Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that from 350 amino acid (A-A) derivatives five were selected after the primary in vivo and in vitro screening tests. The five compounds which were found to possess potential antitumor activity against Ehrlich ascites carcinoma are as follows: beta-naphthalene-sulfonyl-DL-tryptophan (A-91), beta-naphthyl-aminomethyl-gamma-aminobutyric acid (A-144), N-ethylcarbaminomethyl-L-isoleucine (A-145), n-9-fluorenylactyl-L-phenylalanine (A-192), and N-propoinyl-L-valine (A-195). The effect on life prolongation and tumor growth of these selected A-A derivatives against various types of tumors, including ascites and solid tumors in mice and ascites hepatomas in rats, was examined. A-A derivatives were administered once daily 3 consecutive days starting 24 hours after tumor implantation. Experimental results showed that among the five A-A derivatives possessing considerable activity against Ehlich carcinoma, A-144 and A-145 were found to be more effective than chromomycin A and showed activity similar to that of cyclophosphamide against ascites Sarcoma 180. A-A derivatives showed slight antitumor activity against SR61 and L1210 leukemias. In rat ascites hepatoma, such as AH13, AH7974, AH60C, and Yoshida sarcoma, only A-145 showed a significant prolongation of the lifespan in the control groups. The five selected A-A derivatives significantly inhibited the growth of Nakahara-Fukuoka sarcoma and solid Sarcoma 180. These findings indicate that among the five A-A derivatives, A-15 appeared to be the most active against ascites and solid tumors.
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PMID:Antitumor activity of selected amino acid derivatives against various tumor systems. 16 35

Approximately 350 amino acid derivatives were synthesized and tested for antitumor activity in four tumor systems. The effect on life prolongation and tumor growth was examined using mouse leukemia SR-61, Ehrlich ascites carcinoma, ascites sarcoma-180, and rat ascites hepatoma (AH-60C). Among these 350 derivatives, 29 compounds were found to be significantly effective in prolongation of the median life-span and inhibitory effect on tumor growth in the primary screening. Among these 29 compounds, the following five compounds were found to possess potential antitumor activity: N-(2-Naphthalene)sulfonyl-DL-tryptophan (A-91), 2-naphthylaminomethyl-gamma-aminobutyric acid (A-144), N-ethylcarbaminomethyl-L-isoleucine (A-145), N-9-fluorenylacetyl-L-phenylalanine (A-192), and N-propionyl-L-valine (A-195). These five compounds were active in prolongation of the life-span of mice bearing Ehrlich ascites carcinoma and in the inhibition of the cell growth. Some of these amino acid derivatives inhibited biosynthesis of macromolecules, DNA, RNA, and protein, in tumor cells. These results suggest that the site of action of the five amino acid derivatives appears to result from the inhibition of macromolecules and another unknown mechanism.
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PMID:Antitumor activity of amino acid derivatives in the primary screening. 16 14

To explore the role of the pool of intracellular free valine in the processes of protein synthesis and protein degradation, cultured hepatoma (HTC) cells were incubated in media containing varying concentrations of L-valine, under conditions of constant rates of protein synthesis and protein breakdown, and at steady state levels of intracellular valine specific radioactivities. Two types of experiments were compared: in the first (designated "incorporation experiment"), unlabeled cells were exposed to [3H]valine for a short period of time. In the second (termed "reincorporation experiment"), cells were prelabled with [3H]valine and then incubated for a brief period with media containing different concentrations of unlabeled valine; reincorporation of [3H]valine was calculated by the difference between the release of [3H]valine from labeled cellular proteins at low valine concentrations, and the maximal rate of the release at high valine concentrations. In both types of experiments, the rates of [3H]valine incorporation or reincorporation were compared with the respective specific radioactivities of free intracellular valine. In the incorporation experiment, the rates of [3H]valine incorporation into protein calculated by the intracellular specific radioactivities were not constant, but showed an upward deviation at low valine concentrations. This is in agreement with the results of Mortimore, G.E., Woodside, K.H., and Henry, J.E. ((1972) J. Biol. Chem. 247, 2776-2784) in the perfused rat liver. By contrast, in the reincorporation experiment, the calculated rates of [3H]valine reincorporation based on intracellular specific radioactivities were constant throughout the range of valine concentrations. The constant value of calculated valine reincorporation was lower by 30 to 50% than the calculated rate of valine incorporation at high valine concentrations. The following model is proposed to explain these results. There is one common pool of free intracellular valine, but there are two sites where valyl-tRNA can be formed. The first is an internal site that utilizes valine from the intracellular pool, and the second is an external (possibly membranous) system that converts extracellular valine directly to valyl-tRNA. Valine originating from protein degradation flows into the intracellular pool, from which it can be reutilized by the internal system. According to these assumptions, in the incorporation experiment and at low valine concentrations, the specific activity of valyl-tRNA is higher than that of the intracellular pool of free valine, due to the contribution of the external system. On the other hand, in the reincorporation experiment the specific activity of extracellular valine is negligible in comparison with that of the intracellular pool. Therefore, in this case the specific activity of valyl-tRNA is proportional to that of the intracellular pool, with a constant dilution by unlabeled valine of extracellular origin...
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PMID:Relationship of the pool of intracellular valine to protein synthesis and degradation in cultured cells. 93 42

The role of protein synthesis in the control of phosphoenolpyruvate carboxykinase (PEPCK; 4.1.1.32) mRNA turnover was studied in FTO-2B rat hepatoma cells. A previous study demonstrated that incubation of these cells with cAMP prolongs the half-life of the otherwise short-lived PEPCK mRNA. The decay rate of PEPCK mRNA was also slowed in cells incubated with cycloheximide, but not in cells incubated with other translation inhibitors, such as puromycin or pactamycin, even though protein synthesis was inhibited 85-95% by these agents. No correlation was noted between the rate of L-[3H]valine incorporation into cellular proteins and PEPCK mRNA half-life, suggesting that protein synthesis per se is not required for breakdown of the mRNA. Exposure of cells to the translation initiation inhibitor pactamycin together with cycloheximide abolished the "slowing" effect of cycloheximide, and PEPCK mRNA decayed at the same rate as in cells incubated in the presence of pactamycin alone. In contrast, pactamycin did not reverse the effect of cAMP, and the mRNA decayed at the same slow rate in cells incubated in the presence of either (Bu)2cAMP alone or (Bu)2cAMP together with pactamycin. Since pactamycin promotes polysomes dissociation, these results suggest that cAMP enhances the stability of a polysome-free PEPCK mRNA. Furthermore, these results strongly indicate that neither the rapid decay of PEPCK mRNA nor the cAMP-mediated stabilization of the mRNA requires on-going protein synthesis.
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PMID:The role of protein synthesis in the decay of phosphoenolpyruvate carboxykinase messenger RNA. 133 75

The polymorphism of mammalian aromatic hydrocarbon (Ah) responsiveness appears to be correlated with genetic differences in risk of bronchogenic carcinoma caused by cigarette smoking. The human polymorphism has been uncovered, largely as the result of corresponding genetic differences characterized first in the mouse. The murine Ah locus has been defined as the gene encoding the aromatic hydrocarbon-responsive (Ah) receptor, responsible for the inducibility of a battery of at least six genes, two of which encode P450 enzymes. The high-affinity receptor and, hence, more highly induced levels of P450, can result in greater concentrations of polycyclic aromatic reactive intermediates that form DNA adducts and, ultimately, mutation fixation (tumour initiation). The Ah receptor is also likely to participate in growth and differentiation signal transduction pathways (tumour promotion). Positive and negative control regions flanking the murine Cyp 1a-1 and human CYP1A1 (cytochrome P(1)450) genes have been identified. A DNA motif approximately 1 kb upstream of the transcription start site appears to affect the translatability of the CYP1A1 mRNA and activity of the enzyme. Expression of the CYP1A1 or CYP1A2 enzyme in mouse hepatoma Hepa-1 cells lacking endogenous CYP1A1 activity represses constitutive transcription of not only the endogenous Cyp1a-1 gene but other genes in the dioxin-inducible [Ah] battery. Human polymorphisms involving a Msp I site 450 bp downstream from the last CYP1A1 exon have been described in Japan, the Eastern Mediterranean, Norway and the USA. The '1.9 allele' is associated with an increased incidence of Kreyberg Type I bronchogenic carcinomas in Japan and has recently been correlated with a valine-to-isoleucine substitution at position 462 in the haeme-binding region. This allele is about 3 times more frequent in Japan than in Caucasians of Norway and the USA, in which no correlation has been found between this allele and lung cancer. More work is needed to clarify these findings. Isolation and sequencing of the human Ah receptor cDNA, and the subsequent screening of populations for polymorphisms, hold great promise for predicting interindividual risk of cancer caused by smoking and other environmental pollutants.
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PMID:Human AH locus polymorphism and cancer: inducibility of CYP1A1 and other genes by combustion products and dioxin. 184 73

We examined the incidence of point mutation in codons 12, 13 and 61 of c-Ki-ras and N-ras genes in human hepatocellular carcinoma (HCC) using the polymerase chain reaction and oligonucleotide hybridization techniques. Among 34 tissues specimens surgically resected from 30 patients and 5 cell lines of human HCC, only two had ras point mutations; in one case, codon 12 of c-Ki-ras was altered from GGT, coding glycine, to GTT, coding valine; in the other case, codon 61 of N-ras was altered from CAA, coding glutamine, to AAA, coding lysine. Thus, point-mutational activation of ras oncogenes is an uncommon event in human HCC.
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PMID:Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. 254 5

For the purpose of developing amino acid imbalance solution applicable to cancer treatment, we prepared seven kinds of amino acid imbalance solutions based on a 10% balanced amino acid solution and investigated the anti-tumor effects of each solution. The administration of valine-depleted amino acid solution for 8 days at a daily dose of 53 ml/rat (79.5 kcal/rat) resulted in the most significant inhibitory effects on the growth of hepatoma (AH109A) and mammary tumors (MRMT-1), the rate being 82.8% and 90.8%, respectively. Side effects observed were inhibition of increases in host body weight, weight loss of the spleen and thymus, loss of hair, and a decrease in the amounts of total plasma protein and albumin. When the daily dosage of valine-depleted amino acid solution was reduced to 40 ml/rat (58.3 kcal/rat), anti-tumor effects were still noticed, while side effects were abated. These findings indicate that side effects accompanying the use of this solution can be alleviated by controlling the ingredients of the solution as well as the amount administered. It is thus suggested that valine-depleted amino acid imbalance solution is a valuable tool in the treatment of cancer.
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PMID:Anti-cancer therapy with valine-depleted amino acid imbalance solution. 315 Aug 73

Ochratoxin A (OTA), a naturally occurring mycotoxin of Aspergillus and Penicillium species, consists of a 5' chlorinated dihydromethyl isocoumarin linked to L,beta-phenylalanine by an alpha-amide bond. 8 analogues of OTA were prepared in which the phenylalanine was always substituted by another amino acid. The effects of these analogues on yeast tRNA amino acylation reaction and on growth and protein synthesis of hepatoma culture cells were compared with those of OTA. In addition, Ochratoxin B (OTB) and ochratoxin alpha (OT alpha) were examined. All the analogues of OTA had inhibitory effects in the 3 test systems, although to a lesser degree than OTA. The degree of inhibition depended on the kind of substituted amino acid, the tyrosine, valine, serine and alanine analogues being most effective, in contrast to the proline analogue. OTB and OT alpha were ineffective.
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PMID:Comparative study of the effect of ochratoxin A analogues on yeast aminoacyl-tRNA synthetases and on the growth and protein synthesis of hepatoma cells. 636 78

On RPC-5 column chromatography, the main valine acceptor activity of tRNA (tRNA2Val) from rat ascites hepatoma cells was eluted later than that of normal rat liver tRNA (tRNA1Val). The tRNA2Val was aminoacylated by E. coli amino-acyl-tRNA synthetase, while tRNA1Val from normal rat liver was not. Rat fetal liver tRNAVal was also aminoacylated by E. coli aminoacyl-tRNA synthetase. tRNA1Val (rat liver) and tRNA2Val (ascites hepatoma) were each purified to a homogeneous state by RPC-5 column chromatography and two-dimensional polyacrylamide gel electrophoresis, and their sequences were determined by post-labeling techniques. Ascites hepatoma tRNA2Val differed from rat liver tRNA1Val in that Gm18, C32 and an unknown modified nucleoside, N34, in the latter tRNA were mostly replaced by G, Cm, and inosine, respectively. In addition, 3'-terminal adenosine was not present in tRNA1Val (normal rat liver), but was in tRNA2Val (ascites hepatoma). Other modifications and the primary structures of the two tRNAValS were found to be the same. Thus it was concluded that the new iso-acceptor species of tRNA Val in ascites hepatoma cells is due to a change of post-transcriptional modification, not to a change of tRNA transcription. The unique feature of the change of post-transcriptional modification in tRNA2Val (ascites hepatoma) is that both hypo- and hyper-modification take place simultaneously in the tRNA molecule depending the locations of nucleotide residues.
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PMID:Biological and structural differences between tRNAVal species isolated from rat ascites hepatoma cells and normal rat liver. 702 31

Adult rat hepatocytes placed in primary culture contain at least two distinct Na+-independent transport systems for neutral amino acids. The characteristics of the two systems do not allow assignment to previously described Na+ independent agencies, so we have tentatively termed the two processes Systems L1 and L2. Uptake by System L1 is substantially inhibited by cysteine, valine, isoleucine, leucine, methionine, histidine, tryptophan, tyrosine, phenylalanine, and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. In contrast, System L2-mediated transport is completely inhibited by isoleucine, leucine, phenylalanine, and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. Amino acids transported by both systems show biphasic kinetics yielding Km values for the System L1 component in the micromolar range, whereas the corresponding values for System L2 are an order of magnitude higher. In freshly isolated hepatocytes, the activity of System L2 is relatively high and declines over the initial 24 to 48 h of culture. The Na+-dependent Systems N and ASC also show a significant decay in activity during this time period. In contrast to the decrease in uptake by System L2, transport by System L1 increases during culture following an initial lag period of 12 to 24 h. The increase in System L1 activity can be blocked by the addition of either cycloheximide or actinomycin D. System L1 appears to be present also in fetal hepatocytes, although, in the hepatoma cell line, HTC, the Na+-independent component appears to be homogeneous as though one of the two systems present in the normal adult hepatocyte is not expressed in these transformed cells.
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PMID:Evidence for two Na+-independent neutral amino acid transport systems in primary cultures of rat hepatocytes. Time-dependent changes in activity. 711 28


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