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R A Karmali

Publications and source records attributed to R A Karmali.

At least 19 recordsLinked to original sources
PubMed1990

Effect of flurbiprofen and 16,16-dimethyl prostaglandin E2 on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats: glandular epithelium of stomach and duodenum.

The effect of an exogenous synthetic prostaglandin analogue, 16,16-dimethyl prostaglandin E2 (16,16-dm-PGE2), as well as the effect of endogenous prostaglandin synthesis inhibition by a cyclooxygenase inhibitor, flurbiprofen, on chemically induced gastric carcinogenesis has been investigated in rats. Carcinogenesis was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS:70-25-7). Animals were divided into six groups: Group I, treatment with MNNG alone; Group II, treatment with 16,16-dm-PGE2 plus MNNG; Group III, treatment with flurbiprofen plus MNNG; Group IV, treatment with 16,16-dm-PGE2 alone; Group V, treatment with flurbiprofen alone; and Group VI, controls. Treatment with high doses of MNNG resulted in rapid development of malignant tumors originating from the glandular epithelium of the stomach and duodenum in animals of all groups receiving the carcinogen. The first gastric adenocarcinoma infiltrating the muscularis proper was detected after 139 days in an animal treated with a combination of MNNG and flurbiprofen. The incidence of infiltrating adenocarcinoma and the incidence of all neoplastic lesions of the glandular stomach were both significantly higher in animals treated with a combination of MNNG and flurbiprofen compared with treatment by MNNG alone or in combination with 16,16-dm-PGE2 (P less than 0.05 and P less than 0.001). The difference in tumor incidence between the last two groups was not significant. The first duodenal adenocarcinoma was detected on Day 114 in another animal of the group treated with MNNG plus flurbiprofen. When compared with the group treated with MNNG plus 16,16-dm-PGE2, significantly more animals developed duodenal adenocarcinoma when treated with MNNG plus flurbiprofen (P less than 0.005) or with MNNG alone (P less than 0.05). Results of this study indicate that inhibition of endogenous prostaglandin synthesis favors development of adenocarcinoma in the glandular stomach of rats. Vice versa, the addition of an exogenous prostaglandin analogue inhibits the development of duodenal adenocarcinoma. This protective effect of prostaglandins may be due to an increase of the thickness of the mucus gel covering the glandular epithelium, thereby preventing access of carcinogen to the mucosa.

16,16-Dimethylprostaglandin E2↗
PubMed1989

n-3 fatty acids and cancer.

Dietary fat has a positive correlation with cancers of the breast and colon and probably other types of cancer. In experimental tumour systems, linoleic acid (LA) has tumour-promoting effects that are mediated, in part, through eicosanoid production. The feeding of fish oil has resulted in decreased concentrations of LA and arachidonic (AA) and increased concentrations of n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Both n-3 fatty acids antagonize the production of eicosanoids from AA. Recent reports indicate that marine n-3 fatty acids inhibit the development and growth of several experimental tumours. The effect of n-3 fatty acids on 16-alpha-hydroxylation of oestradiol, a putative biomarker for risk of breast cancer, was studied in 25 women at enhanced risk. The control group of 25 high-risk women received vegetable oil. After 4 months, the level of oestradiol 16-alpha-hydroxylation was significantly reduced in women receiving fish oil, but no change was detected in the control group. Although the precise mechanism of action is unclear, these data suggest that use of marine n-3 fatty acids as chemopreventive agents in high-risk women requires further investigation.

Animals↗
PubMed1988

Suppression of monosodium urate crystal-induced acute inflammation by diets enriched with gamma-linolenic acid and eicosapentaenoic acid.

A subcutaneous air pouch formed in Sprague-Dawley rats was used to study the effect of diets enriched in gamma-linolenic acid (GLA) (in plant seed oil) and eicosapentaenoic acid (EPA) (in fish oil) on acute inflammation induced by monosodium urate crystals. The GLA-enriched diet suppressed significantly the cellular phase of inflammation (polymorphonuclear leukocyte accumulation, crystal phagocytosis, and lysosomal enzyme activity), but it had little effect on the fluid phase (exudate volume and protein concentration). In contrast, the EPA-enriched diet suppressed the fluid phase but not the cellular phase of inflammation. The findings indicate that the fluid and cellular phases of acute inflammation can be controlled independently. A combined diet of fish oil and plant seed oil (EPA-enriched and GLA-enriched) reduced both the cellular and fluid phases of inflammation. Thus, dietary provision of alternative substrates for oxidative metabolism (other than arachidonic acid) modifies monosodium urate crystal-induced acute inflammation.

Animals↗
PubMed1987

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.

Animals↗
PubMed1987

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.

Animals↗
PubMed1987

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.

Animals↗
PubMed1987

Effect of flurbiprofen and 16,16-dimethyl-prostaglandin E2 on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats. I. Squamous epithelium and mesenchymal tissue.

The effect of exogenous synthetic prostaglandins and the inhibition of endogenous prostaglandin synthesis on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] was studied in female Wistar rats (100 g). Animals were divided into 6 groups: Group I was treated with MNNG alone (No. = 43); group II was treated with MNNG after application of the cyclo-oxygenase inhibitor flurbiprofen (No. = 44); group III was treated with MNNG after oral administration of 16,16-dimethyl-prostaglandin E2 (16,16-dm-PGE2; No. = 43); group IV received flurbiprofen alone (No. = 15); group V was treated with 16,16-dm-PGE2 alone (No. = 11). Animals in group VI served as controls (No. = 15). All drugs were administered orally. Hyperkeratosis and hyperplasia of the forestomach developed by 10 days after the first treatment with the carcinogen. Later, benign papillomas and dysplastic lesions were noted. Progressive ingrowth of squamous epithelium from the forestomach ridge into the glandular stomach started as early as day 13 and was more frequent in animals treated with a combination of MNNG plus flurbiprofen (P less than .001). The first squamous cell carcinomas of the forestomach were detected on day 51. Their incidence was 38, 60, and 42% in groups I, II, and III, respectively. This difference was not statistically significant. The incidence of mesenchymal tumors (leiomyosarcoma) in the stomach and duodenum was higher following treatment with MNNG plus flurbiprofen as compared to the incidence following treatment with MNNG alone or in combination with 16,16-dm-PGE2 (P less than .005). No malignant tumors developed in the gastrointestinal tracts of animals treated with flurbiprofen or 16,16-dm-PGE2 alone or in controls. The higher incidence of gastric and duodenal leiomyosarcomas after treatment with flurbiprofen suggests that reduction of prostaglandin synthesis favored the development of MNNG-induced cancer in mesenchymal tissues of the upper gastrointestinal tract.

Animals↗
PubMed1986

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.

Animals↗
PubMed1986

Growth inhibition and eicosanoid metabolism in the R3230AC mammary adenocarcinoma by interferon.

The mode of action of rat interferon (IFN) on growth of the R3230AC mammary adenocarcinoma was studied in vivo in Fischer female rats. A dose of 1 X 10(4) units of rat IFN given thrice weekly inhibited the growth of the transplanted mammary tumors. Of the five eicosanoids measured in the tumor, the content of four arachidonate products, prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2, was higher in mammary tumors from IFN-treated rats than the control rats. PGE2 was the major eicosanoid. In vitro PG synthesis (PGE1, PGE2, and PGF2 alpha) was lower in tumor microsomes prepared from IFN-treated tumors. These data suggest that the tumor content of four arachidonate products in the IFN-treated tumors was related to the in vivo effects of rat IFN. Indomethacin, a cyclooxygenase inhibitor, also inhibited tumor growth. Furthermore, when indomethacin was administered daily in combination with rat IFN, the tumor-inhibiting effect of rat IFN was reduced. These observations suggest that the effects of eicosanoids appear to be biphasic in this tumor model. Inhibition of arachidonic acid metabolism resulted in tumor growth inhibition, a finding consistent with the view that eicosanoid production is required for tumor enhancement. Conversely, in the experiments with rat IFN, retardation of tumor growth is associated with a greater amount of arachidonic acid metabolism, and indomethacin prevents this effect. Eicosanoids appear to be required for tumor-inhibiting effects of rat IFN, and yet inhibition in vivo of eicosanoid synthesis also resulted in retardation of tumor growth. Although the precise mechanism of action in each situation is unclear, these apparently contradicting results are consistent with the biphasic actions of eicosanoids reported in some normal tissues and transformed tumor cell lines.

Adenocarcinoma↗
PubMed1986

Dietary fat and mammary cancer. II. Modulation of serum and tumor lipid composition and tumor prostaglandins by different dietary fats: association with tumor incidence patterns.

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 to be determined.

Animals↗
PubMed1986

Eicosanoids and metastasis: experimental aspects in Lewis lung carcinoma.

Lewis lung primary carcinomas have been extracted for eicosanoids, and the findings examined in relation to lung metastases. The order of the 5 compounds measured was PGE2 greater than PGE1 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than TXB2. On the basis of the observation that the balance of PGI2 and TXA2 is altered in metastasis (Honn et al., 1983), the effects of Nafazatrom, a PGI2 enhancing agent, and imidazole, a thromboxane synthetase inhibitor, were tested. The experimental approach taken was to study spontaneous lung metastases after removal of the primary tumour at 13 days after tumour cell inoculation. Both Nafazatrom and imidazole decreased the lung weight when given during the period either before or after the excision of the primary tumour. There was a general trend toward an increase in the number of small lung nodules (greater than 2 mm) and a decrease in large lung nodules (greater than 2 mm) as a result of the chemotherapy. Mean survival time of the mice was significantly different among the five groups, with the mice surviving the longest in the group treated with Nafazatrom after the excision of the primary tumour.

Animals↗
PubMed1985

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.

Animals↗