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Biomedical subjects

O Greengard

Publications and source records attributed to O Greengard.

At least 37 records · Page 2Linked to original sources
PubMed1987

Enzyme pathology of human mesotheliomas.

In samples of 16 surgically resected mesotheliomas arising from the pleura of the human lung, 6 enzymes from different metabolic pathways, DNA, and mitotic frequency were quantified. The mesotheliomas, irrespective of cell type or grade, showed lower gamma-glutamyl transpeptidase (GGT) concentration than 36 of the 38 pulmonary adenocarcinomas. The mean concentration of this enzyme in the 15 mesotheliomas was an eighth of that in the 56 carcinomas, whereas their DNA content was similar. The quantitative correlation of thymidine kinase (TK), uridine kinase (UK), and phosphoserine phosphatase to mitotic frequency was highly significant for mesotheliomas, as well as for carcinomas. As estimated from their TK [and its recently established quantitative correlation to volume doubling time (DT)], the DT of the 16 mesotheliomas ranged from 50 to over 700 days, with a somewhat longer median than the median for pulmonary carcinomas. Subject survival, though shortest for the 2 sarcomatous mesothelioma cases, varied over an overlapping range for mesotheliomas with epithelial or mixed cell type. The biopsy samples' TK and UK concentrations, however, showed a significant inverse correlation with months of survival after diagnosis. Survival time after the first appearance of symptoms decreased linearly (on log scales) with TK concentration (P less than .001) over the 14 cases. The results of this first quantitative study of a spectrum of biochemical constituents of mesotheliomas identify GGT as an enzyme whose measurement guards against mistaking mesotheliomas and adenocarcinomas for one another and show that the TK concentrations of these mesothelioma samples bear a highly significant, inverse correlation to the postdiagnosis survival time of the individual subjects.

Biopsy↗
PubMed1986

Pulmonary carcinoid tumors: enzymic discriminants, growth rate, and early age of inception.

Analyses of enzymes from various metabolic pathways in pulmonary carcinoid tumors and radiological measurements of their volume increase were compared with those for lung carcinomas of various cell types. The results describe new biochemical features in carcinoid tumors, present the first quantitative evidence for their slow growth rate (i.e., long doubling time) in vivo, and show that measurement of 2 or 3 appropriate enzymes in biopsy samples can guard against instances in which carcinoids and adeno- or oat cell carcinomas are mistaken for one another on histological examination. The uridine kinase to thymidine kinase ratio as well as the beta-galactosidase concentration of carcinoid tumors were 5 times higher than of carcinomas, and their gamma-glutamyl transpeptidase was below that of all 35 adeno- and the 11 squamous cell carcinomas. Thymidine kinase, which bears a quantitative inverse correlation to volume doubling time (irrespective of cell type), had much lower titers in the 9 carcinoids than in the 6 oat cell carcinomas and reflects most clearly their very different (despite common histogenesis) clinical malignancy. Owing to their long doubling time, carcinoid tumors on the average required a much longer period (40.5 years) to attain final volume than did carcinomas (17.8 years). The calculated mean age of the subjects when growth began, -0.5 years (as opposed to 51 years for carcinomas), suggests a prenatal or early childhood inception for pulmonary carcinoid tumors.

Carcinoid Tumor↗
PubMed1986

Mechanical responses of developing Fisher rat heart. Effects of steroid hormone.

Age-dependent changes in the mechanical responses of developing Fisher rat heart during the first three postnatal weeks were studied in relation to the hypothesis that the abnormality observed in the mechanical responses of the rat heart might be calcium related. Therefore the effect of frequency of stimulation as well as the response to calcium, epinephrine and ouabain on hearts of untreated and cortisol-treated rats was compared. The positive force-frequency response observed in fetal rat heart reverted to a highly negative response by the 12th to 14th postnatal day. The biphasic mechanical responses directly paralleled reported changes in circulating glucocorticoid levels in developing rat. The force-frequency response was maximally negative when the circulating levels of glucocorticoids were lowest. The reversion of the negative force-frequency responses coincided with a gradual increase reported in the circulating levels of glucocorticoids. The negative force-frequency response was absent in the cortisol-treated developing rat heart and a definite positive pattern was observed as the rats developed. A high sensitivity to free calcium concentration, seen in control fetal and and newborn hearts, diminished after the second postnatal week. By the third postnatal week, the sensitivity to high extracellular calcium concentrations was significantly reduced. The sensitivity to calcium persisted in the cortisol-treated hearts during the 3 postnatal weeks. Cortisol-treated hearts were more responsive to epinephrine than controls. The abbreviation of time to peak tension, a hallmark of the catecholamine effect, was observed at a younger age in the cortisol-treated hearts. Cortisol-treated hearts were more responsive to the inotropic effects of ouabain than controls. The possible involvement of glucocorticoids in the control of calcium handling elements of the myocardium is discussed.

Animals↗
PubMed1985

Biochemical measure of the volume doubling time of human pulmonary neoplasms.

The volume doubling time (DT) of human lung neoplasms, determined from sequential, presurgery roentgenograms, was compared with biochemical and histologic observations on biopsy samples of the same tumors obtained during surgery. The DTs of the 16 neoplasms ranged from 24 days in an oat cell carcinoma to over 500 in a pulmonary carcinoid tumor, and showed a statistically significant, inverse correlation to the TK (thymidine kinase) and the UK (uridine kinase) concentration of the biopsy samples per g wet weight or mg DNA. Log DT bore a linear relationship to log TK (r = 0.75, P = 0.0008) and to log UK (r = 0.69, P = 0.0067), and an even better fit to the straight line was found when plotting the log of the standardized average of the two enzymes against log DT. The results demonstrate the feasibility of a biochemical method for determining the unknown DT of the many tumors that are not amenable (on account of shape, location, or lack of prior chest x-rays) to the direct, radiologic determination of this useful, dynamic parameter of clinical malignancy.

Biopsy↗
PubMed1984

Developmental changes of cerebral phenylalanine uptake from severely elevated blood levels.

Brain phenylalanine concentrations at plasma levels raised to that in phenylketonuric subjects were studied in rats from fetal through postnatal life. Suppression of the hepatic phenylalanine hydroxylase with alpha methylphenylalanine, and injections of age-adjusted doses of phenylalanine on the next day, assured the persistence of the same elevation of plasma levels for at least four hours prior to assay. The net phenylalanine uptake determined under these conditions underwent several-fold decreases between the fourth day and the end of the suckling period, and by about the age of 30 days it was as low as in adulthood. The development of transport properties studied here could contribute to the change with age in the vulnerability of the brain to the same degree of hyperphenylalaninemia and, since the cerebral phenylalanine uptake may decrease to non-damaging levels during childhood, it is pertinent to defining the age at which the rigorous diet of phenylketonurics might be safely relaxed.

Age Factors↗
PubMed1984

Responses of bone marrow gamma-glutamyltranspeptidase and alkaline phosphatase in vitro to tumor-elaborated granulocytopoietic factors.

Evidence has been obtained for the humoral mediation of the recently noted tumor-induced rise of the host bone marrow gamma-glutamyltranspeptidase (gamma GT) and alkaline phosphatase (AP) content in vivo: normal rat bone marrow suspensions, if incubated for 18 hr to 3 days with serum from mammary carcinoma hosts, show 2- to 8-fold elevations (per cell) of the same 2 enzymes. The active substance(s) is in the acid-stable, HCI-ethanol-soluble polypeptide fraction of the mammary carcinoma extract, and of the hosts' blood serum. The larger the size of the neoplasm, and the faster its growth rate, the greater the effect of the host serum on the gamma GT and AP of the normal bone marrow cells. In host rats in vivo, this response is followed by increases in the number (as well as the gamma GT and AP content) of circulating granulocytes. Therefore, a positive response on the part of these enzymes in the bone marrow suspension was also sought, and found, upon incubation with preparations which enhance granulocyte colony formation in agar cultures (i.e., colony-stimulating factor and serum from endotoxin-treated rats). The results indicate: (a) that the increase in gamma GT and AP is a necessary prelude to stimulation of granulocyte multiplication by appropriate growth factors; and (b) that measurement of these enzymes in the short-term liquid culture offers a biochemical test for such factors elaborated by cancers or in nonneoplastic conditions.

Alkaline Phosphatase↗
PubMed1984

Enzyme activities and isozyme patterns in human lung tumors.

The isozyme patterns and activities of six enzymes were determined in surgical biopsy samples of lung tumors and non-neoplastic pulmonary areas. Fetal lungs were also examined. No tissue differences were found in the isozyme pattern of hexokinase or alkaline phosphatase; small differences in pyruvate kinase isozyme proportions were observed. The tumors exhibited significant deviations with respect to the lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) isozyme patterns. Despite the diversity of cell types, the proportions of the M-subunit of LDH in each tumor and that of the mitochondrial isozyme of MDH in all but one tumor were higher than in control samples from the same lung. In contrast, the normal fetal lung showed a higher LDH-H proportion than did adult lung and a mature MDH isozyme pattern. The alpha-glycerophosphate dehydrogenase and adenylate kinase activities of the tumors were about one-tenth and one-fourth, respectively, of those of nonneoplastic adult lung. These lower activities (evident also in normal fetal lung) were accompanied by 3- to 5-fold increases in the LDH, MDH, pyruvate kinase, and hexokinase activities of the tumors; fetal lungs had lesser increases (2- to 3-fold) for the first 3 enzymes. The common features of tumors with different cell types and histological grade identified here point to several enzymes the quantitation or isozyme analysis of which may be of practical use in distinguishing cancerous from nonneoplastic human lung samples. A combination of different indicators, such as opposite changes in LDH and alpha-glycerophosphate dehydrogenase activity, coupled with elevated proportions of LDH-M, may be used to diagnose neoplasia most reliably.

Alkaline Phosphatase↗
PubMed1983

Effect of tumors with different growth rates on enzymes in host liver.

In response to extrahepatic neoplasms, ornithine aminotransferase, malic enzyme, alanine aminotransferase and glucokinase activity of the 'uninvolved' liver is diminished and that of hexokinase is increased. Comparison of rats at various times after the implantation of ascites tumor, mammary carcinoma, fibrosarcoma and Morris hepatomas indicate that the faster the growth rate of tumors, the earlier the onset of these hepatic changes. The results also show that, when the different tumors are the same size, the magnitude of the enzymic deviations in the liver is directly related to characteristic growth rate of the tumor lines. These and previous observations on other host tissues suggest that tumor-doubling time, which is a known factor in metastatic spread and survival, may also be a variable in the production of systemic agents through which neoplasms affect the metabolic state of the cancer host.

Animals↗
PubMed1983

Hormonal and dietary regulation of hepatic enzymes in tumor-bearing rats.

Enzymes in the histologically normal liver of hosts of mammary carcinomas were examined for their responsiveness to endocrine and dietary modulations. Treatments with the developmental stimuli of alanine aminotransferase (glucocorticoids) and of pyruvate kinase (thyroid hormone) which had no effect in control adult rats raised the levels of these enzymes in the tumor-bearing rats. The latter also showed a greater percentage of increase in malic enzyme upon thyroid hormone administration than did control animals. The tumor-induced increase in hexokinase remained unaltered by the various dietary treatments; enzymes at subnormal levels were raised (glucokinase, malic enzymes, and pyruvate kinase) or further decreased (alanine aminotransferase and ornithine aminotransferase) by excessive carbohydrate intake in immature and adult experimental rats. The normal upsurge of glucokinase and malic enzyme upon weaning to the standard solid diet (from the relatively low-carbohydrate-containing milk) was prevented by cancerous growth in the organism. Similarly, the standard diet, which reversed within 2 days the partial loss of these enzymes in normal adult rats fasted for 48 hr, had no restorative effect on the essentially complete loss of the glucokinase and the very low malic enzyme activity in the fasted tumor bearers. The results suggest that failure in the dietary adaptations of hepatic enzymes as well as diminutions of their basal levels contributes to the clinically observed abnormalities in the glucose metabolism of cancer subjects.

Alanine Transaminase↗
PubMed1982

Modulation of cerebral catecholamine concentrations during hyperphenylalaninaemia.

Hyperphenylalaninaemia induced by daily injections of alpha-methylphenylalanine plus phenylalanine caused 20-40% decreases in cerebral dopamine (3,4-dihydroxyphenethylamine) and noradrenaline in 7- and 11-day-old rats. alpha-Methylphenylalanine alone as well as phenylalanine alone caused cerebral dopamine depletion. However, the effects were not additive, in that the depletion caused by alpha-methylphenylalanine was greater, not less, than that after treatment with both it and phenylalanine. Increased concentrations of tyrosine in the brain, owing to administered or endogenously formed tyrosine, could overcome the effect of excess phenylalanine on cerebral dopamine content. The fact that the inhibition of tyrosine hydroxylase by phenylalanine (or alpha-methylphenylalanine) in vitro was overcome by tyrosine concentrations similar to those effective in vivo further implicates the tyrosine hydroxylase inhibition as the mechanism underlying the dopamine depletion in hyperphenylalaninaemia. These results provide a theoretical basis for elevation, by tyrosine supplementation, of the cerebral phenylalanine/tyrosine ratio as a possible treatment modality for phenylketonuria.

Animals↗
PubMed1982

Enzyme pathology and the histologic categorization of human lung tumors: the continuum of quantitative biochemical indices of neoplasticity.

The purpose of the present enzymic and histologic analysis of pulmonary samples from 39 subjects was to discern a common, meaningful pattern which may underlie the biochemical heterogeneity of lung neoplasms. The distribution among the different tumors of thymidine kinase, uridine kinase, phosphoserine phosphatase, hexokinase and adenylate kinase was found to correlate with each other. By averaging their standardized units (normal lung = 0) an enzymic index of neoplasticity was calculated for each tumor and used (in increasing order) to rank all 39. The index, showing a significant positive correlation with mitotic frequency, encompassed a continuous 100-fold range. Poorly differentiated carcinomas ranked high while neoplasms with better differentiation and prognosis placed in the lower half of the range. The results indicate that enzymes showing coordinated variations over a broad spectrum of tumors could contribute objective criteria to the rating of any individual tumor against a continuous, quantitative scale of neoplasticity.

Adenocarcinoma↗
PubMed1982

The effects of hyperphenylalaninemia on fetal development: a new animal model of maternal phenylketonuria.

A new model has been developed for the study of maternal phenylketonuria. Beginning on the 12th day of gestation the diet of pregnant rats was supplemented with 0.5% alpha-methylphenylalanine and 3% phenylalanine. This resulted in an 83% reduction of hepatic phenylalanine hydroxylase activity. The maternal plasma phenylalanine was elevated 10-20-fold for two-thirds of the day, but the degree and persistence of the fetal hyperphenylalaninemia may have been even greater. The brain phenylalanine concentrations in the fetus were raised up to 2900 nmole/g brain, whereas the highest level observed in the dam was 382 nmole/g. Experimentally-treated fetuses showed small reductions in both body and brain weight when compared to age-matched controls; however, no differences were seen in crown to rump length, litter size, DNA and protein concentrations per g, or in postnatal survival. Initiation of the diet at conception rather than on the 12th day caused a significantly greater inhibition of fetal growth, and 21% mortality. The fetal cerebral concentrations of methionine and the branched chain amino acids (valine, leucine and isoleucine) were decreased by hyperphenylalaninemia. From the 16th day on, the concentration of the inhibitor neurotransmitter glycine was elevated. Cerebral serotonin showed a 20-30% deficit and its primary metabolite 5-hydroxyindoleacetic acid a 71-77% deficit. Of twelve enzymes quantified in the brains of hyperphenylalaninemic fetuses only phosphoserine phosphatase showed any change. From the 20th to the 22nd day of gestation its activity was 46-67% higher in experimental than in normal fetuses. Measurement on the 22nd day of gestation showed that the increases in phosphoserine phosphatase activity and glycine content were present in brain stem, cerebellum, and forebrain.

Animals↗
PubMed1982

Effect of neoplasms on the content and activity of alkaline phosphatase and gamma-glutamyl transpeptidase in uninvolved host tissues.

In rats carrying s.c. or i.p. neoplasms, there were striking (3- to 20-fold) rises in the gamma-glutamyl transpeptidase and alkaline phosphatase activity of several tissues. These included liver, lung, spleen, bone marrow, and circulating granulocytes but not lymphocytes. In response to mammary carcinoma 5A, for example, the gamma-glutamyl transpeptidase activity changed from 0.27 to 1.18 units/g lung and from 0.3 to 4.0 milliunits/million granulocytes; from 2.3 to 17 units and from 2.4 to 46 milliunits were the accompanying increases in alkaline phosphatase. These abnormalities in each host tissue were reversible in that 3 to 7 days after tumor resection the enzymes returned to control levels. Among the secondary factors which might have been responsible for the host tissue changes, it was possible to exclude stimulated adrenocortical secretion, tissue necrosis, and transplantation trauma. Comparisons of the effects of two mammary carcinomas, a fibrosarcoma, and two hepatomas on the gamma-glutamyl transpeptidase and alkaline phosphatase of various "noninvolved" tissues indicate that the faster the growth rate of the tumors, the more striking is this host syndrome.

Alkaline Phosphatase↗
PubMed1980

The effect of hyperphenylalaninaemia on glycine metabolism in developing rat brain.

The brains of 3--16-day-old rats that were rendered hyperphenylalaninaemic by daily injections of alpha-methylphenylalanine plus phenylalanine were subjected to biochemical analysis. Fluctuations throughout the treatment period in the concentrations of branched-chain amino acids, methionine and serotonin were in agreement with the known interference of excess plasma phenylalanine with transport. The glycine content, however, became abnormal only by day 5, remained so through the treatment, and the elevation was equally apparent at 4, 8 or 24 h after the last daily injections. On the last day of treatment there were small increases in the taurine, glutamate, aspartate and 4-aminobutyrate concentrations, attributable mainly to the diencephalon or brain stem. After day 3 of treatment there were persistent elevations in the specific activity of phosphoserine phosphatase and glycine synthase (but not serine hydroxymethyltransferase) of the brain in each of the regions analysed. The observations indicate that chronic hyperphenylalaninaemia interferes with the normal regulation of intracerebral glycine metabolism during a critical period of early postnatal development, and suggest that the resulting excess in this amino acid (particularly marked in the cortex) contributes to the behavioural abnormalities that these animals exhibit in later life.

Aging↗
PubMed1980

Enzyme activities in human fetal and neoplastic tissues.

The concentrations of ten or 12 enzymes involved in the metabolism of DNA, collagen, amino acids, or glucose have been determined in variants of human intestinal and pulmonary tissues. In comparison to nonneoplastic adult colon, normal fetal colon had elevated concentrations of thymidine kinase, peptidyl proline hydroxylase, phosphoserine phosphatase, ornithine transcarbamylase, gamma-glutamyl transpeptidase, and ornithine aminotransferase. Raised activities of the first five of these enzymes, and of hexokinase, glucose-6-phosphate dehydrogenase, and pyrroline-5-carboxylate reductase distinguishes neoplastic from nonneoplastic sections of adult colon. Study of a wide range of pulmonary specimens permitted comparisons of different types of tumors, and revealed some subtle differences between lungs of noncancer patients and nonneoplastic portions of host lungs. The concentrations of eight previously identified enzymic indicators were less in moderately or well differentiated than in poorly differentiated pulmonary adenocarcinomas. The latter differed from epidermoid carcinomas (also poorly differentiated) by containing lower concentrations of thymidine kinase (both soluble and particulate) and hexokinase.

Adenocarcinoma↗
PubMed1980

Enzyme pathology of the liver in patients with and without nonhepatic cancer.

Preliminary studies of 13 enzymes subserving various metabolic pathways were undertaken in tumor-free liver biopsy samples from cancer patients and control subjects. The observations indicate that as a result of nonhepatic neoplasms, with (7 cases) or without (6 cases) hepatic involvement, the biochemical composition of the liver becomes partially undifferentiated. Quantification of appropriate enzymes in histologically normal liver samples could thus distinguish clearly between cancer hosts and controls. The best discriminators include two hepatic enzymes whose concentrations were decreased to less than 30% of normal (soluble glutamate dehydrogenase and the cold stable pyrroline-5-carboxylate reductase) and three for which it was elevated two to four-fold (hexokinase, peptidyl proline hydroxylase and thymidine kinase) in response to distant neoplasms. The same alterations in hepatic enzyme pattern were not seen in any cancer-free patients with or without morphologic liver damage.

Animals↗
PubMed1980

Pulmonary and hepatic activities of membrane-bound enzymes in man and rat.

The lung of adult man contains several times more 5'-nucleotidase (EC 3.1.3.5), alkaline phosphatase (EC 3.1.3.1) and gamma-glutamyl-transpeptidase (EC 2.3.2.2) per gram than does that of the 12- to 16-week fetus. In rat lung, too, there is a drastic developmental rise in these activities. Opposite changes in two of the enzymes occur during hepatic differentiation: alkaline phosphatase decreases in the rat, and gamma-glutamyl-transpeptidase is ten times higher in the fetal than in the adult liver of both species.

5'-Nucleotidase↗