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.

Protein pyrolysate products.

Diet and nutrition may be responsible for 60% of the total cancer incidence for women and greater than 40% for men. Fat, animal protein, and meat consumption are highly correlated with colon cancer incidence. The charcoal broiling of meat and fish yield mutagenic substances. Many findings support the hypothesis that the predominant mutagens are formed by the Maillard reaction. A number of mutagenic compounds have been identified both from cooked foods and from protein pyrolysates. The identified compounds are N-heterocyclic primary amine derivatives of either carbolines, imidazoquinolines, or imidazoquinoxalines. The carboline-type mutagens are structurally related to the known carcinogens 2-acetylaminofluorene (AAF) and 2-aminofluorene (AF), while the imidazoquinoline and imidazoquinoxaline types are believed to resemble 3,2'-dimethyl-4-aminobiphenyl (DMAB). Studies support the theory that these compounds require metabolic activation and are carcinogenic. The major metabolites of several compounds have been identified as the N-hydroxy derivatives. DNA binding was found to be a necessary but not a sufficient condition for mutagenesis. The modified base products have been identified as C-8-guanyl derivatives, resembling adducts formed by the carcinogenic aromatic amines.