Rashida A. Karmali

Eicosanoids in neoplasia

Dietary fat has been shown to exert a wide variety of actions that result in enhanced mammary and colon tumorigenesis. Such a range of mechanisms suggests the involvement of intermediary or secondary messenger molecules. Eicosanoids, produced from arachidonic acid (C20:4, n-6), are known to have various effects on physiological and biochemical events. The production of these dienoic eicosanoids is controlled during normal physiological events, but excessive quantities of some products are produced in some pathological conditions such as cancer. Often dienoic eicosanoids affect some of the same processes that are influenced by dietary fat, such as linoleic acid (C18:2, n-6). Therefore, eicosanoids may represent a potential system for mediating or modulating the effect of a linoleate-rich diet. The feeding of fish oil has resulted in decreased concentrations of linoleic and arachidonic acids and increased concentrations of eicosapentaenoic acid (C20:5, n-3) and docosahexaenoic acid (C22:6, n-3). Both eicosapentaenoic and docosahexaenoic acids antagonize the production of eicosanoids from arachidonic acid. We have examined the effects of fish oil on the growth of the R3230AC mammary adenocarcinoma, the 7,12-dimethylbenz[a]-anthracene-induced mammary tumors, and the DU-145 human prostatic tumor. Although the precise mechanisms of action are unclear, currently available data suggest that eicosapentaenoic acid + docosahexaenoic acid, at an optimal ratio of n-3/n-6 fatty acids, may have protective effects against development and/or progression of the tumor models studied.

Omega-3 Fatty Acids: Modulation of Estrogen Metabolism and Potential for Breast Cancer Prevention

AbstractA collaborative program is exploring potential endocrine biomarkers of breast cancer risk and the effects of omega-3 fatty acids and levothyroxine on these biomarkers.

Antitumor activity in a rat mammary adenocarcinoma: the effect of cyclooxygenase inhibitors and immunization against prostaglandin E2.

Female Fischer 344 rats bearing the R3230AC mammary tumor were treated with three different inhibitors of cyclooxygenase--indomethacin, ibuprofen, and flurbiprofen (5 mg/kg body weight). After three weeks, the weight and volume of tumors from treated animals were smaller than those of control rats. Rats bearing the same tumor but immunized against PGE2 conjugated to bovine serum albumin showed similar trends in tumor growth inhibition. Thus we conclude that PGE2 plays an important role in the establishment and growth of the R3230AC mammary tumor.

Effect of dietary fatty acids on experimental manifestation of salmonella-associated arthritis in rats II. Effect of dietary fatty acids on experimental manifestation of salmonella-associated arthritis in rats

Dietary supplementation with a marine lipid concentrate rich in n-3 fatty acids and pure ethyl ester of dihomo-gamma-linolenic acid (DHLA) resulted in inhibition of the chronic phase of inflammation in Salmonella-associated arthritis. The anti-inflammatory effect of DHLA was much stronger than that of two n-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) present in marine oil. Fatty acid profiles in phosphoglyceride fractions of red blood cells showed incorporation of the respective supplemented fatty acids. Concentrations of 4 cyclooxygenase products in femoral vein plasma were smaller in the fatty acid supplemented rats. These studies suggest that DHLA and marine n-3 fatty acids may have useful anti-inflammatory effects in Salmonella-associated arthritis.

Modulation of growth, prostaglandin synthesis, and prolactin-binding in two cultured rat mammary carcinoma cell lines by flurbiprofen

The effect of treatment with flurbiprofen (FB), a non-steroidal anti-inflammatory drug, on growth, prostaglandin synthesis, and prolactin receptor levels was examined in two established rat mammary carcinoma cell lines. Growth of NMU cells was suppressed with a concentration of 1 microgram FB/ml culture medium (4 x 10(-5) M); RBA cells, in contrast, were less sensitive, being inhibited only by a 100 micrograms/ml (4 x 10(-4) M) concentration of the drug. Prostaglandin (PG) synthesis by both cells lines, as indicated by decreased release of PGE2 and PGF2 alpha into the culture medium, was inhibited by 0.1, 1 and 10 micrograms/ml of FB. Both carcinoma cell lines exhibited high levels of specific prolactin receptors (PRLR) (9-11,000 sites/cell); binding was diminished in cells exposed to 1 microgram/ml (4 x 10(-6) M), and abolished completely by 10 micrograms/ml (4 x 10(-5) M) of FB. In marked contrast to the results at higher concentrations, at 0.1 microgram/ml (4 x 10(-7) M), the drug caused a significant increase in the prolactin binding capacity of RBA cells and a diminution in PG production, but in the absence of any measurable effect on cell proliferation. A similar, but less pronounced trend was seen in the NMU cell line. When NMU cells were cultured in the presence of 10 micrograms/ml FB for 4 days, and then in inhibitor-free medium for a further 3 days, recovery of growth was demonstrated, together with the reappearance of prolactin-binding capacity. The effect of FB on RBA cell PRLR expression was also reversible, though concomitant changes in cell growth were less obvious. Hence, the inhibitory effect of FB on PG synthesis, and the associated decrease in prolactin binding capacity, was specific and reversible and not the result of a generalized toxic effect.

The role of prostaglandin E2 in seminal immunosuppression

Seminal plasma, which has high antigenic potential and the capacity to induce immunosuppression, has been incriminated as a possible factor in the acquired immunodeficiency syndrome (AIDS). Seminal plasma contains high concentrations of prostaglandins, which are capable of inducing immunosuppression. As prostaglandin E2 is noted for its immunosuppressive actions, we designed this study to determine whether this prostaglandin is responsible for seminal immunosuppression. Diluted and undiluted samples of semen from 5 heterosexual donors induced a significant suppression of phytohaemagglutinin-stimulated thymidine incorporation into lymphocytes. However, when the prostaglandin E2 levels of the semen samples were extrapolated to a standard prostaglandin E2 dose-response curve, the estimated values did not agree with the prostaglandin E2 levels. We conclude that prostaglandin E2 may contribute to seminal immunosuppression, but is not solely responsible for it.

Modulation of arachidonic acid metabolism in experimental arthritis induced by salmonella enteritidis I. Effect of ibuprofen and flurbiprofen on experimental arthritis induced by salmonella enteritidis

Oral administration of two nonsteroidal anti-inflammatory drugs, ibuprofen and flurbiprofen, can suppress the Salmonella-induced arthritis in rats. The joint swelling index of arthritic paws showed suppression of arthritis in animals treated with the drugs, this effect being greater with flurbiprofen. Measurement of 5 eicosanoids in femoral vein plasma showed increase of arachidonic acid products in Salmonella-treated rats. Inhibition of joint inflammation resulting from treatment with ibuprofen and flurbiprofen is reflected by a decrease in concentration of all 5 eicosanoids which were found in the order: PGE2 greater than TXB2 greater than 6-keto-PGF1 alpha greater than PGF1 greater than PGF2 alpha. These studies indicate that flurbiprofen is a more powerful anti-inflammatory agent than ibuprofen. However, since the joint disease was not completely cured, optimal intervention is quite likely to require modulation of the lipoxygenase pathway.

Dietary w-3 and w-6 Fatty Acids in Cancer

The evidence that dietary fat relates to cancers of the breast and colon, and probably other types of cancer, has been built on descriptive and metabolic epidemiology, correlation studies, migrant studies, case-control studies, and experimental animal studies1. This overall evidence has led to recommendations that dietary fat intake be reduced to decrease the risk of developing certain types of cancer.2,3