dinoprost and Cocarcinogenesis

We investigated the effects of a gamma-tocopherol-rich mixture of tocopherols (gamma-TmT, containing 57% gamma-T, 24% delta-T, and 13% alpha-T) on colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice. In experiment 1, 6-week-old male CF-1 mice were given a dose of AOM (10 mg/kg body weight, i.p.), and 1 week later, 1.5% DSS in drinking water for 1 week. The mice were maintained on either a gamma-TmT (0.3%)-enriched or a standard AIN93M diet, starting 1 week before the AOM injection, until the termination of experiment. In the AOM/DSS-treated mice, dietary gamma-TmT treatment resulted in a significantly lower colon inflammation index (52% of the control) on day 7 and number of colon adenomas (9% of the control) on week 7. gamma-TmT treatment also resulted in higher apoptotic index in adenomas, lower prostaglandin E2, leukotriene B4, and nitrotyrosine levels in the colon, and lower prostaglandin E2, leukotriene B4, and 8-isoprostane levels in the plasma on week 7. Some of the decreases were observed even on day 7. In experiment 2 with AOM/DSS- treated mice sacrificed on week 21, dietary 0.17% or 0.3% gamma-TmT treatment, starting 1 week before the AOM injection, significantly inhibited adenocarcinoma and adenoma formation in the colon (to 17-33% of the control). Dietary 0.3% gamma-TmT that was initiated after DSS treatment also exhibited a similar inhibitory activity. The present study showed that gamma-TmT effectively inhibited colon carcinogenesis in AOM/DSS-treated mice, and the inhibition may be due to the apoptosis-inducing, anti-inflammatory, antioxidative, and reactive nitrogen species-trapping activities of tocopherols.

Topics: Adenocarcinoma; Adenoma; Animals; Antioxidants; Apoptosis; Azoxymethane; Carcinogens; Cell Transformation, Neoplastic; Cocarcinogenesis; Colon; Colonic Neoplasms; Dextran Sulfate; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; gamma-Tocopherol; Inflammation; Leukotriene B4; Male; Mice; Tyrosine

When applied to NMRI mouse skin in vivo, phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) have been found to induce two early waves of prostaglandin E2 (PGE2) synthesis after 15 and 90 min and a delayed accumulation of prostaglandin F2 alpha (PGF2 alpha) after 2 h. With respect to PGF2 alpha formation different activities of both agents were observed, in that TPA but not RPA induced additional PGF2 alpha waves after 4 and 17 h. Functionally, PGE2 was previously shown to be an endogenous mediator of the TPA- or RPA-induced epidermal hyperproliferation and hyperplasia. A functional role of PGF2 alpha could be attributed to the post-initiation stages of tumor development in initiated mouse skin, i.e. the conversion stage (stage I of tumor promotion) elicited by two TPA applications and the promotion stage (stage II of promotion) brought about repetitive RPA treatments. PGF2 alpha, appearing as one distinct biosynthetic wave 3-4 h after TPA application seems to be critically involved in the conversion steps since (i) inhibition of its accumulation by indomethacin led to an inhibition of tumor formation, (ii) the inhibitory effect of indomethacin could be reversed by PGF2 alpha and (iii) RPA was not able to give rise to the accumulation of PGF2 alpha 4 h after application as obtained by TPA treatment. Moreover, RPA-induced promotion of DMBA- and TPA-treated mouse skin was inhibited by indomethacin. The inhibitory effect of indomethacin on papilloma formation was again reversed by PGF2 alpha treatment concomitant with RPA.

Topics: Animals; Cocarcinogenesis; Dinoprost; Dinoprostone; Epidermis; Indomethacin; Mice; Papilloma; Phorbol Esters; Skin Neoplasms; Tetradecanoylphorbol Acetate

For investigation of the role of linoleic acid (LA) and its biologically significant metabolites in mammary tumor promotion by dietary fat, a detailed study of the fatty acid group composition of serum lipids, tumor neutral lipids, tumor phospholipids, and tumor prostaglandins (PG's) was conducted in female inbred F344 rats initiated with N-nitrosomethylurea (CAS: 684-93-5) and fed diets containing various types and amounts of fat. The oils, safflower [23%, high fat (HF); 5%, low fat], corn (23%, 5%), olive (23%, 5%), and coconut (23%) varied widely with respect to their LA content and their polyunsaturate:monounsaturate:saturate ratios (9:1:1, 4.6:2.6:1, 0.6:5.9:1, and 0.008:0.05:1, respectively, for safflower, corn, olive, and coconut oils). A modified hexane-based technique was used for extraction of serum and tumor lipids. Total tumor lipids ranged from a low of 5 to a high of 228 mg/g (wet wt) with no differences found among the 7 dietary groups. The phospholipid content of the tumors ranged from 27 to 47% of total tumor lipid, again with no differences seen among dietary groups. Total serum lipids varied from a low of 3.77 mg/ml (safflower oil, 23%) to a high of 6.11 mg/ml (coconut oil, 23%), and an overall inverse trend was observed between total serum lipids and tumor incidence for the 4 HF diet groups. Serum cholesterol levels were significantly depressed in the HF safflower oil and corn oil groups compared to those in all other dietary groups and, in general, varied inversely with respect to mammary tumor incidence. Serum and tumor neutral fatty acid profiles closely reflected those of the diet, while tumor phospholipids appeared more resistant to diet-induced changes. Olive oil-fed animals exhibited high levels of oleic acid in both serum and tumor lipids. The levels of the major metabolite of LA, arachidonic acid (AA), in tumor phospholipids were highly variable and did not equate with dietary or serum LA levels. A positive association was found among dietary LA, tumor PGE2, and mammary tumor incidence among the 4 HF groups; however, no association was found between tumor AA levels and either tumor PGE2 levels or mammary tumor incidence. The results of this study suggest that dietary LA may exert its effects on mammary tumor promotion by virtue of its role as a PG precursor; but the precise steps in this sequence and possible competitive interactions between essential fatty acids, monoenes, and saturates and the PG-synthesizing system remain t

Topics: Animals; Cholesterol; Cocarcinogenesis; Dietary Fats; Dinoprost; Dinoprostone; Fatty Acids; Female; Mammary Neoplasms, Experimental; Methylnitrosourea; Oils; Phospholipids; Prostaglandins; Prostaglandins E; Prostaglandins F; Radioimmunoassay; Rats; Rats, Inbred F344; Triglycerides

Topics: Calcimycin; Cell Division; Cocarcinogenesis; Dinoprost; Dinoprostone; Epidermal Cells; Hyperplasia; Indomethacin; Prostaglandins E; Prostaglandins F; Skin; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

TPA promotion of skin tumors in mice can be modified by application of various prostaglandins or their precursors. The effects depend on the particular prostaglandin used: PGF2alpha enhances promotion, whereas PGE1 consistently inhibits promotion. Time of application of the prostaglandin with respect to TPA determines whether PGE2 enhances or inhibits. Dose-dependent inhibition was observed for arachidonic acid. The prostaglandins alone were unable to elicit tumors in initiated mice.

Topics: Animals; Arachidonic Acid; Carcinogens; Cell Transformation, Neoplastic; Cocarcinogenesis; Dinoprost; Dinoprostone; Female; Mice; Mice, Inbred SENCAR; Oxytocics; Papilloma; Prostaglandins; Skin Neoplasms; Tetradecanoylphorbol Acetate