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

Ribose 1-phosphate concentrations have been measured in tumor cells incubated with purine and pyrimidine nucleosides and with glucose. Highest concentrations (0.15 to 0.2 mumol/ml of cells) were attained in cells incubated with inosine. Although uridine was cleaved at approximately the same rate as inosine, as judged by lactate accumulation, concentrations of ribose 1-phosphate that accumulated were only approximately 0.06 mumol/ml. Ribose 1-phosphate accumulation in tumor cells incubated with inosine was dependent on the phosphate concentration of the medium up to at least 25 mM. Ribose 1-phosphate formed from inosine was readily converted both to phosphoribosyl pyrophosphate and to lactate.
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PMID:Ribose 1-phosphate metabolism in Ehrlich ascites tumor cells in vitro. 92 6

The clinical application of cytostatic drugs requires knowledge of their biochemistry, pharmacology, pharmacokinetics as well as their action at the cellular level within the generation cycle. The principles apply to tumor cells as well as to normal, rapidly proliferating tissues. The intensive research on cancer treatment all over the world is leading to a rapid accumulation of experimental data about the action of single cytostatic drugs in tissue culture and on transplantable animal tumor systems, especially in rodents. Clinical chemotherapy in human malignancies today preferentially uses combinations of different cytostatics. Inumerable combinations of drugs are available, especially if variations in respect to drug dose and intervals of drug application are taken into consideration. The experimental basis for such combinations of drugs and drug interactions is scanty. Using the pyrimidine analog cytosine arabinoside and the two antibiotics daunorubicin and doxyrubicin (adriamycin) as examples, it is demonstrated that information on the pharmacolinetic behaviour of cytostatic drugs is a prerequisite for their success in clinical application, but is on its own insufficient to predict the tumor response.
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PMID:[Clinical problems of optimum bioavailability, in particular in cytostatic therapy (author's transl)]. 94 92

Effect of the administration of 4-hydroxypyrazolo([3,4-d]pyrimidine (allopurinol) on the growth of Ehrlich ascites tumor cells was investigated in an in vivo system. Oral administration of allopurinol (0.1% in diet) suppressed the growth of both ascites and solid types of the tumor after the implantation of Ehrlich tumor cells in mice. The inhibitory action depended on the dose but was lost repidly when the administration was interrupted. Possible mechanisms involved in the inhibitory effect of allopurinol on tumor growth were briefly discussed.
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PMID:Effect of 4-hydroxypyrazolo[3,4-d]pyrimidine (allopurinol) administration of growth of Ehrlich tumor cells. 102 10

N-(Phosphonacetyl)-L-aspartate (PALA) is an analog of the transition state for the aspartate transcarbamylase reaction and has been reported previously to be a potent and specific inhibitor of de novo pyrimidine nucleotide biosynthesis. It is now shown that PALA has considerable antitumor activity against certain transplantable tumors in mice. PALA, unlike other antimetabolites, was less effective against ascitic leukemias than against two solid tumors, B16 melanoma and Lewis lung carcinoma. Another solid tumor, Ridgway osteogenic sarcoma, which is sensitivie to many established chemotherapeutic agents, did not respond to PALA. Daily or intermittent treatment with PALA did not significantly increase the life-span of mice bearing i.p. leukemia L1210. The survival time of mice bearing i.p. P388 leukemia was prolonged by PALA treatment by up to 64%. In a number of experiments mice bearing i.p. B16 melanoma survived 77 to 86% longer than did controls when treated with PALA (490 mg/kg) on Days 1, 5, and 9. Lewis lung carcinoma, a tumor refractory to most established antineoplastic agents, was highly sensitive to PALA. Treatment on Days 1, 5, and 9 following s.c. implantation of Lewis lung carcinoma was curative to 50% of the mice. If treatment was delayed until s.c. Lewis lung tumors had reached about 500 mg, PALA neither cured the mice nor produced significant tumor regression. However, extensive delay of tumor growth and prolongation of survival were still observed.
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PMID:Antitumor activity of N-(phosphonacetyl)-L-aspartic acid, a transition-state inhibitor of aspartate transcarbamylase. 106 66

The diaquo species of cis-dichlorodiammineplatinum (II) reacts with pyrimidines and substituted pyrimidines to form very soluble, deep blue complexes. These are believed to consist of mainly monomeric species containing one pyrimidine moiety liganded to each platinum. The structures of the complexes are largely uncertain at this time. We describe the methods of synthesis and characterization of approximately 70 such complexes, with a suggested classification scheme, incluse complexes show superior activity against the ascites Sarcoma 180 tumor in Swiss mice when compared to cis-dichlorodiammineplatinum (II). Initial screening test results and dose schedule-dependency results indicate we can achieve 100% cures in this tumor-host system. Activity is also shown against the Rauscher leukemia, Ehrlich ascites, and ADJ/PC6A tumors. Microscopic histopathologic studies of resulting kidney lesions show that the "platinum-uracil blue" complex causes only minor focal damage to the proximal convoluted tubules at a therapeutic dose level, rather than the generalized degenerative changes so prominent and dose limiting noted with cis-dichlorodiammineplatinum (II).
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PMID:"Platinum-pyrimidine blues" and related complexes: a new class of potent antitumor agents. 114 7

Specific biochemical molecules used as potential biologic markers, including modified nucleosides, polyamines, and pyrimidine catabolic end-products, were quantitatively measured in the urine of seven patients with Burkitt's lymphoma before, during, and after one or more courses of therapy. The results of this preliminary study demonstrated that patients with this disease frequently excrete significantly increased amounts oof modified nuceleosides (considered to be derived primarily from transfer ribonucleic acid), polyamines, and beta-aminoisobutyric acid during the course of their disease. With successful treatment and rapid destruction of tumor cells, a concomitant rise in these molecules occurs. Elevations were observed prior to chemotherapy and changes in levels associated with treatment or tumor progression appeared to correlate with disease status and to aid in assessing antitumor response. Periodic follow-up analysis of these molecules may be helfful in appraising relapse or recurrence of the malignancy prior to overt evidence of tumor by existing clincial means.
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PMID:Potential biologic markers in Burkitt's lymphoma. 117 66

The bioligical photosensitizing properties of furocoumarins are due to the formation of adducts with the pyrimidine bases of DNA under irradiation with long wavelength ultraviolet light. The greatest importance is attributed to the difunctional adducts, which form cross-linkings between the 2 strands of DNA. As angelicin, photoreacting with DNA, forms only monofunctional adducts, and therefore no cross-linkings, its photosensitizing properties have been studied in order to evaluate the ability of monofunctional adducts to produce biological effects. The results obtained studying the inhibition of DNA, RNA and protein synthesis in Ehrlich ascite tumor cells after irradiation in the presence of angelicin and psoralen (for a comparison), and the inhibition of the ability of identically treated cells to transmit the tumor showed a remarkable ability of monofunctional adducts to produce biological effects.
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PMID:Studies on the photosensitizing properties of angelicin, an angular furocoumarin forming only monofunctional adducts with the pyrimidine bases of DNA. 121 77

Studies were undertaken to (a) assess intracellular methotrexate (MTX) levels at extracellular drug concentrations comparable to those achieved in high-dose MTX-folinic acid rescue protocols and (b) establish whether there is a rationale for the use of vincristine in these regimens. The data indicate that only low levels of exchangeable MTX (intracellular MTX in excess of the tightly bound fraction) accumulated in Ehrlich ascites tumor cells at high extracellular MTX concentration. For instance, the exchangeable steady-state intracellular MTX level was approximately 6.5 muM when the extracellular drug concentration was 85 muM. Over the interval of these experiments, exchangeable intracellular MTX did not exceed approximately 10 muM even when extracellular MTX was raised to 250 muM. These exchangeable intracellular MTX concentrations are comparable to those levels required experimentally to suppress (a) tetrahydrofolate synthesis from dihydrofolate and (b) tetrahydrofolate-dependent purine, pyrimidine, and amino acid synthesis in these cells in vitro. Vincristine (10 muM) augmented net MTX accumulation when the extracellular MTX level was 10, 100, or 250 muM. The limited capacity of cells to accumulate exchangeable intracellular MTX and the apparent role for this intracellular MTX component in achieving the metabolic effects of this agent may account for the necessity for high MTX blood levels in the treatment of some tumors and may be the basis, in part, for the enhanced chemotherapeutic efficacy of high-dose MTX regimens. These studies provide a rationale for the combined use of vincristine and MTX in high-dose MTX protocols. The addition of vincristine may permit the achievement of the level of exchangeable intracellular MTX that is required to critically inhibit tetrahydrofolate synthesis without an increase in the extracellular MTX concentration. This may permit a reduced MTX dose, diminishing the excretory load on the kidney and minimizing nephrotoxicity due to deposition of MTX in the renal tubule and interstitium. While the data indicate that the ratio of the concentration of exchangeable intracellular MTX to the extracellular drug concentration may be very low under steady-state conditions at high extracellular drug levels, further studies are required to establish that these steady-state gradients for MTX represent nonequilibrium conditions.
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PMID:Exchangeable intracellular methotrexate levels in the presence and absence of vincristine at extracellular drug concentrations relevant to those achieved in high-dose methotrexate-folinic acid "rescue" protocols. 124 6

Biochemical and biological studies have been carried out with 2-desamino-2-methylaminopterin (dmAMT), which inhibits tumor cell growth in culture but is only a weak inhibitor of dihydrofolate reductase (DHFR). Since it was possible that the species responsible for growth inhibition are polyglutamylated metabolites, the di-, tri-, and tetraglutamates of dmAMT were synthesized and tested as inhibitors of purified recombinant human DHFR, murine L1210 leukemia thymidylate synthase (TS), chicken liver glycinamide ribonucleotide formyltransferase (GARFT), and murine L1210 leukemia aminoimidazolecarboxamide ribonucleotide formyltransferase (AICARFT). The compounds with three and four gamma-glutamyl residues were found to bind two orders of magnitude better than dmAMT itself to DHFR, TS, and AICARFT, with 50% inhibitory concentration values in the 200 to 300 nM range against all three enzymes. In contrast, at a concentration of 10 microM, dmAMT polyglutamates had no appreciable effect on GARFT activity. These findings support the hypothesis that dmAMT requires intracellular polyglutamylation for activity and indicate that replacement of the 2-amino group by 2-methyl is as acceptable a structural modification in antifolates targeted against DHFR as it is in antifolates targeted against TS. In growth assays against methotrexate (MTX)-sensitive H35 rat hepatoma cells and MTX-resistant H35 sublines with a transport defect, dmAMT was highly cross-resistant with MTX, but not with the TS inhibitors N10-propargyl-5,8-dideazafolic acid and N-(5-[N-(3,4-dihydro-2-methyl-4-ox-oquinazolin-6-yl)-N- methylamino]thenoyl)-L-glutamic acid, implicating DHFR rather than TS as the principal target for dmAMT polyglutamates in intact cells. On the other hand, an H35 subline resistant to 2'-deoxy-5-fluorouridine by virtue of increased TS activity was highly cross-resistant to N10-propargyl-5,8-dideazafolic acid and not cross-resistant to MTX, but showed partial cross-resistance to dmAMT. Both thymidine and hypoxanthine were required to protect H35 cells treated with concentrations of dmAMT and MTX that inhibited growth by greater than 90% relative to unprotected controls. In contrast, N10-propargyl-5,8-dideazafolic acid and N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)-N-methylamino] thenoyl)- L-glutamic acid required only thymidine for protection. Like MTX, therefore, dmAMT appears to inhibit purine as well as pyrimidine de novo synthesis, and its effect on cell growth probably reflects the ability of dmAMT polyglutamates to not only block dihydrofolate reduction but also interfere with other steps of folate metabolism, either directly or indirectly via alteration of reduced folate pools.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical and biological studies on 2-desamino-2-methylaminopterin, an antifolate the polyglutamates of which are more potent than the monoglutamate against three key enzymes of folate metabolism. 131 37

Chromosomal origins of DNA replication in higher eukaryotes differ significantly from those of E. coli (oriC) and the tumor virus, SV40 (ori sequence). Initiation events appear to occur throughout broad zones rather than at specific origin sequences. Analysis of four chromosomal origin regions reveals that they share common modular sequence elements. These include DNA unwinding elements, pyrimidine tracts that may serve as strong DNA polymerase-primase start sites, scaffold associated regions, transcriptional regulatory sequences, and, possibly, initiator protein binding sites and inherently destabilized regions. Based on the novel organization of chromosomal origin regions, we propose a model for initiation of DNA replication in higher eukaryotes. Unwinding of duplex DNA during initiation may be uncoupled, both temporally and spatially, from DNA synthesis, resulting in transient single-stranded intermediates that function in lieu of conventional replication forks during chromosomal DNA replication. DNA synthesis begins subsequently at multiple sites within the unwound regions rather than at specific origin sequences.
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PMID:On the nature of origins of DNA replication in eukaryotes. 136 78


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