Decreased prostatic arachidonic acid in human prostatic carcinoma.

OBJECTIVE: To measure prostatic and blood fatty acid composition in a large group of patients undergoing prostatectomy for benign or malignant prostate disease, as there is evidence linking arachidonic acid metabolism and prostate cancer through its role as an eicosanoid precursor, and earlier studies showed lower prostatic arachidonic acid content in a few patients. PATIENTS AND METHODS: Prostatic phospholipid fatty acid composition was determined in prostate tissue from 173 patients undergoing prostate surgery, i.e. radical prostatectomy, cystoprostatectomy or transurethral resection (TURP). Blood fatty acid composition was determined in 99 of these patients and in 85 undergoing prostatic needle biopsy. RESULTS: There was a significantly lower percentage of arachidonic acid in malignant than in benign portions of the prostate (15.2% vs 17%) in all patients assessed. The changes were greatest in those undergoing TURP for known prostate cancer (13.4% vs 17.2%), these patients having the greatest proportion of malignancy in the specimens. There were no consistent changes in blood fatty acid composition. CONCLUSION: This is the first prospective study of arachidonic acids levels involving many consecutive patients undergoing prostate surgery for either benign or malignant disease. The lower prostatic arachidonic acid level is probably a result of the increased use of arachidonic acid for producing prostaglandins and/or leukotrienes. Further understanding of the cause and/or consequence of this finding might lead to a better understanding of prostate cancer.

Increased prostatic lysophosphatidylcholine acyltransferase activity in human prostate cancer: a marker for malignancy.

PURPOSE: Phospholipase A2 and lysophosphatidylcholine acyltransferase (LAT) constitute a deacylation-reacylation cycle that incorporates arachidonic acid into the lipid membrane. In a preliminary report we found increased LAT activity in malignant prostate tissue. We measured LAT activity in prostate tissue from a large number of patients undergoing prostatectomy. MATERIALS AND METHODS: Prostate tissue from 93 patients undergoing radical prostatectomy for prostate carcinoma, 14 undergoing cystoprostatectomy for bladder cancer, 55 undergoing transurethral resection for benign prostatic hyperplasia and 11 with prostate cancer undergoing transurethral resection for relief of obstructive symptoms was analyzed for LAT activity. RESULTS: In radical prostatectomy specimens using oleoyl coenzyme A as substrate mean increase in LAT activity between malignant and benign portions of the same specimen was 0.68 +/- 0.12 nmol./mg. protein per minute (p <0.00001). In all radical prostatectomy specimens analyzed LAT activity was 43% higher in the malignant than benign portions (2.25 +/- 0.15 versus 1.57 +/- 0.11 nmol./mg. protein per minute, p <0.001). In the 10 benign prostate specimens obtained from cystoprostatectomy mean LAT activity was 1.12 +/- 0.18 nmol./mg. protein per minute, which was significantly lower than that of benign portions of radical prostatectomy (p <0.05). LAT activity in benign cystoprostatectomy specimens was significantly higher than that in the 50 benign transurethral resection specimens (0.54 +/- 0.05, p <0.01), possibly due to heat damage in transurethral resection specimens during collection. However, LAT activity in transurethral resection specimens from patients with known prostate cancer was similarly increased. Similar results were obtained using arachidonoyl coenzyme A. CONCLUSIONS: We demonstrated increased LAT activity in malignant tissue from patients with prostate cancer. Thus, the deacylation-acylation remodeling cycle may be enhanced to provide more arachidonic acid to meet the demand for prostaglandin E2 synthesis in malignant tissue.

Increased phospholipid fatty acid remodeling in human and rat prostatic adenocarcinoma tissues.

PURPOSE: To study the mechanism of diminished arachidonic acid levels in malignant prostatic tissues. MATERIALS AND METHODS: Benign and malignant prostate tissues were obtained from human radical prostatectomy specimens and from rats using Pollard's Lobund/Wistar rat prostate cancer model. Fatty acid composition and a variety of enzyme activities involved in maintaining phospholipid fatty acid composition were compared in malignant and benign prostatic tissues. RESULTS: Decreased arachidonic acid levels, previously reported in human prostate cancer, were present in malignant rat as well as in human tissues. There were 21% and 26% decreases of arachidonic acid levels in the rat and human malignant tissues compared with benign tissues. Fatty acid desaturase activity was undetectable. Fatty acyl-CoA hydrolase and synthetase activities were not altered in the malignant tissues. However, there was a 2-fold increase in phospholipase A2 activity and a 4- to 12-fold increase in fatty acyl-CoA lysophosphatidylcholine acyltransferase activity in malignant rat and human prostatic tissues. CONCLUSIONS: These data indicate that, in malignant prostate tissues, the fatty acid remodeling mechanism is activated through the deacylation-reacylation cycle. This process may be a result of increased use of arachidonic acid for the formation of prostaglandins that may be crucial for the further development and growth of the malignant tissues.

Platelet phosphoinositide turnover in streptozotocin-induced diabetes.

Increased platelet aggregation and secretion in response to various agonists has been described in both diabetic humans and animals. Alterations in the platelet membrane fatty acid composition of phospholipids and changes in the prostacyclin and thromboxane formation could only partly explain the altered platelet function in diabetes. In the present study, we have examined the role of phosphoinositide turnover in the diabetic platelet function. We report alterations in 2-[3H] myo-inositol uptake, phosphoinositide turnover, inositol phosphate and diacylglycerol (DAG) formation, phosphoinositide mass, and phospholipase C activity in platelets obtained from streptozotocin (STZ)-induced diabetic rats. There was a significant increase in the 2-[3H] myo-inositol uptake in washed platelets from diabetic rats. Basal incorporation of 2-[3H] myo-inositol into phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol (PI) in platelets obtained from diabetic rats was, however, not affected. Thrombin stimulation of platelets from diabetic rats induced an increase in the hydrolysis of [32P]PIP2 but indicated no change in the hydrolysis of [32P]PIP and [32P]PI as compared to their basal levels. Thrombin-induced formation of [3H]inositol phosphates was significantly increased in both diabetic as well as in control platelets as compared to their basal levels. This formation of [3H]inositol phosphates in diabetic platelets was greater than controls at all time intervals studied. Similarly, there was an increase in the release of DAG after thrombin stimulation in the diabetic platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary hypertensive effect of heparin and protamine interaction: evidence for thromboxane B2 release from the lung.

The characteristic pulmonary hypertensive effect of the heparin and protamine interaction has been studied in the isolated pig lung preparation using sequential autologous blood perfusate and dextran perfusate. A significant (p less than 0.001) increase in pulmonary artery pressure at constant flow was seen in 10 of 14 dextran and 12 of 15 blood perfusions. The average increase for dextran was 112 percent and for blood, 109 percent. Antihistamines did not inhibit the response. However, this was abolished in all 11 animals treated with aspirin. In 11 intact swine, thromboxane B2 blood levels increased significantly (p less than 0.01) from 0.46 +/- 0.38 ng/dl to 2.97 +/- 1.5 ng/dl. Thus, pulmonary hypertension associated with protamine reversal of heparinization is associated with prostaglandin release from the lung, and this does not require mediation of platelets or leukocytes.

The life history of poly(ADP-ribose).

We present arguments and data in support of the following sequence of events in ghost cells. Poly(ADP-ribose, ADPR) synthetase, activated by binding to DNA at a break or other anomaly, synthesizes chains of polymer upon itself, adding new residues at the proximal 1" terminus of the growing chain. Free chains of poly(ADPR) are produced by release from the active site or by internal glycohydrolysis of the growing chains without hindering the continued elongation. Subsequent glycohydrolysis cuts the free chains down to monomers. ADP-ribosylation of core histones may involve soluble intermediates of some form. Glycohydrolysis generates a limit digest with only short histone-bound chains. Most ADP-ribosylation of histone H1 occurs by the addition of single free ADPR residues independently of poly(ADPR) synthetase.

Core (2'-5')oligoadenylate and the cordycepin analog: inhibitors of Epstein--Barr virus-induced transformation of human lymphocytes in the absence of interferon.

The 3'-deoxyadenosine (cordycepin) analog of (2'-5')oligo(A) [(2'-5')oligoadenylate with a triphosphate at the 5' end], synthesized enzymatically from cordycepin 5'-triphosphate in lysed rabbit reticulocytes or L-cell extracts was (i) inhibitory to translation in lysed rabbit reticulocytes and (ii) metabolically stable in extracts of either L cells or C85-5C lymphoblasts. The 5' dephosphorylated (core) (2'-5')oligo(A) and the core cordycepin analog can replace human fibroblast interferon in preventing the transformation of human lymphocytes after infection with Epstein--Barr virus B95-8 (EBV) as determined by the decreased incorporation of [3H]thymidine into cellular DNA and the inhibition of morphological transformation of EBV-infected lymphocytes. Whereas the naturally occurring core (2'-5')oligo(A) was cytotoxic to uninfected lymphocytes and proliferating lymphoblasts, the core cordycepin analog was not. Human leukocyte interferon was more effective than human fibroblast interferon in the inhibition of EBV-induced transformation of human umbilical cord lymphocytes and adult peripheral blood lymphocytes.

The transsulfuration pathway in Tetrahymena pyriformis.

Four enzymes necessary for the metabolism of methionine by the trans-sulfuration pathway, methionine adenosyltransferase (EC 2.5.1.6), adenosylhomocysteinase (EC 3.3.1.1), cystathionine beta-synthase (EC 4.2.1.22) and cystathionine gamma-lyase (EC 4.4.1.1) were identified in Tetrahymean pyriformis. The ability of these cells to transfer 35S from E135S]methionine to form [35S] cysteine was also observed and taken as direct evidence for the functional existence of this pathway in Tetrahymena. An intermediate in the pathway and an active methyl donor, S-adenosylmethionine, was qualitatively identified in Tetrahymena and its concentration was found to be greater in late stationary phase cells than in early stationary phase cells.