UMLS:C0684249 - FACTA Search

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of action of 5-hexyl-2-'deoxyuridine (HUdR), a compound with antitumor activity, has been investigated in the HM cell lines derived from the highly metastatic variant of Lewis lung carcinoma (3LL-HH). It was shown that this pyrimidine analog did not inhibit the biosynthesis of nucleotides but modified the biosynthesis of glycoconjugates. The incorporation of [14C]-glucosamine into cytoplasmic glycoconjugates [glycosaminoglycan (GAG), glycolipid (GL), glycoprotein (GP), neutral polysaccharide (NP)] decreased to a similar level. The [14C]-glucosamine derived radioactivity was reduced to about 60-70% of the untreated controls in the presence of 15 micrograms/ml HUdR, which caused no inhibition of cell proliferation. These results might be explained by the reduced conversion of glucosamine into uridine-5'-diphospho-hexosamine. As more reduction was observed in the glucosamine labeling of glycoconjugates in nuclei and extracellular compartment, it may be conceivable that the intracellular transport of certain glycoconjugates (GAG, GP) is also affected by HUdR. In the extracellular compartment the reduced level of GAG labeling was the most apparent change. However, at a higher concentration of HUdR (75 micrograms/ml) there was a higher radioactivity in the combined GL + GP fraction. Using [35S]-labeling, the GAG fractions also showed a decreased radioactivity but only at the concentration of 75 micrograms/ml HUdR.
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PMID:Modulation of glycoconjugate biosynthesis by 5-hexyl-2'-deoxyuridine in highly metastatic Lewis lung carcinoma cells. 223 12

A new cytotoxic acridine alkaloid that exhibited antitumor activity in vivo was isolated from a marine Dercitus species sponge collected at a depth of 160 m in the Bahamas. This violet alkaloid, designated dercitin, inhibited the proliferation of cultured murine and human leukemia, lung, and colon tumor cells at nM concentrations (IC50 values of 63-150 nM) and prolonged the life of mice bearing ascitic P388 tumors (%T/C = 170, 5 mg/kg, i.p., QD1-9). Dercitin was also active against i.p. B16 melanoma and modestly inhibited the growth of s.c. Lewis lung carcinoma on the same schedule. DNA blocked the antiproliferative effects of the agent in culture, and incorporation studies indicated that dercitin disrupted DNA and RNA synthesis with less effects on protein synthesis, similar to the effects of known DNA intercalators. After 1-h exposure to 400 nM dercitin, the rates of incorporation of [3H]uridine, [3H]thymidine, and [3H]leucine by cultured P388 cells were inhibited 83, 61, and 23%, respectively. Equilibrium dialysis indicated that dercitin bound calf thymus DNA with an affinity of 3.1 microM and maximal binding of 0.20 mol dercitin/mol base pair. Binding involved intercalation as evidenced by ability to relax supercoiled phi X174 DNA (half maximal concentration for dercitin relaxation was 36 nM). The effects of dercitin on DNA mobility were reversible, and complete relaxation of DNA with topoisomerase I in the presence of dercitin followed by phenol extraction resulted in the appearance of supercoiled DNA. Dercitin, at microM concentrations, had a small effect in the K+-sodium dodecyl sulfate assay using cultured P388 cells, suggesting minimal inhibition of topoisomerase activity. But, dercitin completely inhibited DNA polymerase I/DNase nick translation of DNA at 1 microM. Relaxation of DNA at a given concentration was greater than inhibition of nick translation suggesting that the effects of dercitin on enzyme activity were secondary to changes in DNA conformation. Results indicate that dercitin is a new marine natural product that probably exerts its biological effects through intercalation into nucleic acids.
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PMID:Antitumor activity and nucleic acid binding properties of dercitin, a new acridine alkaloid isolated from a marine Dercitus species sponge. 254 17

Three novel heterocyclic compounds, mycalamide-A and -B and onnamide, were isolated from Mycale sp. and Theonella sp. sponges collected in New Zealand and Okinawan waters. Each exhibited potent in vitro toxicity and in vivo efficacy against murine and human tumor cells. Concentrations of each that inhibited replication of cultured murine lymphoma P388 cells by 50% were 5 nM or less. Mycalamide-A and -B were also potent inhibitors of HL-60, HT-29, and A549 human tumor cell replication (50% inhibitory concentration less than 5 nM), while values for onnamide were greater (50% inhibitory concentrations between 25 and 200 nM). Mycalamide-A (10 micrograms/kg) and -B (2.5 micrograms/kg) were moderately active against P388 leukemia (increase in life span, approximately 50%), while onnamide was inactive (40 micrograms/kg; increase in life span, 15%). Mycalamide-A was also active against B16 melanoma, Lewis lung carcinoma, M5076 ovarian sarcoma, colon 26 carcinoma, and the human MX-1, CX-1, and Burkitt's lymphoma tumor xenografts. Mechanism of action studies indicate that the three agents inhibited protein synthesis. For example, after 1-h exposures to 20 nM mycalamide-A and -B, the rates of [3H]leucine incorporation into acid-precipitable material of cultured P388 cells were inhibited 54 and 99%, while the effects on incorporation of [3H]uridine and [3H]thymidine were less. The relative effects of 20 to 2000 nM mycalamide-A on protein, RNA, and DNA synthesis were consistent with those observed during exposure of P388 cells to 1 microM emetine, a known inhibitor of protein synthesis. Also, the three agents inhibited translation of RNA into protein in a cell-free lysate of rabbit reticulocytes. Although mycalamide-A disrupted DNA metabolism, the agent apparently did not intercalate into DNA, and a mixture of four deoxynucleosides (250 microM each) did not decrease the antiproliferative effects of the agent. Collectively, these data indicate that this class of compounds represents novel antitumor agents which should be further evaluated to define their potential.
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PMID:Antitumor activity and mechanism of action of the novel marine natural products mycalamide-A and -B and onnamide. 272 Jun 52

The biodistribution of radiolabelled 1-(2'-fluoro-2'-deoxy-beta-D-ribofuranosyl)uracil (2'-FUdR) and 1-(2'-chloro-2'-deoxy-beta-D-ribofuranosyl)uracil (2'-ClUdR) was evaluated using in-vivo and in-vitro tumour models. 6-[3H]-2'-FUdR exhibited a maximum tumour:blood (T:B) ratio (Walker 256 carcinosarcoma) of 1.0 at 15 min after injection whereas 2-[14C]-2'-FUdR and 2'-[36Cl]-2'-ClUdR exhibited maximum T:B ratios (Lewis lung carcinoma) of 3.0 and 4.1 respectively at 120 min. Clearance of blood radioactivity after injection of 6-[3H]-2'-FUdR, 2-[14C]-2'-FUdR and 2'-[36Cl]-2'-ClUdR was rapid and best described by a biexponential function. The clearance half-lives of the short-lived components were calculated as 1.6 min (95.5%), 2.3 min (94.7%) and 1.2 min (96.0%) respectively. The clearance half-lives of the long-lived components were 23 h (4.5%) for 6-[3H]-2'-FUdR, 89 min (5.3%) for 2-[14C]-2'-FUdR, and 49 min (4.0%) for 2'-[36Cl]-2'-ClUdR. Less than 36% of the 14C radioactivity present in the urine 2 h after injection of 2-[14C]-2'-FUdR was associated with 2'-FUdR, whereas greater than 91% of the 36Cl radioactivity in the urine 2 h after injection of 2'-[36Cl]-2'-ClUdR was associated with 2'-ClUdR. Both 6-[3H]-2'-FUdR (less than 3.1 pmol/10(6) cells) and 6-[3H]-2'-ClUdR (1.0 +/- 0.2 pmol/10(6) cells) were incorporated into cultured Raji tumour cells in vitro to a lesser extent than the natural nucleosides uridine (137.2 +/- 3.8 pmol/10(6) cells) and 2'-deoxyuridine (23.5 +/- 2.5 pmol/10(6) cells) after a 20 min incubation.
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PMID:Tumour uptake of radiolabelled pyrimidine bases and pyrimidine nucleosides in animal models. IX. Radiolabelled 1-(2'-fluoro-2'-deoxy-beta-D-ribofuranosyl)uracil and 1-(2'-chloro-2'-deoxy-beta-D-ribofuranosyl)uracil. 293 14

Monoclonal antibodies (MAbs) 126 (immunoglobulin M) and 14.18 (immunoglobulin G3) react strongly with the cell surface of small cell carcinoma of the lungs (SCCL) and are unreactive with most normal tissues and other neoplasms with the notable exception of tumors derived from cells of neural crest origin. These MAbs react specifically with the oligosaccharide portion of the disialoganglioside GD2. Analysis of total gangliosides from cultured cell lines derived from SCCL indicates that GD2 is a predominant ganglioside. A comparison of the reactivities of MAbs against GD2 with those directed against gangliosides GM2 and GD3, each differing from GD2 by a single sugar residue, clearly indicates that GD2 is preferentially expressed by cultured cells derived from SCCL. Membranes isolated from these cells exhibit GD2 synthetase activity which specifically converts the precursor GD3 to GD2 in the presence of uridine diphosphate-N-acetyl galactosamine as the glycosyl donor. We present evidence that in SCCL, GD2 serves as a relevant target antigen for monoclonal antibody-mediated cytolysis. Specifically, we demonstrate that MAb 14.18 (immunoglobulin G3), can lyse small cell carcinoma of the lung targets by either complement- or antibody-dependent cellular cytotoxicity.
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PMID:Biosynthesis and expression of the disialoganglioside GD2, a relevant target antigen on small cell lung carcinoma for monoclonal antibody-mediated cytolysis. 301 21

In response to cell-free conditioned medium derived from the human bladder carcinoma line T24 (T24 SN), we found greatly reduced incorporation of tritiated thymidine and uridine ([3H]TdR, [3H]UR) by the human carcinoma lines UCHNCu (small-cell lung carcinoma) and LS174T (colon carcinoma). The effect was not due to an excess of nucleosides or cytokines known to be present in T24 SN. Cell-cycle distribution, increase in cell numbers, and de novo nucleoside synthesis in the indicator cells were only slightly altered. This was in contrast to the gross reduction in [3H]TdR/[3H]UR incorporation and seemed to indicate selective downregulation of pyrimidine-salvage pathways, despite ongoing polynucleotide synthesis. Spontaneous [3H]TdR uptake remained low for several passages in vitro but was readily restored by pharmacological inhibition of de novo pathways with 5-fluoro-deoxy-uridine (5-FUdR). This suggested a stable but reversible regulatory effect of T24 SN on the pyrimidine metabolism of the indicator cells. Further investigation showed degradation of [3H]TdR by a particle-bound activity in T24 SN. Mycoplasma contamination of T24 had not been detectable using standard cultural and staining methods, but became apparent when T24-cell lysates were hybridized with a recently described DNA probe (Goebel & Stanbridge, 1984). We conclude that latent mycoplasma contamination can stimulate changes in cellular pyrimidine metabolism. Our results provide an example for latent mycoplasma infection mimicking metabolic changes in cultured cells by direct interference of a microbial enzyme with the assay system. We describe a rapid and simple bioassay to detect and distinguish particle-associated and soluble phosphorylase activity by [3H]TdR degradation. It may be a useful screening assay for mycoplasma contamination in tissue culture.
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PMID:Rate of incorporation of radiolabelled nucleosides does not necessarily reflect the metabolic state of cells in culture: effects of latent mycoplasma contamination. 333 17

The polysaccharide levan exerted a direct effect on Lewis lung carcinoma cells in vitro. Tumor cells incubated with levan showed a pronounced decrease in oncogenic properties when inoculated sc in the syngeneic hosts (C57BL mice), although the viability of cells as determined by the trypan blue exclusion test was not diminished. The effect of pretreatment of inoculated mice with levan. Radiolabel incorporation into DNA, RNA, and protein was not affected in cells incubated with levan, but transport properties were selectively altered: Thymidine, uridine, and leucine transport was enhanced, whereas deoxyglucose transport was unchanged. The results indicated that levan exerted a direct antitumor effect on Lewis lung carcinoma cells in vitro.
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PMID:Direct antitumor effect of high-molecular-weight levan on Lewis lung carcinoma cells in mice. 693 Dec 56

Pools of uridine triphosphate and cytidine triphosphate are greatly (90%) reduced in cultured L1210 cells exposed to N-(phosphonacetyl)-L-aspartate (PALA) or pyrazofurin; the concentration of the deoxynucleotides deoxycytidine triphosphate, deoxythymidine triphosphate, and deoxyguanosine triphosphate also decreases, but deoxyadenosine triphosphate pools are enlarged. Associated with these pool depletions is a pronounced inhibition of DNA synthesis even when pools are only moderately reduced; RNA synthesis is only slightly inhibited under these same conditions. DNA synthesis in permeabilized preparations of L1210 cells was also more sensitive than was RNA synthesis when the concentrations of ribonucleotide and deoxyribonucleotide triphosphates presented were equivalent to those found in PALA- or pyrazofurin-treated cells. The specific sensitivity to depletion of DNA precursors was also seen in protection of both DNA synthesis and growth of L1210 cells by deoxycytidine and thymidine. This supplement restored deoxycytidine triphosphate, deoxythymidine triphosphate, and deoxyguanosine triphosphate pools to normal but of course did not affect the marked depletions of uridine triphosphate and cytidine triphosphate or the less marked effect of PALA on RNA synthesis. The relative ability of PALA to reduce uridine triphosphate and cytidine triphosphate pool size in L1210 ascites and Lewis lung carcinoma in vivo correlates with the intrinsic sensitivity to this agent.
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PMID:Kinetics of N-(phosphonacetyl)-L-aspartate and pyrazofurin depletion of pyrimidine ribonucleotide and deoxyribonucleotide pools and their relationship to nucleic acid synthesis in intact and permeabilized cells. 712 93

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

Two new modified uracil nucleosides, 5-carbamoylmethyuridine (ncm5U, I) and 5-carbamoylmethyl-2-thiouridine (ncm5s2U, II) were isolated from a 24 hr collection of a normal human urine. The structures were assigned on the basis of UV, NMR and mass spectral data and confirmed by comparison of the spectral data and HPLC mobilities with those of authentic samples. On the basis of experimental data it appears possible that 5-carbamoylmethyl-2-thio-uridine (ncm5s2U, II) may be a degradation product produced from a labile precursor by the chemical treatments during the isolation procedure. However, the other nucleoside (ncm5U,I) certainly appears to be of metabolic origin and was also found in the urines of one chronic myelogenous leukemia and one lung carcinoma patient. Abbreviations used are: tRNA-transfer ribonucleic acid, TMS-trimethylsilyl, RP-HPLC--reverse phase high performance liquid chromatography, EI--electron impact, cm5U-5-carboxymethyluridine, mcm5U-5-methoxycarbonylmethyluridine, cm5s2U-5-carboxymethyl-2-thiouridine, mcm5s2U-5-methoxycarbonylmethyl-2-thiouridine, t6A-9-beta-D-ribofuranosyl-[N(purin-6-yl)carbamoyl]-1-threonine, C-cytidine, acp3u-3-(3-amino-3-carboxypropyl)uridine, AICR-aminoimidazole carboxamide riboside, alpha-4-PCNR & beta-4-PCNR-9-alpha-D-(or beta-D)-ribofuranosyl-pyridin-4-one-3-carboxamide, H x 7R-7-beta-D-ribofuranosyl hypoxanthine, m3U-3-methyluridine, m1I-1-methylinosine, m1G-1-methylguanosine, DI-5'-deoxyinosine, dms5OA-5'-deoxy-5'-methylthioadenosine sulfoxide, m2(2)G-N2-dimethylguanosine, psi-psi-uridine, A-adenosine, I-inosine, CML-chronic myelogenous leukemia mam5s2U-5-methylaminomethyl-2-thiouridine, ncm5U-5-carbamoylmethyluridine, ncm5s2U-5-carbamoylmethyl-2-thiouridine, UV-ultraviolet, NMR-nuclear magnetic resonance, HPLC-high performance liquid chromatography, GC-MS-gas chromatography-mass spectrometry.
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PMID:Isolation and characterization of 5-carbamoylmethyluridine and 5-carbamoylmethyl-2-thiouridine from human urine. 1061 23

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