Anticancer agents: N'-(2-chloroethyl)-N'-nitrosocarbamoyl amino acid derivatives of steroid hormones.
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Amino Acids↗
Biomedical subjects
W Tang
Publications and source records attributed to W Tang.
The accumulation of free arachidonic acid, diacylglycerols, prostaglandins, and lipoxygenase reaction products in the brain during experimental epilepsy.
There has been increasing biochemical evidence since 1970 that one of the targets for convulsion-induced changes is the cell membrane of neurons. This is partly based on the observation that following seizures, there are increased levels of diacylglycerols and free fatty acids, which are products of the degradation of the major component of cell membranes, phospholipids. In addition, the production of prostaglandins from the free fatty acid, arachidonic acid, is activated after convulsions. This implies that alterations in the metabolism of lipids in brain are a major effect of seizures, and that the further study of these biochemical pathways may reveal important information pertinent to defining the basic mechanism of seizures and seizure-related pathology and may help in the development of potentially effective treatments. The effects of seizures on brain lipid metabolism and some recent studies from our laboratory are described in this chapter. Our results demonstrate that in rat brain, dexamethasone--a phospholipase A2 inhibitor--attenuates bicuculline-induced free fatty acid accumulation in a dose-dependent manner; bicuculline-induced status epilepticus does not alter the activation (synthesis of arachidonoyl coenzyme A) or acylation of fatty acids as assayed in vitro, indicating that the availability of high-energy cofactors (ATP) may be the critical factor responsible for decreased fatty acid acylation in vivo; bicuculline-induced fatty acid accumulation is localized mainly in the synaptosomal fraction of the rat brain; induction of seizures in the rat by bicuculline treatment produces a marked stimulation of lipoxygenase activity in synaptosomes that, in turn, results in a large increase in the synthesis of hydroxyeicosatetraenoic acids (HETEs). This effect is also observed following membrane depolarization with 45 mM K+, and bicuculline-induced status epilepticus stimulates the synthesis of prostaglandin D2. Possible mechanisms and consequences of alterations in specific lipids are described. Also, the possible involvement of a stimulated arachidonic acid cascade, particularly of hydroxylated products, in the release of neurotransmitters is discussed. Other aspects of the interaction between neurotransmission and the production of eicosanoids are reviewed. The metabolic pathways leading to the "lipid effect"--i.e., the production of free fatty acids, diacylglycerols, and arachidonic acid metabolites (eicosanoids)--are numerous and involve a wide variety of enzymes. The mechanism of this "lipid effect" may involve a seizure-induced overstimulation of normal lipid pathways that operate in neurotransmission.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Metabolic relationship between arachidonate activation and its transfer to lysophospholipids by brain microsomes.
Evidence is presented to indicate a metabolic relationship between arachidonic acid activation and its transfer to lysophospholipids by brain microsomes. Thus, in the presence of 1-acylglycerophosphocholines or 1-acyl-glycerophosphoinositols, the activation of labeled arachidonate to its acyl-CoA was enhanced, and the acyl-CoA formed was, in turn, transferred to the lysophospholipids to form the respective diacyl-glycerophospholipids. The "coupling effect" seems to pertain mainly to the lysophospholipids which are good substrates of the acyltransferase. Other lyso-compounds were either not effective or inhibitory to the arachidonate activation process. The activation-transfer activity mediated by the fatty acid ligase and acyltransferase could be dissociated by Triton X-100, which apparently stimulated the acyl-CoA ligase activity but inhibited the acyltransferase. These results suggest that fatty acid ligase and acyltransferase are located in close proximity within the membrane domain. The existence of a close metabolic relationship between these two enzymic reactions is important for maintaining a dynamic equilibrium between the free fatty acids and the membrane phospholipids. The mechanism is also useful in regulating the cellular acyl-CoA and lysophospholipid metabolism, because both compounds have membrane perturbing properties when present in excessive quantity.
Acyl Coenzyme A↗
Serum albumin washing specifically enhances arachidonate incorporation into synaptosomal phosphatidylinositols.
Arachidonate incorporation into synaptosomal phospholipids was shown to be affected by factors including the procedure for preparation of the membrane fractions and preincubation of synaptosomes prior to assay of incorporation of arachidonate into both phosphatidylcholine (PC) and phosphatidylinositol (PI). However, the inhibition toward incorporation into PIs, but not PCs, was fully reversed when the membranes were washed with bovine serum albumin. A twofold increase in arachidonate incorporation into PIs was also observed when freshly prepared synaptosomes were washed with serum albumin immediately before assay of incorporation activity. The inhibitory action is thought to be due to an increase in polyunsaturated fatty acids and/or their oxidation products which may then elicit a special effect on the acyltransferase responsible for transferring arachidonate into phosphatidylinositols. The differences in fatty acid uptake and response to serum albumin also suggest the presence of different acyltransferase for acyl transfer to PIs and PCs.
Animals↗
Chemotherapeutic activity of 2-chloroethylnitrosocarbamoyl derivatives of amino acids in a transplanted rat leukemia (L 5222).
The therapeutic activity of a single-dose treatment with 14 2-chloroethylnitrosocarbamoyl derivatives of amino acids (CNU-analogs) in L 5222 rat leukemia is presented. Compounds under study included free carboxylic acids, a methylester, a toluidide, four glucosamides and one derivative of a dipeptide. All substances proved to be active effecting at least an increase in life span of greater than or equal to 120% compared with untreated controls at the optimal dose; 2 compounds effected isolated cures (90-day survivors). Compared with previous data obtained with established and new nitrosoureas under the same conditions, the effectivity of the compounds presented here should be classified, however, only as moderate.
Amino Acids↗
Clinical studies on the antitumor action of mecaphane.
Over a period of 4 years, 241 patients with advanced cancer were treated with mecaphane alone in 11 hospitals. Effective objective responses were obtained in 100 patients (41.4%). The response was most conspicuous in chronic granulocytic leukemia, with remission in 37 of 40 patients; in Hodgkin's disease and lymphosarcoma response rates were 60% and 47.3%, respectively. Mecaphane had an analgesic action in metastatic osteolytic bone cancer, and two patients with such metastases even attained recalcification of the osteolytic destructive lesions. The common toxic manifestations of mecaphane were leukopenia (33.6%), gastrointestinal upsets (28.2%), and thrombocytopenia (12.8%). It is concluded, therefore, that mecaphane could be a good antitumor agent in clinical use. It is less expensive and can be taken orally. Further trials of this drug are recommended.
Adult↗
Metabolism of oleoyl-CoA in rat brain synaptosomes: effects of calcium and post-decapitative ischemia.
The hydrolysis of acyl-CoA by acyl-CoA hydrolase (EC 3.1.2.2.) in brain synaptosomes was inhibited by calcium. This inhibition was partly due to interaction of Ca2+ with the acyl-CoA, which was present in the soluble form, and partly due to complex formation among acyl-CoA, Ca2+ and membrane phospholipids. The inhibition of acyl-CoA hydrolase activity, as well as the complex formation, could be reversed if incubation was carried out in the presence of Ca2+ chelating agents. Synaptosomes isolated from brain samples after 1 min of postdecapitative treatment showed a decrease in oleoyl-CoA hydrolase activity. The physiological implication of acyl-CoA metabolism in relation to synaptic function is discussed.
Acyl Coenzyme A↗
[The epidemiology and etiology of esophageal cancer in China (author's transl)].
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Carcinoma↗
Enzymic regulation of arachidonate metabolism in brain membrane phosphoglycerides.
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Acetyltransferases↗
Fluorinated analogues as mechanistic probes in valproic acid hepatotoxicity: hepatic microvesicular steatosis and glutathione status.
It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis ( > 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg) and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.
Animals↗
Measurement of cadmium-induced metallothionein in urine by ELISA and prevention of overestimation due to polymerization.
Urinary metallothionein (MT) is a biological marker of cadmium (Cd) exposure and Cd-induced renal dysfunction. The MT is prone to oxidation due to high cysteine content and forms polymers, which can result in overestimation of the protein by immunochemical methods. The objectives of the present study were to develop an enzyme-linked immunosorbent assay (ELISA) for the measurement of MT in urine and to find ways by which the protein could either be preserved in its monomeric form or converted to this form before analysis to avoid overestimation. Urine specimens analyzed were either from rats repeatedly injected with Cd or from individuals chronically exposed to cadmium through their diets. The MT in rat urine remained in the monomeric form if the urine was collected at 4 degrees C but did not if it was collected at room temperature. The MT was also polymerized if the urine was subjected to repeated freezing and thawing. Overestimation of MT in rat urine occurred (as much as 12-fold) if the MT was polymerized. Addition of 5mM mercaptoethanol to freshly collected rat urine retarded MT polymerization, and addition of 50mM mercaptoethanol converted the polymerized MT to its monomeric form. Analysis of MT in frozen human urine samples revealed that if the urines were not treated with mercaptoethanol, the estimates of MT concentration were up to 11-fold higher than in the treated samples. We conclude that the polymerization of MT in rat and human urines is a serious problem and results in overestimation of the protein by ELISA and that this problem could be overcome by the addition of mercaptoethanol to the urine samples prior to analysis.
Aged↗
Mitochondrial polymorphisms as risk factors for endometrial cancer in southwest China.
It is just in recent years that mitochondrial DNA (mtDNA) mutations have been found in solid tumors. Although a direct link between the presence of mtDNA mutations and the development of tumors has not been made, mtDNA mutations might prove significant in the detection of tumor recurrence and possibly in the detection of genotoxic damage. To investigate the relationship between mtDNA variation and endometrial cancer, we collected blood samples from subjects with Han native background in Yunnan province in China, 49 of them with pathologically conformed endometrial cancer and 31 as controls with no cancer disease and sequenced two hypervariable segments of control region, part of 16sRNA gene, tRNA(leu) (tRNA is transfer RNA) gene and ND1 gene of mtDNA and identified some diagnostic polymorphisms by restriction fragment length polymorphism of coding region of mtDNA. We could not identify the suspected mutations that are related to diabetes and obesity from our endometrial cancer patients. However, our data showed that patients with endometrial cancers clustered in haplogroup D in a significantly higher frequency when compared with controls, implicating a possible association of haplogroup D to endometrial cancer. We concluded that mitochondrial polymorphisms in haplogroup D might play a genetic role in predisposing to endometrial cancer.
Case-Control Studies↗
Cytologic grading of invasive breast carcinoma. Correlation with clinicopathologic variables and predictive value of nodal metastasis.
OBJECTIVE: To estimate cytologic grade and correlate it with the other known prognostic factors, such as tumor differentiation, growth fraction, estrogen receptor status and nodal status. STUDY DESIGN: Fine needle aspirates from 104 invasive ductal carcinomas were stained by the Papanicolaou method and examined for necrosis, cellular size, nuclear/cytoplasmic ratio, nuclear pleomorphism, nucleoli, chromatin granularity and density of chromatin. We established a semiquantitative scoring system based on the above features and correlated cytologic findings with clinicopathologic variables. RESULTS: Histologic grade correlated positively with cytologic grade and negatively with estrogen receptor positivity. Moreover, high cytologic grade was associated with nodal metastasis and proliferative index labeling by MIB-1. CONCLUSION: This study showed that our grading system for breast cancer on fine needle aspiration cytology is feasible on a routine diagnostic basis. Cytologic grading can provide more information than usual on tumor biologic behavior.
Antigens, Nuclear↗
Thymidine phosphorylase expression in invasive carcinoma: correlations with clinicopathologic variables and in vitro chemosensitivity to 5-fluorouracil.
BACKGROUND: Thymidine phosphorylase (TP) is critical for angiogenic activity, but little information is available on the relationship between TP expression and other Clinicopathologic variables. Furthermore, the relationship between TP and chemosensitivity is still debated. MATERIALS AND METHODS: The expression of TP was examined in 116 primary breast carcinomas and in vitro chemosensitivity was assessed in 67 of them by histoculture drug response assay (HDRA) using 5-fluorouracil (5-FU). RESULTS: Tumor cell TP expression was significantly inversely correlated with histological grade and positively correlated with Bcl-2 expression, but no association with other tumor variables was found. Unexpectedly, TP immunoreactivity was not related to 5-FU chemosensitivity. CONCLUSION: The present results suggest that TP is important for remodeling the existing vasculature early in tumor development and intraductal extension, expressions of TP and Bcl-2 are tightly linked and TP status can not generally predict chemotherapeutic sensitivity for 5-FU as a single molecular marker.
Antimetabolites, Antineoplastic↗
[Cloning, sequence analysis and heterologous expression of a beta-mannanase gene from Bacillus subtilis Z-2].
Mannanase, an extracellular enzyme catalyzes the hydrolysis of hemicelluloses to produce oligosaccharides, has a potential to be applied in food industries. In this study, a mannanase gene from B. subtilis Z-2 was isolated through PCR screening of a genomic DNA library. The nucleotide sequence of the mannanase gene, man, contained an open reading frame of 1.080 bp, which codes for a deduced 26 amino-acid signal peptide and a mature protein with the deduced molecular mass of 38 KDa. The man gene can both be expressed heterologously into the periplasm in plasmid pET22b(+) containing intact signal peptide (pET-NdeI18) and the pelB signal peptide of the pET22b(+)vector (pET-NcoI3). The Escherichia coli BL21 (DE3) containing pET-NcoI3 secreted about twice as much mannanase as that harboring pET-NdeI18. In E. coli DH5alpha, expression of man was under the control of the lac promoter in the pRK415 vector and was much more effective when the Shine-Dalgamo (SD) sequence was changed from GGGGAG to AAGGAG and the start codon was changed from TTG to ATG, respectively. These results suggest that genetic modification of the SD sequence and start codon is practical for high-level expression of mannanase in different bacterial strains.
Bacillus subtilis↗