of two synthetic retinamides of relatively low toxicity against N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer was studied in rats and mice and all three retinoids reduced the incidence, number, and severity of the low-grade papillary transitional cell carcinomas of the urinary bladder.
Abstract: The chemopreventive activity of two synthetic retinamides of relatively low toxicity against N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer was studied in F344 rats and C57BL/6 X DBA/2 F1 mice. Female and male rats were given a total dose of either 1800 or 3200 mg OH-BBN over a period of 6 or 8 weeks, respectively. Male mice were given a total dose of either 90 or 180 mg OH-BBN over a period of 9 weeks. Seven days after the final intubation of a period of 9 weeks. Seven days after the final intubation of OH-BBN, animals were fed either a placebo diet or a diet supplemented with the following retinoids: for rats, 0.8 mmol 13-cis-retinoic acid, 2 mmol N-(ethyl)-all-trans-retinamide, or 2 mmol N-(2-hydroxyethyl)-all-trans-retinamide per kg diet; and for mice, either 0.5 or 1.0 mmol of N-(ethyl)-all-trans-retinamide or N-(2-hydroxyethyl)-all-trans-retinamide per kg diet. Animals were killed 6 months after the initial gastric intubation. In comparison to male and female rats fed placebo diets, all three retinoids reduced the incidence, number, and severity of the low-grade papillary transitional cell carcinomas of the urinary bladder. Similarly, treatment of mice with either of the two retinamides reduced the incidence of highly invasive urinary bladder carcinomas. The chemopreventive effect of the less toxic retinamides was equal to or greater than that of 13-cis-retinoic acid.

38 citations


Journal ArticleDOI
TL;DR: Further in vitro metabolism of [3H]retinyl acetate paralleled the metabolism of [/14C]retinoic acid suggesting that these two compounds are being metabolized through similar pathways.

26 citations


Journal ArticleDOI
TL;DR: Analysis of the bile by reverse-phase high-pressure liquid chromatography demonstrated that the retinoic acid was being metabolized to several more polar compounds, with a greater proportion of the all-trans-retinoic Acid being converted to compounds that eluted in the more polar regions of the column effluent.

25 citations