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)

Daunorubicin was bound to poly-L-aspartic acid via the methylketone side chain of the drug to avoid reaction of the sugar amino group believed to be essential for optimal drug activity. Attachment of the drug to the polyamino acid by an ester linkage was achieved by nucleophylic substitution reaction of 14-bromo-daunorubicin. Compared with free daunorubicin, the polymeric derivative was less cytotoxic to HeLa cells in vitro, but more effective against all tumor models tested (P388 leukemia, Gross leukemia, MS-2 sarcoma). The binding to the polypeptide markedly reduced drug toxicity but only slightly decreased drug potency. The daunorubicin-poly-L-aspartic acid conjugate demonstrated antitumor activity comparable to that of doxorubicin in leukemia models, but superior to that of doxorubicin in a solid tumor model (MS-2 sarcoma).
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PMID:Anti-tumor activity of daunorubicin linked to poly-L-aspartic acid. 714 41

The effects of amino acids on the enhanced agglutinability of bladder cells with concanavalin A induced by subcarcinogenic treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine were examined. The amino acids examined were L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, L-glycine, DL- and L-histidine, L-hydroxyproline, L-isoleucine, D- and L-leucine, L-lysine, L-methionine, DL- and L-phenylalanine, L-proline, L-serine, L-threonine, DL-, D- and L-tryptophan, L-tyrosine and D- and L-valine. They were added to powdered diet at a concentration of 2.0%. L-Leucine, L-isoleucine, L-valine, DL- and D-tryptophan prolonged the period during which the bladder cells showed enhanced agglutinability with concanavalin A. Leupeptin, a protease inhibitor, and L-leucyl-L-leucine were also examined at a concentration of 0.1% because of their similar chemical structures, and were found to have the same effect. The tumor-promoting effects of DL-tryptophan and leupeptin have already been established by in vivo carcinogenesis experiments. The effects of L-leucine, L-isoleucine, L-valine, D-tryptophan and L-leucyl-L-leucine, detected by this short term assay, suggest that these compounds may also be promoters of bladder cancer in rats.
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PMID:Detection of amino acids as possible promoters of bladder cancer in rats by measuring their enhancement of agglutination of bladder cells by concanavalin A. 716 May 80

Tissue polypeptide antigen (TPA) is a complex protein which has been originally identified in extracts of pooled tumors using horse antisera raised against the insolubles of human tumor cells. The antigen is now routinely detected and measured by a previously described hemagglutination inhibition assay. It has been shown by this method that the concentration of the antigen is higher in tumor tissues and in sera of cancer patients as compared to normal tissues or normal sera, respectively. In aqueous solutions, pH 2-12, TPA has a tendency to form high molecular weight aggregates. However they can be dissociated in sodium dodecyl sulfate into subunits, each appearing as a single chain peptide: B1 (Mr 4.3 x 10(4)), B2 (Mr 3.0 x 10(4)), C (Mr 1.7 x 10(4)). The subunits saturate anti-TPA serum indistinguishably from TPA. Amino acid composition of TPA and subunits is dominated by glutamic acid, aspartic acid and leucine, cysteine being absent in subunit B1. The isoelectric point of the main subunit, B1, is 4.4-4.6. Sedimentation and diffusion analyses indicate that pure subunit B1 in aqueous solution exists in distinct oligomeric states.
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PMID:Biochemical properties of tissue polypeptide antigen. 740 46

By means of enzymatic and autoradiographic techniques, it has been demonstrated that, 24 hr after a single dose of the antitumor amino acid N-phosphonacetyl-L-aspartic acid (PALA), (400 mg/kg i.p.; 1.15 mmol/kg) to C57BL x DBA/2 F1 mice, the agent accumulates in bone to a concentration of approximately 400 microM; this is 3000 times greater than the Ki of PALA for its target enzyme, aspartate carbamoyltransferase. However, disproportionately low inhibition of enzyme activity was demonstrated in homogenates of bone from these recipients, suggesting that the drug was sequestered from its target in this tissue. Autoradiography of sections of femoral shafts from mice treated with 14C-labeled drug demonstrated that autoradiogram density due to [14C]PALA equivalents was confined to the bony matrix, with no label above background resolvable in bone marrow. Following in vivo administration of PALA (400 mg/kg i.p.), the half-life of the drug in the bone was approximately 23 days. In vitro, with equilibrium dialysis at pH 7.4, it was demonstrated that: (a) normal pulverized and decalcified bone bound PALA with capacities of 3.5 nmol/mg and 0.1 nmol/mg bone, respectively, at a PALA concentration of 5 mM; (b) binding of PALA to normal bone reached saturation at a concentration of 200 mM; and (c) PALA functions as a solubilizer of bone at concentrations above this. Since administration of PALA was shown to produce long-lasting inhibition of aspartate carbamoyltransferase in liver and tumor and since its ultimate half-life in the plasma of mice, following a single 400-mg/kg administration of the drug, is 8 days, it is suggested that bone serves as a reservoir from which PALA is released at a slow rate into plasma and other tissues.
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PMID:Long-term association of N-(phosphonacetyl)-L-aspartate with bone. 744 55

The interaction of N-(phosphonacetyl)-L-aspartic acid (PALA) with L-aspartate transcarbamoylase (ATCase), the putative target for the antineoplastic activity of this drug, has been studied in the blood of patients participating in a phase I trial of PALA. ATCase activity in human blood is most abundant in granulocytes and lymphocytes; comparatively little activity is seen in erythrocytes. Utilizing peripheral leukocytes from patients given infusions of PALA, we find that leukocyte ATCase in inhibited rapidly and strongly. After cessation of therapy the rate of restitution of enzyme activity is slow: half-maximal restoration is achieved in about 280 hours. As a correlate of this gradual recovery of enzymatic activity, nanomolar concentrations of PALA are detectable in the plasma 2 weeks after infusion. The apparent Ki of PALA for leukocyte ATCase with carbamoyl phosphate as the variable substrate is 5 nM. Uptake of PALA into leukocytes in vitro is saturable and occurs at a moderate rate comparable to that measured in murine tumor cells. Correspondingly, inhibitory concentrations of PALA (approximately 10(-7) M) are found in the leukocytes of patients throughout the course of PALA treatment. It is concluded that although leukocytes are not targets for PALA toxicity, they may serve as accessible and pertinent indicators of the enzymatic effects of this new oncolytic drug.
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PMID:Peripheral leukocytes as indicators of the enzymatic effects of N-(phosphonacetyl)-L-aspartic acid (PALA) on human L-aspartate transcarbamoylase (ATCase) activity. 744 31

Variants of the Lewis lung carcinoma were selected for resistance to N-(phosphonacetyl)-L-aspartic acid (PALA) by treatment of tumor-bearing mice with repetitive subcurative doses of PALA. The specific activity of the target enzyme, L-aspartic acid transcarbamylase (ATCase), was measured in the four variants developed. Three had markedly elevated ATCase activities; however, the fourth line, LL/PALA-C, had an ATCase activity identical to that of the parent, PALA-sensitive line (LL/O). One high-ATCase variant, LL/PALA-J, and LL/PALA-C were compared with LL/O in subsequent biochemical studies on the mechanism of resistance to PALA. Enzyme activities in the salvage pathways which phosphorylate pyrimidine nucleosides and deoxynucleosides were found to be similar in all three lines. ATCase in these lines exhibits closely comparable kinetics with its natural substrates as well as with PALA. The time courses of restitution of ATCase after a single therapeutic dose of PALA show that both resistant variants recover full activity more rapidly than the parent. Additionally, inhibition of ATCase 24 hr following graded doses of PALA is lower in the resistant lines. The uptake of [14C]PALA in vitro into cell lines derived from the three Lewis lung carcinomas apparently occurs by passive diffusion and at comparable rates in both sensitive and resistant cells. Analysis of the nucleotide content of tumors reveals comparable spectrums of purine and pyrimidine nucleotide levels in the LL/O and LL/PALA-C lines, whereas the LL/PALA-J line has augmented nucleotide pools. In all three lines, 24 hr after treatment with PALA (400 mg/kg), uridine and cytidine nucleotide levels were substantially diminished (70 to 80%) while adenosine 5'-triphosphate and guanosine 5'-triphosphate levels were elevated (50 to 100%). Estimations of precursor flux through the de novo pyrimidine pathway by measuring orotate and orotidine levels in tumors of mice treated with pyrazofurin (an inhibitor of orotidine-5'-monophosphate decarboxylase) and either 0.9% NaCl solution or PALA shows that PALA treatment eliminates orotate and orotidine accumulation in LL/O but reduces it by only 75 and 50% in LL/PALA-C and LL/PALA-J, respectively. Similarly, PALA treatment (20 microM) of tumor lines in culture provokes a dramatic decrease in the incorporation of NaH14CO3 into pyrimidine intermediates and nucleotides in the LL/O cell line only. Determinations of specific activities of the other enzymes in this pathway reveal that the activity of carbamyl phosphate synthetase II, the rate-limiting step, is elevated 2- to 3-fold in both resistant lines. Since carbamyl phosphate synthetase II exists as a complex with ATCase, the suggestion is made that levels of carbamyl phosphate synthetase II are collaterally important determinants of PALA activity. An augmented pool of carbamyl phosphate in the resistant variants may serve to competitively displace PALA from ATCase, diminish enzyme inhibition, and allow pyrimidine biosynthesis to proceed despite therapy.
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PMID:Mechanism of resistance of variants of the Lewis lung carcinoma to N-(phosphonacetyl)-L-aspartic acid. 745 75

N-(Phosphonacetyl)-L-aspartic acid (PALA) was given as a 5-day continuous infusion in a phase I trial. Dose-limiting toxic effects noted were diarrhea occurring at doses of greater than or equal to 6 g/m2/course, mucositis occurring at doses of greater than or equal to 7.5 g/m2/course, and skin rash occurring at doses greater than 9 g/m2/course. No significant CNS, hemorrhagic, gastrointestinal, or hematologic toxicity was noted. In patients with measurable tumor volume, no significant antitumor responses were seen. A dose of 9 g/m2/course is recommended for a phase II trial.
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PMID:Phase I trial of N-(Phosphonacetyl)-L-aspartic acid (PALA). 745 92

Triflavin, a 7.5-kDa cysteine-rich polypeptide purified from Trimeresurus flavoviridis snake venom, belongs to a family of RGD-containing peptides, termed disintegrins, that have been isolated from the venoms of various vipers and shown to be potent inhibitors of platelet aggregation. The interaction of tumor cells with extracellular matrices such as fibronectin, vitronectin, and collagen has been shown to be mediated through a family of cell surface receptors that specifically recognize an arginine-glycine-aspartic acid (RGD) sequence within each adhesive protein. In this study, we show that triflavin dose-dependently inhibited adhesion of human cervical carcinoma (HeLa) cells to extracellular matrices (ECMs; i.e., fibronectin, fibrinogen, and vitronectin). On the other hand, triflavin exerted a limited inhibitory effect on cell adhesion to laminin and collagen (type I and IV). On a molar basis, triflavin is approximately 800 times more potent than Gly-Arg-Gly-Asp-Ser (GRGDS) at inhibiting cell adhesion. When immobilized on plate, triflavin significantly promoted HeLa cell adhesion, and this attachment was inhibited by GRGDS. Furthermore, FITC-conjugated triflavin bound to cells in a saturable manner and its binding was inhibited by GRGDS. In addition, triflavin did not affect [3H]thymidine uptake of HeLa cells during a 3-day incubation. These results suggest that triflavin probably binds to integrin receptors expressed on HeLa cell surface via its RGD sequence within its molecule, thereby inhibiting the adhesion of extracellular matrices to HeLa cells.
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PMID:Triflavin, an Arg-Gly-Asp-containing peptide, inhibits human cervical carcinoma (HeLa) cell-substratum adhesion through an RGD-dependent mechanism. 770 Aug 42

We synthesized four new tumor imaging agents, 99mTc-labeled metalloporphyrins (99mTc-STA-R12, -STA-R21, -STA-RN101 and -ATN-12) for the tumor imaging. We compared the differences of tumor imaging potency among these agents in CDF1 mice implanted with colon 26 tumor. Tumor images with these agents were obtained by using digital gamma-camera (RC135-E, Hitachi, Tokyo) and the biodistributions were analyzed by computerized medical radionuclide imageanalyser (RP-200, Hitachi, Tokyo). The highest tumor organ ratio and the excellent tumor image were obtained by 99mTc-STA-R12 (13,17-Bispropanyl aspartic acid-3-ethenyl-8-[N,N',N",N"-tetrakis (carboxylmethyl-2,7,12,18-tetramethyl-porphyrinato]-manga nes e(III). The maximum concentration of 99mTc-STA-R12 in tumor tissue was observed at around 120 minutes after i.v. injection. On the contrary, the uptake rates of other organs and tissues such as liver, brain, muscle, lung, bone and blood continuously decreased. The rapid accumulation of STA-R12 in cancer tissue and the clearance from other tissue suggested a potential usefulness of this compound for tumor imaging agent.
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PMID:[Usefulness of newly developed 99mTc-labeled STA-R12 for tumor imaging]. 783 7

Cyclopentenyl uracil, a non-cytotoxic inhibitor of uridine kinase, was found to effectively block the salvage of circulating uridine by host and tumor tissues in the intact mouse. Dose-response characteristics of the inhibition were determined. Large doses (1 g/kg) of cyclopentenyl uracil were required, and the effect of a single dose fell rapidly over a 24-hr period. A sustained inhibition of uridine salvage of > 64-79% could be maintained by multiple doses of 1 g/kg given on an every 8-hr schedule. Mice given cyclopentenyl uracil (1 g/kg) every 8 hr for 5 days continued to gain weight and showed no signs of toxicity; however, the combination of cyclopentenyl uracil with a non-toxic dose of N-(phosphonacetyl)-L-aspartic acid (PALA; 200 mg/kg daily for 5 days) was lethal to mice, indicating that circulating uridine modifies the toxicity of agents that act on enzymes of the de novo pyrimidine pathway. Although the duration of action and potency of cyclopentenyl uracil are not ideal, this is the first demonstration of an effective inhibition of uridine salvage in the intact mouse with a non-cytotoxic agent. This makes possible the evaluation of concurrent inhibition of de novo and salvage routes to pyrimidine nucleotides as an approach to chemotherapy.
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PMID:Cyclopentenyl uracil: an effective inhibitor of uridine salvage in vivo. 784 Jul 97


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