Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of new nitrosoureas is described using selected examples. Results obtained with water-soluble analogs and with compounds linked to biomolecules as for instance amino acids, oligopeptides and steroids, are presented. The pronounced antineoplastic effect of some water-soluble analogs is paralleled by an increased rate of DNA-interstrand cross-links and by an increased suppression of hematopoietic stem cells. The suppression of bone marrow stem cells is followed by their rapid regeneration. Water-soluble nitrosoureas induce significant less inhibition of glutathione reductase as compared with established compounds. With regard to long-term toxicity and carcinogenicity water-soluble are superior to established compounds as for instance BCNU. Linking of the nitrosourea moiety to amino acids and oligopeptides led to some analogs with outstanding therapeutic ratio. Out of a group of steroid-linked nitrosoureas, CNC-L-alanine-estradiol-17-ester (CNC-ala-17-E2) is chosen to demonstrate the possibility of reducing bone marrow toxicity despite unchanged or increased therapeutic activity by attachment of the nitrosourea moiety to a steroid. Results of a comparative interspecies in vitro evaluation of CNC-ala-17-E2 in transplanted MXT mammary carcinoma of the mouse, MNU-induced autochthonous rat mammary carcinoma and primary human mammary carcinomas are presented and the question is discussed to what extent in vitro activity of such receptor agents using the tumor stem cell assay reflects their in vivo activity.
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PMID:[Chemotherapeutic characterization of new nitrosourea compounds]. 341 33

Activated ras transforming genes have been described in a variety of neoplasms and encode 21,000-Dalton (p21) proteins with amino acid substitutions at positions 12, 13, and 61. In this report we describe a monoclonal antibody designated DWP that reacts specifically with synthetic dodecapeptides containing valine at position 12, to a lesser extent with peptides containing cysteine at position 12 and not with peptides containing glycine, arginine, serine, aspartic acid, glutamic acid or alanine at the same position. Western blot and immunoperoxidase studies showed that DWP specifically reacts with activated rasH or rasK proteins in NIH cells transformed by DNA from the human carcinoma cells that encode valine at position 12. DWP did not react with normal p21s encoding glycine at position 12, nor with activated p21s encoding aspartic acid, glutamic acid, arginine, serine, or cysteine at position 12. A survey of human tumor cell lines demonstrated that DWP reacted with the human bladder carcinoma cell line T24 but not with human tumor cell lines previously shown to contain other activating mutations at positions 12 or 61. DWP and perhaps additional antibodies that specifically react with alterations at positions 12 or 61 of the ras protein may be valuable in determining the presence and frequency of activated ras proteins in human malignancy.
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PMID:A monoclonal antibody reactive with an activated ras protein expressing valine at position 12. 353 74

A series of estradiol-linked N-(2-chloroethyl)-N-nitrosocarbamoyl(CNC)-L-alanines attached in various positions (positions 3, 6 alpha, 17, 3 + 17 of estradiol) have been synthesized and tested in hormone-dependent MNU-induced rat mammary carcinoma. Compounds were given i.p. on day 1, 8, 22 and 29 after randomization in equimolar dosage. Equimolar mixtures of unlinked agents were tested in comparison. The results show that the 17-linked derivative was significantly superior to the other congeners and to the unlinked equimolar mixture. The 6 alpha-linked analogue unexpectedly was highly toxic and ineffective. Binding affinities to cytosolic estrogen receptors cannot fully explain the findings of the chemotherapy experiments. Especially the 3-linked derivative we found to exhibit much higher values for relative binding affinity than the 17-analogue, which was a distinctly more effective antineoplastic agent. Estradiol liberation by facile cleavage of the phenolic 3-ester bond might be responsible. Estradiol receptor contents in tumours were diminished or disappeared completely during treatment with individual analogues, progestin receptor contents behaved differently. After a single dose of CNC-L-alanine-estradiol-17-ester, a long-lasting disappearance of estradiol-receptors, measured for up to 192 hr, and a strong induction of progesterone receptors was observed with a maximal value reached at 16 hr, and return back to normal at 192 hr. In the Dorfman uterine weight test in mice, all compounds exhibited distinct uterotrophic activity with no clearcut differences. The relevance of estradiol receptor contents in tumours for antineoplastic activity of the most effective analogue, the 17-ester, became evident from the observed reduced responsiveness of MNU-induced rat tumours after ovariectomy. In these hormone-independent tumours the linked compound revealed only the same antitumour efficacy as CNC-L-alanine alone.
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PMID:Estrogen-linked 2-chloroethylnitrosoureas: anticancer efficacy in MNU-induced rat mammary carcinoma, uterine activity in mice and receptor interactions. 381 11

A cDNA library derived from human carcinoma cells was used to isolate a clone, pULB1000, coding for the preproenzyme form of human urokinase. This clone carries the full-length sequence coding for the signal peptide and for the A chain (157 amino acids) and B chain (253 amino acids) of urokinase in tandem. The sequence of the cDNA predicts the presence of a single lysine residue between the last amino acid of the mature A polypeptide (Phe-157) and the first amino acid of the mature B polypeptide (Ile-1). The amino acid sequence deduced from the cDNA sequence fits the published amino acid sequence data with three exceptions, the reported cysteine residue at position 131 in the A chain is a tryptophan, and glycine 366 and alanine 410 in the B chain are, respectively, a cysteine and a valine in our clone. A large Bgl I fragment (1482 bp), derived from the clone pULB1000 coding for most of the signal peptide and for the A and B chains, has been subcloned into the expression vector pCQV2. Heat induction of E. coli cells carrying the recombinant plasmid leads to the production of urokinase-like polypeptides having the expected molecular weights and being specifically recognized by antibodies raised against natural human urokinase.
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PMID:Molecular cloning, sequencing, and expression in Escherichia coli of human preprourokinase cDNA. 388 71

Alpha-aminoisobutyric acid (AIB), or alpha-methyl alanine, is a nonmetabolized amino acid transported into cells, particularly malignant cells, predominantly by the 'A' amino acid transport system. Since it is not metabolized, [1-11C]-AIB can be used to quantify A-type amino acid transport into cells using a relatively simple compartmental model and quantitative imaging procedures (e.g. positron tomography). The tissue distribution of [1-11C]-AIB was determined in six dogs bearing spontaneous tumors, including lymphosarcoma, osteogenic sarcoma, mammary carcinoma, and adenocarcinoma. Quantitative imaging with tissue radioassay confirmation at necropsy showed poor to excellent tumor localization. However, in all cases the concentrations achieved appear adequate for amino acid transport measurement at known tumor locations. The observed low normal brain (due to blood-brain barrier exclusion) and high (relative to brain) tumor concentrations of [1-11C]-AIB suggest that this agent may prove effective for the early detection of human brain tumors.
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PMID:Evaluation of [1-11C]-alpha-aminoisobutyric acid for tumor detection and amino acid transport measurement: spontaneous canine tumor studies. 397 10

The serum activity of glycylprolyl-p-nitroanilidase (GPN) has been compared with isocitrate dehydrogenase and with alanine and aspartate aminotransferases in patients with hepatobiliary diseases, myocardial infarction and chronic inflammatory bowel disease. Serum GPN was markedly increased in all hepatobiliary diseases, especially secondary carcinoma and chronic alcoholic hepatitis, but no abnormal values were seen in patients with chronic inflammatory bowel disease. Slightly elevated GPN activities were noticed in a few cases of myocardial infarction. It is suggested that serum GPN would be useful for monitoring hepatic function, especially in the clinical trials of new drug.
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PMID:Glycylprolyl-p-nitroanilidase in hepatobiliary disease. 611 Apr 97

The primary structures of three polypeptides, possessing high intrinsic growth hormone-releasing activity and derived from a human pancreatic carcinoma which had caused acromegaly, were established by sequence analyses of the intact peptides and their cyanogen bromide digestion fragments with a gas-phase sequenator. The three human pancreas growth hormone-releasing factors contain 44 (hpGRF-44), 40 (hpGRF-40), and 37 (hpGRF-37) amino acids in identical sequences from their NH2 termini. High pressure liquid chromatography of the native peptides and their synthetic replicates showed that hpGRF-37 and hpGRF-40 possess free carboxyl termini while that of hpGRF-44 is amidated. The structure of hpGRF-44 was established as: Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly Ala-Arg-Ala-Arg-Leu-NH2.
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PMID:Primary structures of three human pancreas peptides with growth hormone-releasing activity. 613 96

The antitumor and antimetastatic activities of the water-soluble peptidoglycan monomer GlnNAc-Mur-NAc-L-Ala-D-iso-Gln-meso-diamminopimelic acid (omega-NH2)-D-Ala-D-Ala (PGM), which has immunostimulant effects, have been evaluated in CBA mice bearing MCa mammary carcinoma. The antineoplastic effects of PGM depend strictly on the dosage and treatment schedule used. Though a significant inhibition of the primary tumor growth is observed over a wide range of dosage, only the IV administration of daily doses of 50 mg/kg/day on days 1, 5, 10, 15 inhibits spontaneous lung metastasis formation and in parallel prolongs the survival time of the treated mice. The magnitude of the antimetastatic effects of PGM depends on the degree of dissemination of the tumor, and is greater when the number of metastatic foci is low. Examination of the therapeutic potential of PGM in combination with surgery has further indicated that the timing of administration plays an important role in the overall effectiveness of this substance. A 5-day interval is necessary between two consecutive injections for the induction of significant increases of the survival times.
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PMID:Antitumor and antimetastatic activity of the immunoadjuvant peptidoglycan monomer PGM in mice bearing MCa mammary carcinoma. 656 78

Glucose metabolism is affected by various pathologic states including tumors. In this project, glucose turnover and recycling rates in 11 patients with colorectal carcinoma were measured using a double-labelled 3-3H and 1-14C glucose injection technique. Fasting blood glucose, lactate, pyruvate, alanine, glycerol, 3-hydroxybutyrate, acetoacetate, plasma cortisol, and plasma insulin concentrations were also measured. No patient in the study had a history of diabetes mellitus or endocrine disorders, nor any abnormal liver function tests. The findings demonstrated a significantly elevated glucose turnover rate in patients with Dukes C and D lesions in comparison to patients with Dukes B lesions. Cori recycling rates were not significantly different between Dukes B vs. Dukes C and D patients. There were no differences between Dukes B and Dukes C and D patients in any of the metabolites measured. Furthermore, there were no significant differences in glucose turnover or recycling rates as a function of pre-illness weight loss. These data suggest that, when colorectal carcinoma extends beyond the limits of the bowel wall, glucose metabolism is significantly altered.
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PMID:Glucose turnover and recycling in colorectal carcinoma. 663 60

Influence of total parenteral nutrition and operation on alanine turnover and venous alanine concentration was determined in 5 patients with stomach carcinoma using single technique of U-14C alanine. Every patient served at his own control. In the postabsorptive state alanine turnover was 1.63 +/- 0.31 mgatC . min-1, not different from a control group (1.84 +/- 0.60 mgatC . min-1); during total parenteral nutrition alanine turnover increased to 3.21 +/- 0.5g mgatC . min-1 with a rise in alanine concentration from 0.96 +/- 0.17 mgatC . L-1 + 0.69 +/- 0.22 mgatC . L-1. After surgery during the same total parenteral nutrition alanine turnover increased further to 3.78 +/- 0.17 mgatC . min-1 with a lowering of alanine concentration to 1.44 +/- 0.22 mgatC . L-1. The present results show the distinct influence of TPH on alanine kinetics. The present data indicate that alanine turnover cannot be deduced from blood alanine concentration.
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PMID:Alanine turnover in the postabsorptive state and during parenteral hyperalimentation before and after surgery. 678 88


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