Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is a water-soluble, folate-based thymidylate synthase (TS) inhibitor designed to be a less toxic and more potent analogue of the clinically tested N10-propargyl-5,8-dideazafolic acid. Inhibition of isolated L1210 TS by ICI D1694 is mixed noncompetitive (although tending toward competitive), with a Ki of 62 nM (Kies = 960 nM). The synthetic gamma-polyglutamates are up to 2 orders of magnitude more potent as inhibitors of TS; e.g., the tetraglutamate (glu4) has a Ki of 1.0 nM (Kies = 15 nM). Although inhibitory activity of ICI D1694 toward rat liver dihydrofolate reductase was similar to that of TS (Ki = 92 nM; competitive inhibition) the polyglutamate derivatives did not show enhanced activity. ICI D1694 was also a very potent inhibitor of L1210 cell growth (50% inhibitory activity = 8 nM). L1210 growth inhibition was not observed in the presence of thymidine, consistent with TS being the locus of action. Folinic acid antagonized L1210 growth inhibition in a competitive fashion such that the highest folinic acid concentration used (25 microM) increased the 50% inhibitory activity 6000-fold. When given as a 4-h delayed "rescue", folinic acid was much less effective in antagonizing growth inhibition. These observations are consistent with folinic acid competing with ICI D1694 for uptake into the cell and/or intracellular polyglutamation. The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694 (121-fold), suggesting that ICI D1694 is dependent on this uptake mechanism for good cytotoxic potency in L1210 cells. L1210 cells that were incubated for 4 h with 0.1 microM 3H-ICI D1694 accumulated approximately 1.5 microM intracellular 3H, and the high performance liquid chromatography analysis of the cell extracts demonstrated that 96% of the 3H was associated with the ICI D1694 polyglutamate fractions (principally glu4). Upon resuspension in drug-free medium for 24 h, approximately 75% of the cellular 3H was retained, this being the higher polyglutamate pool (glu4-6). In mice, after a single bolus injection of 10 mg/kg of ICI D1694, TS was inhibited greater than 80% for 24 h in ascitic L1210:NCI cells (as measured by the rate of 3H release from [5-3H]deoxyuridine). ICI D1694 cured the L1210:ICR ascitic tumor in mice at 0.4 mg/kg daily for 5 days (maximum tolerated dose, approximately 50 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. 191 76

The C-erbB-2 gene was first found in human genomic DNA as a sequence which had homology in nucleotide sequence to the V-erbB by molecular hybridization under relaxed conditions. The product of this gene is a receptor type protein-tyrosine kinase which has a structure highly related to that of epidermal growth factor receptor (EGF-r: C-erbB-1). The proto-neu gene is a rat counterpart of the C-erb B-2 gene. The C-erbB-2 gene is also called as the HER-2 gene. The C-erbB-2 gene acquires the ability to transform NIH 3 T 3 cells by, 1) mutation which alters valine 659 in transmembrane region to glutamic acid as was found in neu gene activation, 2) deletion of c-terminal regulatory domain or 3) gene-amplification or overexpression. C-erbB-2 expresses in human embryos on mucous membranes and glands, but only faintly in adult tissues. High expression or gene amplification in human tumor appeared to be an indication for high risk of metastasis or high degree of malignancy.
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PMID:[Proto-oncogene C-erbB-2 and human cancer]. 196 37

ras genes have been shown to become oncogenes by single point mutations which result in amino acid substitutions that affect either their GTPase activity (positions 12, 13, 59, 61) or their affinity for GTP and GDP. Ras oncogenes and their corresponding proteins have been described in a variety of human cancers as well as in animal tumors induced by physical and chemical carcinogens. One of these animal tumor systems involves the induction of mammary carcinomas in rats by a single dose of N-nitroso-N-methylurea (NMU), a methylating carcinogen. These NMU-induced mammary carcinomas contain transforming H-ras genes activated by G----A transitions in the second nucleotide of their 12th codon, presumably a consequence of the pre-mutagenic lesions induced by NMU. These G----A mutations result in the replacement of the normal glycine in the 12th position of the ras p21 protein by a glutamic acid residue. In this study, we report the generation of monoclonal antibodies (Mab) reactive with oncogenic ras p21 proteins containing glutamic acid at position 12 (p21 Glu-12). Mab designated E184 specifically recognized activated ras p21 Glu-12 proteins but not normal p21 (Gly-12) or p21 proteins activated by other position 12 substitutions including arginine, aspartic acid, cysteine, valine or serine residues. Western blot analysis of NMU-induced mammary carcinomas demonstrated that Mab E184 recognized p21 proteins expressed in these rat tumors but not p21 present in normal tissues nor in other carcinogen-induced tumors known to carry H-ras oncogenes activated by mutations at position 61.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Generation of monoclonal antibodies specific for ras p21 Glu-12 oncoproteins: detection in carcinogen-induced mammary carcinomas. 203 37

The double-stranded genome of the small DNA tumor virus, polyomavirus, is enclosed in a capsid composed of a major protein, VP1, which associates as pentameric capsomeres into an icosahedral structure, and two minor proteins, VP2 and VP3, whose functions and positions within the structure are unknown. The N-terminal glycine of the VP2 coat protein has been shown to be cotranslationally acylated with myristic acid. To study the function of this modification and the role of VP2 in the life cycle of polyomavirus, the N-terminal glycine, critical to the myristylation consensus sequence, has been altered to a glutamic acid or a valine residue by site-directed oligonucleotide mutagenesis. The glycine----glutamic acid mutant DNA has been further studied. When transfected into cells permissive for the polyomavirus full lytic life cycle, this mutant DNA replicated at levels comparable to those of wild-type viral DNA, and small amounts of nonrevertant (mutant) virus could be harvested from the cultures. The virus particles viewed by electron microscopy appeared slightly distorted, but the ratio of full to empty particles was similar to that produced in a wild-type viral infection. Mutant virus was capable of reinfecting permissive cells but with a considerably reduced efficiency.
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PMID:Myristylated polyomavirus VP2: role in the life cycle of the virus. 216 22

A novel therapy for improving selectivity in cancer chemotherapy aims to modify distribution of a cytotoxic drug by generating it selectively at tumour sites. In this approach an antibody-enzyme conjugate is allowed to localise at the tumour sites before injecting a prodrug which is converted to an active drug specifically by the targeted enzyme in the conjugate. We present here pharmacokinetic studies on the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its activated derivative, benzoic acid mustard. The glutamic acid is cleaved from the prodrug to form the active drug by carboxypeptidase G2 (CPG2), an enzyme from Pseudomonas sp., which is not found in mammalian cells. The prodrug and its parent active drug were rapidly distributed in plasma and tissues after administration of prodrug or active drug (41 mumol kg-1 intraperitoneally) to mice bearing human choriocarcinoma xenografts. Prodrug and active drug both followed a two-compartment kinetic model. Prodrug was eliminated more rapidly (t1/2 alpha = 0.12 h, t1/2 beta = 0.70 h) than active drug (t1/2 alpha = 0.37 h, t1/2 beta = 1.61 h). Conversion of the prodrug to the activated parent drug was detected within 5 min of administration to mice which had previously received a F(ab')2-anti-human chorionic gonadotrophin antibody (W14A) conjugated to the enzyme, CPG2 (1,000 U kg-1). Tumour was the only tissue that activated all the prodrug reaching the site. It contained the highest concentration of targeted enzyme conjugate capable of catalysing the reaction of prodrug to drug. Plasma and other tissues were also capable of activating the prodrug but active drug production was limited by the amount of enzyme present. The active drug measured in plasma and tissues other than tumour was attributable to residual antibody-enzyme conjugate at non-tumour sites. Low levels of conjugate in tissues and plasma militate against the advantage of tumour localised enzyme therefore necessitating removal of non-localised enzyme.
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PMID:Disposition of the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its active parent drug in mice. 225 18

The synthesis of three novel prodrugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (7), 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (8), and 4-[bis(2-chloroethyl)amino]benzoyl-L-glutamic acid (9), for use as anticancer agents, is described here. Each is a bifunctional alkylating agent in which the activating effect of the ionized carboxyl function is masked through an amide bond to the glutamic acid residue. These relatively inactive prodrugs are designed to be activated to their corresponding nitrogen alkylating agents (10, 11, and 12, respectively) at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2). The viability of two different tumor cell lines was monitored with each prodrug in the presence of CPG2. All three compounds showed substantial prodrug activity--with conversion to the corresponding active drug leading to greatly increased cytotoxicity.
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PMID:Novel prodrugs which are activated to cytotoxic alkylating agents by carboxypeptidase G2. 229 34

A glutamine analogue, L-glutamic acid gamma-monohydroxamate (GAH) demonstrated complete cytotoxicity against L1210 cells in culture and marked anti-tumoral activity in vivo against L1210 leukemia and B16 melanoma. In vitro, GAH caused concentration-dependent inhibition of L1210 cell growth, with complete cell death being reached at 72 hr and at a 500 microM concentration. A minimal incubation time of 38 hr with 500 microM GAH was necessary to obtain complete cell death at 72 hr. During incubation, GAH is metabolized to hydroxylamine. Hydroxylamine acts as the active form of GAH, since the concentration-dependent inhibition of cell growth caused by hydroxylamine is the same as that observed with GAH. The cytotoxic effects of GAH and hydroxylamine on L1210 cells were not reversed or prevented by L-glutamine or L-glutamic acid and purine nucleosides but were prevented or reversed by pyruvate, 2-oxaloacetate and 2-oxoglutarate. In vivo, GAH considerably increased survival of mice bearing L1210 leukemia or a solid tumor, the B16 melanoma. Antitumor activity of GAH against L1210 leukemia and B16 melanoma was schedule-dependent. The administration of GAH 3 times daily was more effective than a twice daily treatment and the maximum ILS was observed using split-dose schedules on days 1 through 3 and 7 through 9 without noticeable toxicity. Under these conditions hydroxylamine is highly toxic, suggesting that in vivo GAH might act as an hydroxylamine releaser in the tumor cells and is not significantly metabolized in the body.
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PMID:In vitro and in vivo anti-tumor activity of L-glutamic acid gamma-monohydroxamate against L1210 leukemia and B16 melanoma. 232 50

Cis-diamminedichloroplatinum(II) (cis-DDP) and cis diamminediaquoplatinum(II) nitrate (cis-aq) were complexed to poly-L-glutamic acid (PG) of Mr 13,000 or 58,000. Soluble complexes were formed by mixing the platinum(II) compounds with the PG preparations in water at a molar ratio of one platinum(II) to 5 glutamyl residues of the PG. Compared to free cis-DDP, the complexes were about 2 to 6 times less cytotoxic to F9 embryonal carcinoma cells in vitro. In vivo studies with this tumor indicated that when administered i.p. one day after the tumor cells, the complexes were somewhat less active than cis-DDP. However, in comparison to the free drug which, due to its toxicity, was effective only within a very narrow dose range, the complexes were much less toxic, manifesting a wide therapeutic range in which no mortality occurred either from the tumor or as a result of the toxic effects of the drug. Cis-DDP and cis-aq complexes of PG Mr-58,000 were somewhat more toxic than the complexes of PG Mr, 13,000. The in vivo anti-tumor activity of most complexes was superior to that of free cis-DDP when tested in mice carrying high tumor loads. Due to their wide therapeutic range, the complexes could be given at high drug doses resulting in increased life span of the tumor-bearing mice. Moreover, 3 repeated injections of these high doses did not cause death from toxicity and resulted in partial or total eradication of advanced tumors.
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PMID:Increased therapeutic efficacy of cis-platinum complexes of poly-L-glutamic acid against a murine carcinoma. 243 42

The ras family of proto-oncogenes can be activated into transforming genes by single point mutations resulting in p21 products with amino acid substitutions at positions 12, 13 and 61. Here we describe a monoclonal antibody designated R256 which reacts specifically with a synthetic peptide corresponding to amino acids 5 to 16 of ras p21 activated by the substitution of arginine for glycine at position 12. It does not react with peptides representing other activating substitutions at position 12. Western blot studies showed that R256 reacts specifically with recombinant ras p21 containing an arginine-12 substitution but is unreactive with the normal glycine-12 recombinant p21. R256 binds the activated Kirsten p21 in human lung tumor cell line A2182, which contains an activated arginine-12 p21. R256 is also specific for arginine-12 p21 extracted from NIH3T3 cells transformed by the viral Harvey-ras p21, containing arginine at 12, and is not reactive with transformants containing activated p21s with valine, serine, aspartic acid, glutamic acid, cysteine or normal glycine at position 12. When R256 was used to test for expression of arginine-12 p21 in tissues of transgenic mice containing an MMTV/v-Harvey-ras transgene, the monoclonal antibody was able to determine that the arginine-12 p21 transgene product was present in breast tumors but not in normal tissues. The ability of R256 to react specifically with arginine-12 p21 may prove to be valuable in the study of ras oncogenesis in model systems and in determining the presence of arginine-12 p21 in human tumors.
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PMID:Characterization of monoclonal antibody R256, specific for activated ras p21 with arginine at 12, and analysis of breast carcinoma of v-Harvey-ras transgenic mouse. 247 86

The high-affinity cellular receptor for the basement membrane component laminin is differentially expressed during tumor invasion and metastasis. A cDNA clone encoding the murine laminin receptor was isolated and identified on the basis of sequence homology to the human laminin receptor [Wewer et al. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 7137-7141]. Primer extension experiments demonstrated that the clone contained the complete 5' sequence of the murine laminin receptor mRNA. RNA blot data demonstrated a single-sized laminin receptor mRNA, approximately 1400 bases long, in human, mouse, and rat. The nascent laminin receptor predicted from the cDNA sequence is 295 amino acids long, with a molecular weight of 33,000, and contains one intradisulfide bridge, a short putative transmembrane domain, and an extracellular carboxy-terminal region which has abundant glutamic acid residues and multiple repeat sequences. The precursor of the laminin receptor is apparently smaller than the 67-kilodalton protein isolated from tissue. The apparent molecular weight on SDS-polyacrylamide gels of the rabbit reticulocyte cell-free translation product of selectively hybridized laminin receptor mRNA is 37,000. Antisera to three different domains of the cDNA-predicted receptor were used to study the relationship between the 37- and 67-kilodalton polypeptides. Antisera to cDNA-deduced synthetic peptides of the receptor immunoprecipitated a 37-kilodalton band both from cell-free translation products and from pulse-labeled cell extracts. On immunoblots of cell extracts, one antisynthetic peptide antiserum recognized only the 67-kilodalton receptor, while another antiserum identified both 37- and 67-kilodalton polypeptides, suggesting a precursor-product relationship between the two polypeptides.
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PMID:Evidence for a precursor of the high-affinity metastasis-associated murine laminin receptor. 253 Oct 8


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