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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While many advances have been made in the chemotherapy of gynecologic cancers, treatment failures remain a major clinical problem. A growing understanding of the mechanisms of tumor cell resistance to antineoplastic drugs provides a framework for the development of chemotherapy regimens containing agents capable of modulating tumor response. Using a short-term ATP bioluminescence assay we studied the ability of two methylxanthines (caffeine, pentoxifylline) and an inhibitor of ADP-ribosyl transferase (3-aminobenzamide) to enhance cisplatin cytotoxicity in gynecologic cancer cell lines. Our findings of significantly enhanced cisplatin-induced cytotoxicity with two different analysis techniques confirms the effectiveness of these agents. These results may have future clinical significance.
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PMID:Chemical enhancement of cisplatin cytotoxicity in a human ovarian and cervical cancer cell line. 212 26

Activated macrophages synthesize and release numerous tumoricidal soluble factors that can be divided into receptor- or nonreceptor-dependent agents. Tumor necrosis factor (TNF) would be an example of the former. In our experimental model the killing of EL4 thymoma cells by syngeneic activated macrophages involves, but not exclusively, TNF. Our results show that approximately 50% of the anti-EL4 activity expressed by macrophages can be specifically inhibited with rabbit anti-mouse TNF antibody. EL4 variants resistant to the lytic activity of TNF were still susceptible to macrophage-mediated lysis. A tumor-promoting phorbol ester, TPA, rendered TNF-sensitive and -insensitive EL4 cells resistant to M phi-mediated lysis. However, TPA down-regulated TNF-specific binding sites on both TNF-sensitive and -resistant cell surface membranes, suggesting that resistance to TNF involves postligand:receptor events. Tumor cell G-protein involvement (ADP-ribosylation), as a result of TNF-TNF receptor interactions, was investigated. The results showed that pertussis toxin was cytotoxic against TNF-sensitive and -resistant EL4 cells but not against TPA-treated target cells. Inhibitors of ADP-ribosyltransferase inhibited pertussis toxin cytotoxicity and macrophage-mediated lysis but did not interfere with recombinant TNF lytic activity.
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PMID:TPA induction of EL4 resistance to macrophage-released TNF: role of ADP-ribosylation in tumoricidal activities of TNF and other factors. 213 20

The biochemical pathways through which tumor cell locomotion is mediated are poorly understood. Autocrine motility factor (AMF), which is produced by and stimulates motility in A2058 human melanoma cells, was used to characterize phosphoinositide (PtdIns) metabolism activated in association with tumor cell motility. AMF stimulated up to a 400% increase in de novo incorporation of 3H-myo-inositol into cellular lipids beginning 40 minutes after exposure. In cells prelabeled with 3H-myo-inositol, AMF stimulated a 200% increase in total inositol phosphates (inositol monophosphate, InsP1; inositol bisphosphate, InsP2; inositol trisphosphate, InsP3) after 90 minutes of exposure, with a 300% maximal increase in InsP3 at 120 minutes. InsP1 and InsP2 were maximally increased 130% of control values. Treatment with AMF stimulated a parallel dose-dependent increase in both motility and PtdIns levels. We have shown previously that the A2058 motile response to AMF is inhibited markedly by cell pretreatment with pertussis toxin (PT). Inositol phosphate production was inhibited by a 2-hour pretreatment of cells with PT (0.5 microgram/ml). PT treatment of A2058 membranes was associated with ADP-ribosylation of a 40-kDa protein consistent with the presence of an alpha subunit of a guanine nucleotide-binding protein (G protein). These data indicate that AMF elicits increases in cell motility and phosphoinositide metabolism via a PT-sensitive G protein signal transduction pathway.
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PMID:Autocrine motility factor stimulates a three-fold increase in inositol trisphosphate in human melanoma cells. 215 19

A list of endogenous DNA-damaging agents and processes is given. Endogenous electrophiles are found with the cosubstrates of physiological transfer reactions (S-adenosylmethionine for methylation, ATP for phosphorylation, NAD+ for ADP-ribosylation, acetyl CoA for acetylation). Aldehyde groups (glyceraldehyde-3-phosphate, formaldehyde, open forms of reducing sugars, degradation products of peroxidation) or alkylating degradation products derived from endogenous nitroso compounds represent additional possibilities. Radical-forming reactions include leakage of the superoxide anion radical from terminal cytochromes and redox cycles, hydroxyl radical formation by the Fenton reaction from endogenous hydrogen peroxide, and the formation of lipid peroxides. Genetic instability by spontaneous deaminations and depurinations as well as replicative instability by tautomer errors and in the presence of mutagenic metal ions represent a third important class of endogenous genotoxic processes. The postulated endogenous genotoxicity could form the mechanistic basis for what is called 'spontaneous' tumor incidence and explain the possibility of an increased tumor incidence after treatment of animals with non-genotoxic compounds exhibiting tumor-promoting activity only. Individual differences are expected to be seen also with endogenous DNA damage. The presence of endogenous DNA damage implies that exogenous DNA-carcinogen adducts give rise to an incremental damage which is expected to be proportional to the carcinogen dose at lowest levels. An increased tumor risk due to exposure to exogenous genotoxic carcinogens could therefore be assessed in terms of the background DNA damage, for instance in multiples of the mean level or of the interindividual variability in a population.
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PMID:Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis. 218 25

Adenine nucleotide compartmentation and cytochrome redox state were studied in two Ehrlich ascites tumor cell lines incubated in the presence of 5mM glucose to show differences between their energy metabolisms. Changes in the subcellular distribution of adenine nucleotides were very different in both cell lines. Glucose seemed to energize the less malignant cell line, as shown by the asymmetry of the ATP/ADP ratios between cytosolic and mitochondrial compartments, but this was not the case for the more malignant cell line. The cytochrome contents were similar in both cell lines, but the degree of cytochrome oxidation was higher in the less malignant cell line; this result is in agreement with a higher oxygen consumption in the less malignant cell line.
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PMID:Subcellular distribution of adenine nucleotides in two Ehrlich cell lines metabolizing glucose. 222 61

Two new compounds, 4-[4-[bis-(2-chloroethyl)-amino-]phenyl]-1- hydroxybutane-1,1-bisphosphonic acid (BAD) and aminotris-(methylenephosphonato)-diamminoplatinum(II) (ADP) that both have cytostatic and osteotropic properties, have shown good therapeutic efficacy against an osteosarcoma which metastasizes and kills by lung metastases. We therefore combined each of these drugs with the antimetastic agent razoxane. Razoxane (20 mg/kg i.p., 5 days/week for 6 weeks) was administered in combination with either BAD (30 mg/kg i.p.) or ADP (37.5 mg/kg i.v.) twice weekly for 3 weeks. Tumour volumes, body weight, survival time and occurrence of metastases were recorded, in addition to the measurement of the metastasis area compared to the total lung area in serial histological lung samples. In both experiments, razoxane effected a significant increase in life span while being ineffective in tumour inhibition. Razoxane in combination with BAD displayed an enhanced anticancer activity which was not significant. ADP had a good antineoplastic activity and a large increase in survival time (144 per cent ILS). Razoxane used in combination with ADP did not influence antitumour efficacy. Median survivals of both ADP-treated groups were significantly longer than the razoxane-treated group. Analysis of the lung metastasis area showed a maximum of 57 per cent for the controls while all treated groups occupied a lesser area. The lowest metastases area was found with the combination treatment BAD + RAZ (18 per cent). This was considered an antimetastatic effect, while ADP treatment effected a time delay only. No change in metastatic pattern was observed in any of the treatment groups. Histological examination showed no effect on the capillaries in the proliferating region of the tumours that could account for the lower occurrence of metastases.
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PMID:Therapeutic efficacy of two different cytostatic-linked phosphonates in combination with razoxane in the transplantable osteosarcoma of the rat. 235 Sep 20

Magnetic resonance spectroscopy (MRS) uniquely provides noninvasive access to chemistry in vivo. 31P MRS can be used to monitor the high energy phosphates--phosphocreatine (PCr) and ATP, and their breakdown product--Pi, in situ in animals or patients. In several experimental tumor lines in animals it has been shown that the PCr/ATP and other related ratios steadily decline as the tumor increases in size, and that this effect is reversed when the tumor is treated with a therapeutic modality to which it responds. Acid extracts of freeze-clamped tumors at different stages of growth have confirmed these MRS observations and give additional information on related compounds such as creatine and ADP. Results show that, in the tumors studied, at least 80% of the ADP and about 40% of the Pi are bound and not in solution in the cytosol. Histological sections have indicated that the MRS response to endocrine therapy, in an NMU-induced estrogen-sensitive mammary tumor model, precedes any histological changes or any measurable regression. If these findings can be translated into a clinical setting, this may mean that MRS can be used in the clinic as an early predictor of tumor responsiveness to treatment. In untreated tumor growth, the cause of the decrease in PCr and ATP relative to Pi is probably due to the tumors outgrowing their blood supply and the cells becoming increasingly hypoxic. The PCr is lost more rapidly than ATP, indicating that the equilibrium in the creatine kinase reaction is maintained in these tumors. When the tumor is treated, cellular growth ceases and the requirement for oxygen and other nutrients is greatly reduced. This would allow the cellular energy reserves to be repleted and thus lead to the paradoxical improvement in the high energy phosphate status of a tumor that is about to regress.
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PMID:Monitoring tumor growth and regression by 31P magnetic resonance spectroscopy. 240 32

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.
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PMID:L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. 243 29

Several drugs known to induce differentiation in tumor cells were analyzed for their effects on the beta-adrenergic receptor-coupled adenylate cyclase system in two human carcinoma cell lines, HeLa and A431. Each of the drugs was tested alone or in combination with sodium butyrate (NaBu), a known inducer of this signal transduction system. Puromycine amino nucleoside (PMAN) caused the largest increase in beta-adrenergic receptors in HeLa cells followed by hexamethylenebisacetamide (HMBA) whereas 5'-azacytidine (5AZC) was ineffective. In addition, PMAN but not the others acted together with NaBu to elevate receptor levels 12-fold over control values. In contrast, HMBA and 5AZC were much more effective on A431 cells, PMAN caused only a slight increase in beta receptors and none of the drugs acted in concert with NaBu. The increase in beta receptors was usually accompanied by a corresponding increase in isoproterenol-stimulated adenylate cyclase activity. These effects of the drugs appeared to require protein synthesis as they were blocked by cycloheximide. In addition, some of the drugs caused a substantial decrease in basal adenylate cyclase activity. This effect on basal activity was abolished in cells treated with pertussis toxin, which ADP-ribosylates the inhibitory GTP-binding protein, Gi. Both HeLa and A431 cells contained a 41 kDalton substrate for the toxin which corresponds to the alpha subunit of Gi. The Gi subunit was ADP-ribosylated by the toxin to a similar extent in membranes from control and drug-treated cells. Thus, the drugs appear to induce quantitative changes in beta-adrenergic receptors and qualitative changes in Gi which results in a highly responsive beta-adrenergic-stimulated adenylate cyclase.
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PMID:Modulation of the beta-adrenergic receptor-coupled adenylate cyclase by chemical inducers of differentiation: effects on beta receptors and the inhibitory regulatory protein Gi. 245 8

The antimetastatic activity of the prostacyclin analog Iloprost has been examined in mice bearing Lewis lung carcinoma. An inhibition of lung colony formation is observed when 100 or 200 micrograms/kg Iloprost are administered i.v. 1 h before i.v. injection of tumor cells, which is dependent on the size of tumor inoculum. The effects of 200 micrograms/kg Iloprost persist for 24 h, and are of the same magnitude as those obtained with 10 mg/kg prostacyclin, which last only for 30 min. When treatment with Iloprost is followed by surgical removal of primary tumor, spontaneous metastasis formation is reduced, and the survival time of the treated animals is significantly increased over controls treated with surgery only. The antimetastatic effects of Iloprost appear dissociated from drug's effects on the hemostatic system of the host as indicated by the clot retraction assay, performed after in vivo treatment, using ADP or tumor cells as platelet aggregating agents. Iloprost thus appears to reduce spontaneous metastasis formation and intraoperative tumor cell dissemination, with pharmacological properties more favourable to therapeutic use than those of prostacyclin.
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PMID:Antimetastatic action of the prostacyclin analog iloprost in the mouse. 247 73


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