retinol-acetate and Cocarcinogenesis

The potential modifying effect of retinyl acetate (RA) on butylated hydroxyanisole (BHA)-induced rat forestomach tumorigenesis was examined. Male F344 rats, 5 weeks of age, were maintained on diet containing 1% or 2% BHA by weight and simultaneously on drinking water supplemented with RA at various concentrations (w/v) for 52 weeks. In groups given 2% BHA, although marked hyperplastic changes of the forestomach epithelium were observed in all animals, co-administration of 0.25% RA significantly (P less than 0.05) increased the incidence of forestomach tumors (squamous cell papilloma and carcinoma) to 60% (9/15, 2 rats with carcinoma) from 15% (3/20, one rat with carcinoma) in the group given RA-free water. In rats given 1% BHA, RA co-administered at a dose of 0.05, 0.1, 0.2 or 0.25% showed a dose-dependent enhancing effect on the development of the BHA-induced epithelial hyperplasia. Tumors, all papillomas, were induced in 3 rats (17%) with 0.25% RA and in one rat (10%) with 0.05% RA co-administration. RA alone did not induce hyperplastic changes in the forestomach. These findings indicate that RA acted as a co-carcinogen in the BHA forestomach carcinogenesis of the rat.

Topics: Animals; Body Weight; Butylated Hydroxyanisole; Cocarcinogenesis; Diterpenes; Drug Administration Schedule; Epithelium; Kidney Papillary Necrosis; Male; Neoplasms, Experimental; Organ Size; Rats; Rats, Inbred F344; Retinyl Esters; Stomach Neoplasms; Vitamin A

The effect of high levels of dietary fat and retinyl acetate (ROA) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor development and growth was examined. Female Sprague-Dawley rats, 51-53 days of age, were treated ig with 5 mg DMBA. At 55-57 days of age, the animals were divided into the following dietary treatment groups: A) 4.5% fat [control fat (CF)]; B) CF + 1.0 mmol ROA/kg diet (CF + ROA); C) 20.0% fat [high fat (HF)]; and D) HF + ROA. HF diets significantly increased mammary tumor multiplicity, with or without ROA, but did not significantly influence mammary tumor growth. ROA treatment reduced mammary tumor multiplicity regardless of the level of dietary fat and inhibited mammary tumor growth in the presence of normal levels of dietary fat. High levels of dietary fat did not significantly influence normal mammary gland growth and development. ROA significantly decreased normal mammary gland growth and development regardless of the level of dietary fat. Blood retinoids in rats fed ROA were primarily in the form of retinyl esters, i.e., retinyl linoleate, retinyl palmitate-oleate, and retinyl stearate. Free retinol levels in blood were not significantly influenced by ROA feeding. Blood retinyl ester levels were lower in rats fed the HF + ROA diet as compared to rats fed the CF + ROA diet.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Cocarcinogenesis; Dietary Fats; Diterpenes; Female; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Rats; Rats, Inbred Strains; Retinoids; Retinyl Esters; Time Factors; Vitamin A

A clone of 3-methylcholanthrene-treated 10T1/2 cells has been isolated which possesses basic characteristics expected of "initiated" cells. In the presence of retinyl acetate, this clone exhibits contact inhibited growth control and is morphologically indistinguishable from the parental 10T1/2 cell line. Removal of retinyl acetate in vitro results in neoplastic transformation after a latent period of 3 weeks. The classical 10T1/2 transformation system was reconstructed by coculturing normal and "initiated" 10T1/2 cells formed either Type II or Type III foci after a latent period of 3-4 weeks, and an additional 22% formed Type I foci. Treatment of "initiated" 10T/2 cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate accelerated the formation of transformed foci in the coculture system by reducing the length of the latent period to less than 3 weeks. Injection of 10(6) "initiated" cells/mouse s.c. into nude mice resulted in the appearance of progressively growing fibrosarcomas after a latent period of 5-7 weeks. Dietary supplementation with 4-hydroxyphenyl-retinamide prevented tumor formation; after drug withdrawal, tumors developed in all surviving mice after 6 weeks. We believe this cell line possesses all characteristics expected of "initiated" cells. With this new cell line, designated INIT/10T1/2, we can now study the early biochemical changes in growth control mechanisms resulting in neoplastic transformation and the mechanism(s) of chemoprevention of cancer by vitamin A.

Topics: Animals; Cell Line; Cell Separation; Cell Transformation, Neoplastic; Cocarcinogenesis; Contact Inhibition; Diterpenes; Methylcholanthrene; Mice; Mice, Inbred C3H; Mice, Nude; Neoplasm Transplantation; Retinyl Esters; Tetradecanoylphorbol Acetate; Vitamin A

Feeding of retinyl acetate (82 mg/kg ration) for 13-16 weeks to estrone- and progesterone-treated nulliparous and multiparous inbred GR/A mice resulted in a substantial increase in the incidence of mammary carcinomas. Mammary carcinoma incidence in nulliparous control and retinoid-fed mice in experiment #1 was 22/65 (34%) and 37/65 (57%) (P less than 0.05), respectively; in experiment #2, 27/48 (56%) and 37/48 (77%) (P less than 0.05), respectively. Mammary carcinoma incidence in multiparous control and retinoid-fed mice in experiment #1 was 13/30 (43%) and 23/30 (77%) (P less than 0.05), respectively; in experiment #2, 19/19 (100%) and 19/19 (100%), respectively. The purported chemopreventive activities of retinyl acetate in murine mammary tumorigenesis were not demonstrated in this study; indeed, the vitamin A analog appeared to enhance this oncogenic process in the steroid hormone-treated GR mouse mammary cancer model.

Topics: Animals; Cocarcinogenesis; Diterpenes; Estrone; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Organ Size; Parity; Progesterone; Retinyl Esters; Vitamin A