Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth characteristics, survival time, sex differences and hormonal effects, and various biochemical parameters were evaluated in a transplantable Furth/Wistar rat Wilms' tumor model. Survival time was dependent on site of tumor transplant and ranged from a mean of 28 days for intrarenal implantation to 44 days intramusculary. Maximum tumor weight (130 g) was obtained via subcutaneous implant. Lung metastasis was evident in the majority of animals with the exception of those receiving the tumor implant intraperitoneally. The levels of erythropoietin and serum calcium and phosphatase were comparable to control values whereas hematocrit levels declined. Tumor tissue arginase or total protein remained unchanged during tumor growth. In these same tissues DNA, content and 5-alpha-reductase activity significantly and progressively increased with concomitant tumor growths. Measurements of lactic dehydrogenase, alkaline phosphatase, and their isoenzymes indicated patterns of liver involvement which were not macroscopically evident. After 31 days of subcutaneous tumor transplant, male and female rats had tumors of comparable weights. Orchiectomy or estradiol treatment significantly reduced tumor weight in males. In female rats testosterone treatment significantly increased tumor weights. DNA concentration in tumor tissue was unaffected by treatment. Similiarly, although 5-alpha-reductase activity was higher in tumors from males, and arginase higher in females, these enzymes were not affected by surgical or hormonal treatment.
 ...
PMID:Characterization of a Wilms' tumor model. 16 21

Considerable thymidine kinase and pyrroline-5-carboxylate reductase activities were found in the plasma of rats bearing a transplanted lymphoma; neither activity was detected in plasma of hosts carrying hepatic, renal, mammary, or submaxillary gland tumors. All host livers exhibited signs of biochemical immaturity as indicated by the appropriate increases or decreases in the concentrations of the nine enzymes measured. The extent and time schedule of the changes in host liver varied with the enzyme and with the tumor that caused them. The hepatic concentrations of ornithine aminotransferase, arginase, pyrroline-5-carboxylate reductase, and glucokinase (all diminished), and of peptidyl proline hydroxylase and hexokinase (increased) were sensitive indicators of tumor growth in general. The concentration of ornithine aminotransferase decreased before the tumors became palpable. At more advanced stages, the high hepatic thymidine kinase activity distinguished the presence of hepatoma and lymphoma from those of all other equally fast-growing tumors. However, only in lymphoma-bearing rats did a fivefold elevation of hepatic thymidine kinase occur as early as 4 days after implantation. Additional observations on the lymphoma itself, on blood cells, and on the involuting thymus of normal rats indicate that the striking systemic effects of this tumor cannot be explained by a release of enzymes from the thymus or by the increased number of lymphoma cells present in blood or liver.
 ...
PMID:The effect of lymphoma and other neoplasms on hepatic and plasma enzymes of the host rat. 18 34

A solid lymphoma implanted into normal inbred Kx rats and one partner of parabiotic pairs caused appreciable decreases in hepatic ornithine aminotransferase and arginase about a week earlier (4-6 days after implantation) in single hosts than in parabiotic hosts. By 18-21 days significant decreases in both enzymes were apparent in the host partner also. The hepatic thymidine kinase showed a fivefold elevation in single hosts 4 days after implantation; by 14 days in its levels were about 200 times above normal and had also risen in the parabiotic hosts (20-fold) and host partners (fourfold). Implantation of fibrosarcoma caused qualititatively similar but generally less pronounced changes in these three enzymes in livers of single hosts, parabiotic hosts, and host partners. The splenic thymidine kinase 14 days after implantation was increased from control levels of about 3 U/g to 50.6, 44.8, and 13.5 U/g in single hosts, parabiotic hosts, and host partners, respectively. At later stages, 17-20 days after implantation of the lymphoma, appreciable amounts of thymidine kinase appeared in the plasma: The units of activity per milliliter were 6.2 in single hosts, 0.79 in parabiotic hosts, and 0.55 in host partners (control less than 0.05). Our observations on the changes in hepatic and splenic enzymes in parabiotic rats suggest that effects of neoplasms on distant host tissues are mediated by humoral factors. The less pronounced responses in parabiotic than in single hosts indicate that the tumor-free partner affords some "protection" against these systemic effects.
 ...
PMID:Tissue enzyme changes in parabiotic rats with subcutaneous lymphoma or fibrosarcoma. 63 92

The potential of the immune system to inhibit or stimulate tumor growth is a vivid example of the "two-edged sword" nature of immune responses. Our results provide evidence that this dual capacity can be attributed, in part, to the dual pathways of arginine metabolism exhibited by intratumor macrophages. Specifically, i.p. tumor rejection in P815-preimmunized mice is accompanied by an upshift in intratumor macrophage arginine metabolism to the nitric oxide (NO) synthase pathway that yields citrulline and NO. A rapid and marked local increase in IFN-gamma (both mRNA and protein) in preimmunized mice during tumor rejection suggests that this cytokine plays a role in up-regulating nitric oxide production in vivo. Unlike tumor rejection, progressive i.p. P815 tumor growth in naive mice is associated with a marked decline in the production of citruline/NO by intratumor macrophages. Examination of macrophage arginine metabolism via arginase revealed a pattern opposite that of NO synthase. The local production of ornithine/urea markedly increases during progressive tumor growth whereas arginase activity decreases during tumor rejection. Inasmuch as nitric oxide inhibits tumor cell replication whereas ornithine is the precursor of polyamines required for cell replication, these results are consistent with the conclusion that the pathway macrophages use to metabolize arginine can influence the type of host immune responses against cancer and other conditions.
 ...
PMID:Macrophage arginine metabolism and the inhibition or stimulation of cancer. 140 10

L-Arginine concentrations have been measured in benign and malignant breast and colonic neoplasms and compared with the macrophage content and arginase activity within these tumors. Our study confirmed previous findings of elevated plasma arginine concentrations in malignancy and demonstrated that tissue free-arginine concentrations are substantially higher in malignant (mean 9.8 mumol/g protein) than benign (2.8 mumol/g protein) breast disease. Similarly, malignant colonic neoplasms had a higher free-arginine concentration than benign colonic polyps (14.0 vs. 7.0 mumol/g protein). The macrophage content of the malignant tumors was also significantly higher than in the benign conditions (278 vs 29/high power field in breast disease), but despite this, there was no detectable difference in the arginase activity. These findings suggest that tumor-infiltrating macrophages are not able to produce this enzyme, and/or its activity is inhibited within the tumor cell milieu. The differences observed in the arginine concentrations within these lesions has potentially important implications for the pathway of arginine metabolism and local host antitumor responses.
 ...
PMID:Arginine metabolism in benign and malignant disease of breast and colon: evidence for possible inhibition of tumor-infiltrating macrophages. 180 7

Recently, L-arginine has been shown to be a necessary substrate for murine-activated macrophage-mediated tumor cytostasis and microbiostasis of certain fungi, bacteria, and intracellular protozoa. We report here the effects of the L-arginine-dependent pathway of activated mouse macrophages (MO) on the obligate intracellular prokaryote, Mycobacterium leprae. Due to the inability to culture M. leprae in vitro, a simple, quantitative assay was employed to measure the metabolism/viability of M. leprae released from MO: the metabolic capacity of M. leprae to oxidize 14C-palmitic acid to 14CO2. Murine normal MO or MO activated in vitro with IFN-gamma or in vivo by injection with Corynebacterium parvum were infected with viable M. leprae freshly harvested from the footpads of nu/nu mice. Activated MO strikingly inhibited the metabolism of M. leprae; however, in L-arginine-free medium or in medium containing L-arginase, the inhibitory effects of activated MO on M. leprae metabolism were abolished. The competitive inhibitor of L-arginine, NG-monomethyl-L-arginine, also blocked the inhibitory effects of activated MO for M. leprae, but the addition of supplemental L-arginine overcame the NG-monomethyl-L-arginine-induced block. Furthermore, in the culture supernatants, the levels of NO2-, an end product of L-arginine degradation, were directly proportional to the ability of the activated MO to inhibit M. leprae metabolism. These data present five lines of evidence that suggest that activated MO utilize the L-arginine-dependent pathway to cope with M. leprae.
 ...
PMID:L-arginine-dependent macrophage effector functions inhibit metabolic activity of Mycobacterium leprae. 188 Apr 20

Human alveolar macrophages (HAM) from 28 normal volunteers were found to inhibit replication of Cryptococcus neoformans. Conditions under which fungistasis occurred were different than those required for mouse peritoneal macrophage-mediated fungistasis. Inhibition of fungal replication by mouse peritoneal macrophages (MPM) requires that the macrophages are activated and that the cocultures of C. neoformans and macrophages be done in the presence of serum, L-arginine, and endotoxin. During MPM-mediated fungistasis and tumor cell killing, L-arginine is oxidized to NO2-, NO3-, and L-citrulline. In addition, MPM have arginase activity that converts L-arginine to L-ornithine and urea. HAM-mediated fungistasis was similar to that mediated by MPM in terms of the serum requirement, but HAM did not require L-arginine or endotoxin. HAM did not produce NO2- or NO3- detectable by colorimetric and bioassay, nor did HAM produce L-citrulline or L-ornithine from 14C-radiolabeled L-arginine as detectable by reverse-phase ion-pairing HPLC of macrophage-C. neoformans coculture supernatants. HAM had no detectable arginase activity, hence there was no evidence for L-arginine nitrogen metabolism in HAM. HAM-mediated fungistasis was not enhanced by endotoxin or by recombinant human interferon-gamma (rHIFN-gamma). The combination of endotoxin and rHIFN-gamma inhibited the fungistatic effect of HAM. Human peritoneal macrophages (HPM) from women undergoing laparoscopy were tested for fungistasis and L-arginine nitrogen oxidation. Partial inhibition of cryptococcal replication occurred; however, there was no evidence of L-arginine metabolism to NO2- or NO3-.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate. 212 14

Administration of alpha/beta-interferon (IFN) exerts a marked antitumor effect in DBA/2 mice given injections i.v. of large numbers of IFN-alpha/beta-resistant erythroleukemia cells (FLC). To investigate the possible mechanisms of FLC tumor inhibition in the liver of interferon-treated mice, we developed an in vitro model consisting of a coculture of IFN-alpha/beta-resistant 3Cl8 FLC and syngeneic mouse hepatocytes. Whereas IFN-alpha/beta did not inhibit the multiplication of 3Cl8 FLC cultivated alone, it effectively inhibited the multiplication of 3Cl8 FLC in coculture with hepatocytes. The inhibitory effect was directly proportional to the amount of IFN-alpha/beta added to the cocultures, and more than 90% inhibition of FLC multiplication was noted with 1.6 x 10(5) IU/ml of IFN-alpha/beta on Day 3 of coculture. When FLC were separated from the monolayer of hepatocytes by a pored membrane (0.4 microns), the inhibitory effect on FLC proliferation was unchanged, indicating that a soluble factor(s) released from IFN-treated hepatocytes was most important in the inhibition of FLC multiplication. An inhibitory activity of FLC multiplication was detected only in the conditioned medium of IFN-treated hepatocytes but not in the conditioned medium of control hepatocytes nor in extracts of IFN-treated or control hepatocytes. The inhibitory factor(s) in the conditioned medium of IFN-treated hepatocytes was retained by an ultrafiltration membrane (Mr cut off 10,000), and its activity was completely abrogated by trypsin digestion. Its stability to treatment with 1 M acetic acid as well as lack of correlation between the antiproliferative effect and the amount of L-arginine in the medium distinguished this factor(s) from liver arginase which was also found to be a potent inhibitor of FLC multiplication in vitro. The inhibitory factor(s) was also distinguishable in its biological activity from IFN gamma, interleukin 1 alpha and beta, and transforming growth factor beta 1 and beta 2. These results suggest the possibility that the inhibitory effect of IFN-alpha/beta on the development of 3Cl8 FLC in the livers of IFN-treated mice may be mediated by an IFN-induced inhibitor of FLC multiplication.
 ...
PMID:Inhibition of mouse alpha/beta-interferon of the multiplication of alpha/beta-interferon-resistant Friend erythroleukemia cells cocultured with mouse hepatocytes. 214 Feb 90

An effort was made to investigate the effects of a novel immunopotentiator, N-[4-[(4-fluorophenyl)sulfonyl]phenyl]acetamide (CL 259,763), on the generation of tumoricidal effector cells. It was demonstrated that a single oral dose of the compound (100-600 mg/kg) induced in mice a population of peritoneal macrophages capable of inhibiting the growth of tumor cells. These activated macrophages released proteases which seemed responsible for the tumor cell inhibition because the cytostatic activity was abrogated in the presence of protease inhibitors TLCK and aprotinin. On the other hand, addition of catalase and exogenous arginine to the culture failed to alter the effect, suggesting that hydrogen peroxide and arginase did not participate in this system. Although induction of cytolytic T-lymphocytes (CTL) reactive with syngeneic tumor cells was achievable in mice previously sensitized to the tumor, treatment with CL 259,763 rendered these animals even more responsive to tumor antigens resulting in a significant enhancement of tumor cell destruction. The compound was effective in augmenting the CTL response over a rather broad dose range of 25-200 mg/kg. In contrast to these stimulatory effects, the cytolytic activity of natural killer cells seemed not to be affected by the compound. Taken together, CL 259,763 is an orally active immunomodulator capable of inducing tumor inhibitory macrophages and potentiating CTL responses to syngeneic tumor cells and, therefore, may prove clinically useful in the treatment of neoplastic diseases.
 ...
PMID:Generation of tumoricidal effector cells with a novel potentiator: N-[4-[(4-fluorophenyl)sulfonyl]phenyl] acetamide (CL 259,763). 232 20

L-Arginine is required for expression of the activated macrophage cytotoxic effector mechanism that causes inhibition of mitochondrial respiration, aconitase activity, and DNA synthesis in tumor target cells. This effector mechanism is active in the presence of L-arginine even when the cocultivation medium lacks all other amino acids and serum. Cytotoxic activated macrophage-induced inhibition of mitochondrial respiration in target cells is proportional to the concentration of L-arginine in the medium. L-Arginine must be present during the cocultivation period. Pretreatment of cytotoxic activated macrophages with L-arginine or posttreatment of the target cells after cocultivation is not effective. D-Arginine does not substitute for L-arginine and at high concentrations is a competitive inhibitor of the L-arginine-dependent effector mechanism. Other analogues that could not replace L-arginine include agmatine, argininic acid, arginine hydroxamate, and tosyl-L-arginine methyl ester. L-homoarginine, however, can effectively substitute for L-arginine. NG-monomethyl-L-arginine is a potent competitive inhibitor of this effector mechanism. High concentrations of lipopolysaccharide do not reverse inhibition of the L-arginine-dependent effector mechanism by NG-monomethyl-L-arginine. However, inhibition of the effector mechanism by NG-monomethyl-L-arginine can be overridden by increasing the concentration of L-arginine in the culture medium. We compared NGNG-dimethyl-L-arginine and NGN1G-dimethyl-L-arginine with NG-monomethyl-L-arginine as inhibitors of the L-arginine-dependent effector mechanism. The results show that the inhibitory effect of these guanidino methylated derivatives of L-arginine is highly determined by structure. Guanidine is a weak competitive inhibitor of the L-arginine-dependent effector mechanism. The requirement for L-arginine does not appear to be for protein synthesis, creatine biosynthesis, polyamine biosynthesis, or ADP ribosylation reactions. Bacterial lipopolysaccharide is effective as a second signal only when the cocultivation medium contains L-arginine, and this strict L-arginine dependency is not overridden by increasing the concentration of lipopolysaccharide. Bovine liver arginase, by competing for L-arginine in the cocultivation medium, inhibits the L-arginine-dependent activated macrophage cytotoxic effector mechanism.
 ...
PMID:L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. 243 29


1 2 3 4 5 6 7 8 9 10 Next >>