Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors carried out experiments on mice DBA/2 and BDF1 with leucosis L1210 and lung carcinoma of Lewis and found that psycotropic preparations tempidone and caffeine did not manifest antitumorous effect and toxicity after the used doses and scheme of treatment. Tempidone enhanced antitumorous action of small and mean doses of cyclophosphamide in mice with leucosis L1210. In the triple combination (tempidone, caffeine and cycl phosamide) the caffeine enhanced this action of tempidone without raising toxicity in mice with leucosis L1210, but not in mice with lung carcinoma of Lewis.
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PMID:[Experiment to potentiate the effect of cyclophosphamide combined with tempidon and caffeine in leukemia L1210 and Lewis hepatic carcinoma]. 63 51

The therapeutic usefulness of chlorpromazine (CPZ) and caffeine (CAF) in combination with selected nitrosoureas was investigated in mice bearing L1210 leukemia, Lewis lung carcinoma, and B16 melanoma. We found that using BCNU with either CAF or CPZ was therapeutically superior to using either agent alone to treat mice bearing L1210 leukemia. Administering all three drugs in combination did not improve upon the therapeutic responses obtained with the two-drug combinations. In mice implanted with Lewis lung carcinoma or B16 melanoma, responses to treatment with the triple combination of methyl-CCNU, CAF, and CPZ suggested, but did not clearly establish, superiority over each two-drug combination or methyl-CCNU alone.
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PMID:Therapeutic potentiation of nitrosoureas using chlorpromazine and caffeine in the treatment of murine tumors. 75 16

The in vitro cytotoxicity of 6 amino-5 formylmethylamino-1,3 dimethyluracil (ADMU) a major metabolite of caffeine in rats was studied by cell counts or [3H]thymidine incorporation in the murine Lewis lung carcinoma (3LL) and L929 fibroblast cells and in the human E cell line derived from an ovarian carcinoma. Unlike 5-fluorouracil (5FU) which was markedly cytotoxic, ADMU concentrations up to 60 micrograms/ml were devoid appreciable cytocidal action. Similarly, 1-10 micrograms 5FU markedly inhibited the blastogenic response of rat lymphocytes to PHA, whereas lymphoproliferation was not affected at ADMU concentrations up to 100 micrograms/ml. In vivo administration of ADMU (40 mg/kg, twice a day on day 1 to 3) to L1210 leukaemia-bearing mice caused a transient short-lasting reduction of tumour cell numbers only on day 6 after leukaemia inoculation.U
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PMID:In vitro and in vivo cytotoxicity of 6 amino-5-formyl-methylamino-1,3-dimethyl uracil, a uracilic metabolite of caffeine. 708 Jan 2

Green tea is an aqueous infusion of dried unfermented leaves of Camellia sinensis (family Theaceae) from which numerous biological activities have been reported including antimutagenic, antibacterial, hypocholesterolemic, antioxidant, antitumor and cancer preventive activities. From the aqueous-alcoholic extract of green tea leaves, six compounds (+)-gallocatechin (GC), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG) and caffeine, were isolated and purified. Together with (+)-catechin, these compounds were tested against each of four human tumor cells lines (MCF-7 breast carcinoma, HT-29 colon carcinoma, A-427 lung carcinoma and UACC-375 melanoma). The three most potent green tea components against all four tumor cell lines were EGCG, GC and EGC. EGCG was the most potent of the seven green tea components against three out of the four cell lines (i.e. MCF-7 breast cancer, HT-29 colon cancer and UACC-375 melanoma). On the basis of these extensive in vitro studies, it would be of considerable interest to evaluate all three of these components in comparative preclinical in vivo animal tumor model systems before final decisions are made concerning which of these potential chemopreventive drugs should be taken into broad clinical trials.
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PMID:Inhibitory effect of six green tea catechins and caffeine on the growth of four selected human tumor cell lines. 882 14

This study investigated the effects of the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitors caffeine, theophylline, and 3-isobutyl-1-methyl-xanthine (IBMX) on the proliferation and viability of the small cell lung carcinoma (SCLC) cell lines NCI-H345, NCI-H128, and SCC-9. These effects were correlated with the ability of the drugs to induce intracellular Ca2+ mobilization. Treatment of NCI-H345 cells with caffeine resulted in rapid mobilization of Ca2+, as indicated by Fura-2 fluorescence. Incubation of NCI-H345 cells with 6.25 mM caffeine resulted in a 62% inhibition of [3H]thymidine uptake after 2 hr, indicating reduced DNA synthesis. Incubation with 25 mM caffeine resulted in almost total inhibition of [3H]thymidine uptake after 2 hr. Similar effects on [3H]thymidine uptake were seen upon treatment of NCI-H128 and SCC-9 cells with caffeine; however, these cells did not exhibit caffeine-induced Ca2+ mobilization. Inhibition of DNA synthesis (66-93%) also occurred upon incubation of all cell lines with theophylline and IBMX, which did not mobilize Ca2+. Treatment of NCI-H345, NCI-H128, and SCC-9 cells with caffeine, theophylline, or IBMX markedly reduced cell viability. Levels of cAMP increased in the cells following treatment with caffeine, theophylline, or IBMX, reflecting the ability of these drugs to inhibit cAMP phosphodiesterase. These results suggest that the decrease in DNA synthesis and the subsequent cell death induced by these drugs are due to reduced cAMP phosphodiesterase activity, rather than to changes in intracellular Ca2+. These findings indicate that drugs that alter cAMP signaling pathways are potentially valuable agents to inhibit SCLC survival.
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PMID:Reduced DNA synthesis and cell viability in small cell lung carcinoma by treatment with cyclic AMP phosphodiesterase inhibitors. 980 35

Caffeine exposure sensitizes tumor cells to ionizing radiation and other genotoxic agents. The radiosensitizing effects of caffeine are associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints. The similarity of these checkpoint defects to those seen in ataxia-telangiectasia (A-T) suggested that caffeine might inhibit one or more components in an A-T mutated (ATM)-dependent checkpoint pathway in DNA-damaged cells. We now show that caffeine inhibits the catalytic activity of both ATM and the related kinase, ATM and Rad3-related (ATR), at drug concentrations similar to those that induce radiosensitization. Moreover, like ATM-deficient cells, caffeine-treated A549 lung carcinoma cells irradiated in G2 fail to arrest progression into mitosis, and S-phase-irradiated cells exhibit radioresistant DNA synthesis. Similar concentrations of caffeine also inhibit gamma- and UV radiation-induced phosphorylation of p53 on Ser15, a modification that may be directly mediated by the ATM and ATR kinases. DNA-dependent protein kinase, another ATM-related protein involved in DNA damage repair, was resistant to the inhibitory effects of caffeine. Likewise, the catalytic activity of the G2 checkpoint kinase, hChk1, was only marginally suppressed by caffeine but was inhibited potently by the structurally distinct radiosensitizer, UCN-01. These data suggest that the radiosensitizing effects of caffeine are related to inhibition of the protein kinase activities of ATM and ATR and that both proteins are relevant targets for the development of novel anticancer agents.
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PMID:Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. 1048 86

The effect of doxorubicin treatment on cell cycle parameters in asynchronous populations of multidrug-resistant human lung carcinoma cell lines was investigated. A sensitive (DLKP-SQ) and three resistant (DLKP-SQ A250 10p#7, DLKP-A2B and DLKP-A5F) variants of a human lung carcinoma cell line DLKP were exposed to equitoxic concentrations of doxorubicin. The latter three were 8-fold, 30-fold and 300-fold resistant to doxorubicin, respectively. Irreversible G2/M arrest in sensitive (DLKP-SQ) cells was observed 24 h after initiation of doxorubicin treatment. In resistant variants, G2/M arrest occurred at 12-16 h with a subsequent bypass of the G2/M arrest to re-emerge and accumulate in G1. This transient G2/M arrest and subsequent progression into G1 indicated an inefficient checkpoint for monitoring DNA damage induced by doxorubicin treatment. Caffeine treatment could bypass the G2/M block in DLKP-SQ cells. Doxorubicin treatment did not alter cyclin B or cdc2 protein levels, the ability of cdc2 to form complexes with cyclin B or the levels of cyclin B bound to cdc2. The G2/M arrest seen in sensitive cells was associated with an increase in inhibitory phosphorylation of Tyr15 on cdc2. In contrast, tyrosine 15 phosphorylation did not change in resistant variants after drug treatment and a general increase in cdc2 kinase activity was seen. Cdc25C levels were not altered following drug treatment.
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PMID:Altered cell cycle response of drug-resistant lung carcinoma cells to doxorubicin. 1085 49

Flavopiridol (L86-8275) ((-)-cis-5, 7-dihydroxy-2-(2-chlorophenyl)-8-[4-(3-hydroxy-1-methyl)-piperidinyl] -4H-benzopyran-4-one), a potential antitumor drug, currently in phase II trials, has been shown to be an inhibitor of muscle glycogen phosphorylase (GP) and to cause glycogen accumulation in A549 non-small cell lung carcinoma cells (Kaiser, A., Nishi, K., Gorin, F.A., Walsh, D.A., Bradbury, E. M., and Schnier, J. B., unpublished data). Kinetic experiments reported here show that flavopiridol inhibits GPb with an IC(50) = 15.5 microm. The inhibition is synergistic with glucose resulting in a reduction of IC(50) for flavopiridol to 2.3 microm and mimics the inhibition of caffeine. In order to elucidate the structural basis of inhibition, we determined the structures of GPb complexed with flavopiridol, GPb complexed with caffeine, and GPa complexed with both glucose and flavopiridol at 1.76-, 2.30-, and 2.23-A resolution, and refined to crystallographic R values of 0.216 (R(free) = 0.247), 0.189 (R(free) = 0.219), and 0.195 (R(free) = 0.252), respectively. The structures provide a rational for flavopiridol potency and synergism with glucose inhibitory action. Flavopiridol binds at the allosteric inhibitor site, situated at the entrance to the catalytic site, the site where caffeine binds. Flavopiridol intercalates between the two aromatic rings of Phe(285) and Tyr(613). Both flavopiridol and glucose promote the less active T-state through localization of the closed position of the 280s loop which blocks access to the catalytic site, thereby explaining their synergistic inhibition. The mode of interactions of flavopiridol with GP is different from that of des-chloro-flavopiridol with CDK2, illustrating how different functional parts of the inhibitor can be used to provide specific and potent binding to two different enzymes.
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PMID:Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. 1092 12

Caffeine is a model radiosensitizing agent that is thought to work by abrogating the radiation-induced G(2)-phase checkpoint. In this study, we examined the effect that various concentrations of caffeine had on cell cycle checkpoints and apoptosis in cells of a human lung carcinoma cell line and found that a concentration of 0.5 mM caffeine could abrogate the G(2)-phase arrest normally seen after exposure to ionizing radiation. Surprisingly, at a concentration of 5 mM, caffeine not only induced apoptosis by itself and acted synergistically to enhance radiation-induced apoptosis, but also induced a TP53-independent G(1)-phase arrest. Examination of the molecular mechanisms by which caffeine produced these effects revealed that caffeine had opposing effects on different cyclin-dependent kinases. CDK2 activity was suppressed by caffeine, whereas activity of CDC2 was enhanced by suppressing phosphorylation on Tyr15 and by interfering with 14-3-3 binding to CDC25C. These data indicate that the effect of caffeine on cell cycle checkpoints and apoptosis is dependent on dose and that caffeine acts through differential regulation of cyclin-dependent kinase activity.
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PMID:Caffeine induces TP53-independent G(1)-phase arrest and apoptosis in human lung tumor cells in a dose-dependent manner. 1183 80

This study was performed to investigate how caffeine modifies the cytotoxic effects of paclitaxel on a human lung carcinoma cell line. Caffeine doses up to 5mM had less effect on clonogenic survival. The cell killing effect, due to paclitaxel, increased in a dose-dependent manner up to 50 nM. For combined treatment with caffeine and paclitaxel, added caffeine reduced the cytotoxic effect of paclitaxel not only in dose-response but also in time-response curves. Caffeine combined with paclitaxel clearly suppressed cell proliferation in a dose-dependent manner. In the cell cycle analysis, caffeine alone caused early G1 accumulation, whereas paclitaxel alone caused an early increase in G2-M and a decrease in G1. As for the effect of caffeine on paclitaxel, caffeine suppressed the effect of paclitaxel on cell cycle distribution, where a dose-dependent early increase in G2-M and a decrease in G1 were not clear. We suggest that cell cycle modifying agents, such as caffeine, potentially diminish the cytotoxic activity of paclitaxel, and one should be careful when combining such agents.
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PMID:Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line. 1260 15


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