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R A Karmali

Publications and source records attributed to R A Karmali.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1985

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.

Adult↗
PubMed1985

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.

Adenocarcinoma↗
PubMed1984

Endogenous prostaglandin production by established cultures of neoplastic rat mammary epithelial cells.

The production and release of prostaglandins (PGs) into the growth medium by established cultures of neoplastic, mammary epithelial cells derived from (a) N-nitrosomethylurea (NMU)-induced and (b) 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors, was assessed using radioimmunoassay techniques. Prostaglandin production was determined, to a considerable extent, by in vitro conditions and the tumor line analyzed. In medium supplemented with bovine calf serum (10%), NMU cells synthesized and released nanogram quantities of PGE2, PGE1, and PGF2 alpha (6.7, 4.7, and 1.7 ng/10(6) cells per 48 h, respectively). Concentrations of the two stable protanoid metabolites, 6-keto-PGF1 alpha and TXB2, were indistinguishable from controls. In cells derived from the DMBA-induced tumor (RBA cells), no net production of immunoreactive PGs was detected. In contrast, in media supplemented with fetal bovine serum (10%), both RBA and NMU cells synthesized and released nanogram quantities of PGE2 (1 and 4 ng/10(6) cells per 48 h, respectively). PGE2 production by both NMU and RBA cells was inhibited by ibuprofen, an inhibitor of cyclooxygenase (EC 1.14.99.1). The pattern of PG inhibition by ibuprofen differed in the two cell lines. In NMU cells, a linear dose-response inhibitory pattern was discernable, whereas in RBA cells a biphasic pattern was observed; PGE2 levels increased at low concentrations of ibuprofen and then decreased at higher concentrations. At 100 micrograms/ml ibuprofen, PG synthesis and release was inhibited by 90 and 100% and cell growth by 64 and 66% in NMU and RBA cells, respectively. There was no obvious dose-response relationship between ibuprofen concentration and cell growth inhibition in either cell line. These results underline the importance of the serum component of growth medium when analyzing PG production in vitro and suggest that the epithelial cell components of experimental mammary tumors are capable of producing physiologically relevant amounts of PGS.

Adenocarcinoma↗
PubMed1984

Ultraviolet-evoked prostaglandin biosynthesis in varying stages of keratinocyte differentiation in guinea pig skin.

Prostaglandin (PG) production by guinea pig epidermal cells was evaluated at various incubation intervals in normal and UV-exposed cultures. Prostaglandins have been implicated as mediators of the early phase of erythema in skin exposed to sunlight or UV-radiation. Using a density gradient centrifugation procedure, the epidermal cells were fractionated according to the various maturation stages of epidermal keratinocytes: high-density epidermal cells (HDEC) consisting of round, less mature cells; low-density epidermal cells (LDEC) consisting of polygonal keratinized cells; and intermediate-density epidermal cells (IDEC) consisting of both HDEC and LDEC. When cultures of 1 X 10(6) cells were incubated at 37 degrees C in 5% CO2 the highest concentrations of five PG moieties measured were present in supernatants from the LDEC cultures as compared to those of IDEC or HDEC. Levels of PGF 2 alpha were much higher than the rest, which were found in the order PGF2 alpha greater than PGE2 greater than PGE1 greater than 6-keto-PGF1 alpha greater than thromboxane (TX)B2. UV-irradiation induced increases in all but TXA2 production. These results identify and quantitate five compounds produced as a result of exaggerated activity of the cyclooxygenase induced by UV-irradiation.

Animals↗
PubMed1984

Prostaglandins in carcinomas of the head and neck.

Abnormalities of 5 cyclooxygenase products were studied in tumours from patients with head and neck cancer. The studies were designed to measure tissue prostaglandin content (ng/g wet tissue) as well as production in vitro by tumour microsomes (ng/mg protein/10 min). Head and neck tumours contained large amounts of 5 eicosanoids in the order. PGE2 greater than PGE1 greater than 6-keto-PGF1 alpha greater than PGF2 alpha greater than TXB2. When tumours less than or equal to 2 cm were compared with tumours equal to or more than 3 cm in size, amounts of all but PGF2 alpha were higher in the larger tumours. However, the capacity of tumour microsomes to synthesize PGs in vitro was inversely related to tumour size. These results suggest a defect in removal of eicosanoids from large tumours. The physiological significance of this increase in local levels of eicosanoids remains to be determined in head and neck cancer.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Effect of omega-3 fatty acids on growth of a rat mammary tumor.

The effect of administering marine oil that was rich in omega-3 fatty acids on tumor growth was studied in female inbred F344 rats that received transplants of R3230AC mammary adenocarcinoma. Four groups of rats were maintained on a normal rat chow diet containing 5% fat, and marine oil supplementation was started 1 week prior to transplantation of the tumors. The marine oil provided 17, 33, and 67 mg of 5, 8, 11, 14, 17-eicosapentaenoic acid (EPA) and 16, 32, and 64 mg 4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA) a day. A significant reduction in weight (g) and volume (cm3) of the rat R3230AC mammary tumor was observed after 4 weeks of treatment. EPA (20:5 omega-3) and DHA (22:6 omega-3) were found in choline phospholipid fractions of mammary tumors from rats given marine oil. Both tumor content and synthesis in vitro of prostaglandins of two series were inhibited in the marine oil-treated groups. These data indicated that the mechanism underlying inhibition of mammary tumorigenesis may be linked, in part, to the inhibitory effect of both EPA and DHA on arachidonic acid metabolism.

Adenocarcinoma↗
PubMed1984

Growth inhibition and prostaglandin metabolism in the R3230AC mammary adenocarcinoma by reduced glutathione.

The effect of reduced glutathione (GSH) administered to tumor-bearing rats was studied on growth of the R3230AC mammary adenocarcinoma. A significant inhibition in both tumor weight and volume was observed in rats given 2 g/kg body weight/day of GSH. Prostaglandin content of processed tumors was measured (ng/g wet weight tissue) and in vitro prostaglandin synthesis by microsomal prostaglandin synthetase was studied (ng/mg protein/15 min). Tumor PGE2 content and in vitro synthesis were decreased in tumors from GSH-treated rats. However, PGE1, PGF2 alpha, 6-keto-PG-F1 alpha and TXB2 content of these tumors was increased, and with the exception of PGE1, the trends in tumor content and in vitro enzyme activity were similar. The effect of GSH treatment on PGE2 content of normal mammary tissue was similar to that observed in the mammary tumors. These studies suggest that a selective inhibition in tumor PGE2 by in vivo treatment of rats with GSH may be associated with GSH-induced tumor growth inhibition.

Adenocarcinoma↗
PubMed1984

Prostaglandins in cells of the lymphoid system in AKR leukemia.

AKR mice develop spontaneous lymphoid leukemia late (8 to 12 months) in life, although persistent murine leukemia virus production occurs throughout their life. This suggests that age-related changes are involved in development of leukemia. Prostaglandin biosynthesis was therefore studied in 24-hr cultures in vitro at 37 degrees of peritoneal macrophages, splenocytes, thymocytes, bone marrow, and lymph node cells. AKR mice of 2, 6, and 8 to 12 months of age were studied. Prostaglandin E1, prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha, and thromboxane B2 were measured. In cultures of peritoneal macrophages and cells from spleen, thymus, and lymph nodes, the biosynthesis of all five prostaglandin moieties was higher in those cultures prepared from 8- to 12-month-old spontaneously leukemic mice in comparison with those from 2-month-old nonleukemic AKR mice. However, when leukemia was transplanted in 3-month-old AKR mice, synthesis of all five compounds was reduced significantly in cultures of peritoneal macrophages and splenocytes prepared from these 3-month-old leukemic mice. The present data demonstrate abnormalities in prostaglandin synthesis by various cells of the immune system in leukemic mice. However, the nature of these changes was different in cultures of cells from spontaneously leukemic mice from those with transplanted leukemia. Age-related increases in prostaglandin synthesis by various lymphoid cells from spontaneously leukemic AKR mice (8 to 12 months old) occurred at a much earlier age than in BALB/c mice and may be related to the leukemic condition.

Animals↗
PubMed1983

Prostaglandin concentrations and prostaglandin synthetase activity in N-nitrosomethylurea-induced rat mammary adenocarcinoma.

A comparison of tissue concentrations and biosynthesis of prostaglandin (PG)E2, PGF2 alpha, 6-keto-PGF1 alpha (degradation production of PGI2) and thromboxane (TX)B2 (degradation product of TXA2) was made in normal mammary glands obtained from virgin female Sprague-Dawley rats and in N-nitrosomethylurea (NMU)-induced mammary adenocarcinomas. The tissue concentrations (ng/g wet weight) of all 4 compounds were significantly higher in the NMU-induced tumor than in normal mammary tissue: PGE2, 210 +/- 37 vs 25 +/- 6; PGF2 alpha, 287 +/- 48 vs 23 +/- 8; 6-keto-PGF1 alpha, 294 +/- 42 vs 31 +/- 8; and TXB2, 260 +/- 49 vs 27 +/- 5 (mean +/- S.E.M.). Microsomal prostaglandin synthetase activity in NMU-induced tumors was also significantly higher than in normal tissue for all but 6-keto-PGF1 alpha: PGE2, 226 +/- 16 vs 50 +/- 9; PGF2 alpha, 28 +/- 3 vs 4 +/- 1; 6-keto-PGF1 alpha, 14 +/- 2 vs 11 +/- 2; and TXB2, 17 +/- 1 vs 10 +/- 1 ng/mg protein (mean +/- S.E.M.). There was no apparent relationship between either tumor size or age and the ability of microsomal enzyme to synthesize prostaglandins, although the content of prostaglandins extracted from tumor tissue was inversely related to the tumor size.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Prostaglandins in breast cancer: relationship to disease stage and hormone status.

Tissue prostaglandin (PG) content and production by human breast cancers were measured in 24 human mammary carcinoma specimens. The 5 compounds studied were PGE1, PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and TXB2. The tissue content of all 5 compounds was higher in neoplastic tissue in comparison with the paired noncancerous breast tissue. However, microsomal PG synthetase activity in vitro in noncancerous and neoplastic breast tissue was comparable. Increased thromboxane formation was associated with three clinical variables--tumour size, axillary lymph node metastases and distant metastasis. A lesion negative for either oestrogen or progesterone receptor content tended to produce more TXB2 but lower PGE2 and 6-keto-PGF1 alpha. Results obtained in this pilot study may provide clues as to what direction future larger studies could take in the search for reliable prognostic indicators for breast cancer.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Prostaglandin regulation of murine mammary tumor virus production: a basis for some of the glucocorticoid and prolactin actions on mammary tumor cell cultures.

Hormonal regulation of mouse mammary tumor virus (MuMTV) production has been studied in cell cultures derived from mammary carcinomas of GR mice. The purpose of this study was to define the role of prolactin in dexamethasone-induced MuMTV production and to evaluate the mechanism(s) of action of these hormones. Results of our investigations in vitro establish a central role for prostaglandins, in particular PGF2 alpha. Prolactin treatment up to 1000 ng/ml increased the MuMTV production only slightly when added alone but a maximal stimulatory response was expressed when prolactin was added simultaneously with dexamethasone 2 micrograms/ml. This prolactin-related enhancement of MuMTV production was probably mediated by PGs since it was inhibited by indomethacin, an inhibitor of prostaglandin synthesis. When higher concentrations of indomethacin were used in dexamethasone-treated cultures, MuMTV production, although inhibited, was restored in part by addition of exogeneous PGF2 alpha. PGF2 alpha added alone stimulated the MuMTV production and, in combination with dexamethasone, showed a synergistic effect on stimulation of MuMTV production. Two compounds, PGF2 alpha and TXA2 (measured as TXB2), were produced in significant concentrations by these cultures. These findings suggest that PGF2 alpha exerts a regulating role on production of MuMTV in GR cells and indicate that the actions of both dexamethasone and prolactin are mediated at least in part by prostaglandins.

Animals↗
PubMed1982

Macrophage production of prostaglandins: effects of fetal calf serum and diazepam. Use of an improved method for extracting 6-keto-PGF1 alpha.

Mouse peritoneal macrophages were incubated with varying amounts of heat-inactivated fetal calf serum (FCS) and treated with diazepam at the concentrations of 0.5 and 5.0 mug/ml. These macrophage preparations demonstrate that the capacity for synthesis and release of prostaglandins (PGs) E2, F2 alpha, 6-keto-PGF1 alpha and thromboxane TX(B2) is: (a) sensitive to the concentration of FCS in the culture medium, and (b) altered in the presence of diazepam. A radioimmunoassay for 6-keto-PGF1 alpha is also reported. The efficiency of extraction of PGE2 and 6-keto-PGF1 alpha from buffer or plasma samples was greatly improved when a petroleum ether/ether (1/1) solvent system was employed.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Role of prostaglandins E1, E2, F2 alpha, I2 and thromboxane in salmonella-associated arthritis in rats.

Salmonella-associated arthritis of rats was used as an experimental model for in vivo evaluation of prostaglandins in chronic inflammation. Since the arthritic lesions were localized mainly in the hind paws, femorla vein plasma measurements of prostaglandins were made to estimate the amounts of PGE1, PGE2 alpha, 6-keto-PGF1 alpha and TXB2 produced during the progression of the arthritic disease. PGE1 production was significantly increased in the early phase of infection but these changes were inversely related to the joint swelling in the later stages of the disease. Changes in products of arachidonic acid (20:4 omega 6) were opposite to those observed in PGE1, a product of dihomo-gamma-linolenic acid, (20:3 omega 6), in that measurable levels of these chemicals were lower in the early phase of infection but there was a progressive increase in each compound during the chronic phase of inflammation. Concentrations of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 increased proportionately to the severity of the arthritic lesion.

6-Ketoprostaglandin F1 alpha↗
PubMed1980

Intrarenal growth of the Walker 256 tumour and renal vein concentrations of PGE2, PGF 2 alpha, and TXB2: effects of diazepam.

Walker 256 tumours grafted under the left kidney capsules in rats showed enhanced growth following daily treatment with diazepam 500 micrograms (1.7 mg/kg body weight) subcutaneously but not with 1250 micrograms. Thromboxane B2 (the metabolite of TXA2) levels in venous drainage from both the tumour bearing left kidney and from the right control kidney were reduced significantly in all the three groups of tumour bearing rats. Plasma PGE2 was higher in the venous drainage from the tumour bearing left kidney than from the right control kidney. Significantly higher levels were measured following 500 micrograms but not after 1250 micrograms of diazepam. Plasma PGF2 alpha on the other hand, was lower in the plasma from the tumour bearing kidney and was further lowered in animals receiving diazepam treatment.

Animals↗
PubMed1980

Review: prostaglandins and cancer.

This paper reviews work on the role of prostaglandins in cancer. A substantial body of evidence demonstrates elevated amounts of E series of prostaglandins in human and experimental tumors. Blockade of prostaglandin synthesis in vitro or in vivo results in inhibition of tumor growth. Involvement of prostaglandins is implicated in the actions of tumor promoters like phorbol and polycyclic aromatic hydrocarbon carcinogens. Symptoms like hypercalcemia, osteolysis and tumor metastasis are discussed where disordered synthesis and/or action of prostaglandins and related substances might have a role in the altered metabolism associated with neoplasia.

Animals↗