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)

We used human tumor cell lines from the National Cancer Institute's In Vitro Antineoplastic Drug Screen to assess whether sensitivity to any of the approximately 45,000 compounds tested previously correlated with the presence of a ras oncogene. Among these cell lines, the mutations in Ki-ras2 clustered in non-small cell lung and colon carcinoma subpanels, and five of the six leukemia lines contained mutations in either N-ras or Ki-ras2. These analyses revealed a striking correlation with 1-beta-D-arabinofuranosylcytosine (Ara-C) and 2,2'-O-cyclocytidine sensitivity in the cell lines harboring ras mutations compared to the tumor lines with wild-type ras alleles. Strong correlations were also found with topoisomerase (topo) II inhibitors, especially 3'-hydroxydaunorubicin and an olivacine derivative. These differential sensitivities persisted in an additional 22 non-small cell lung carcinoma lines (ras mutations, n = 12 and wild-type ras, n = 10). Thus, the association with Ara-C sensitivity was greatest while topo II inhibitors showed a lower, but significant, correlation. These results suggest that the ras oncogene may play a determinant role in rendering tumor cells sensitive to deoxycytidine analogues and topo II inhibitors.
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PMID:Enhanced sensitivity to 1-beta-D-arabinofuranosylcytosine and topoisomerase II inhibitors in tumor cell lines harboring activated ras oncogenes. 891 59

Local chemotherapy with biodegradable polymers prolongs survival with minimal morbidity in patients with intracranial high-grade gliomas. However, use of local chemotherapy for metastatic brain tumors has not been defined. We studied the safety and the efficacy of locally delivered chemotherapy with and without concurrent radiation therapy in treating tumors that frequently metastasize to the brain. The chemotherapeutic agents 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), carboplatin, and camptothecin were incorporated into controlled-release polymers and tested individually against intracranial challenges with one of four tumors (lung carcinoma, renal cell carcinoma, colon carcinoma, and melanoma). For each combination of drug and tumor type, four groups were tested: (a) empty polymer (no drug); (b) external beam radiotherapy (XRT) alone; (c) local chemotherapy from biodegradable polymer alone; and (d) local chemotherapy and XRT together. Polymers were implanted 5 days after tumor inoculation; XRT was given on days 7-9 (300 cGy/day). BCNU and XRT together were effective against all four tumors. BCNU polymer alone significantly prolonged survival in mice with intracranial melanoma or renal cell carcinoma. Carboplatin alone was effective against both melanoma and colon carcinoma and in combination with XRT against colon and renal cell carcinomas. Camptothecin was effective only with XRT against melanoma. These studies demonstrate that local delivery of chemotherapy with concurrent radiation therapy is safe and can significantly prolong survival in models of common intracranial metastatic tumors. Concurrent use of local chemotherapy with standard XRT appears to be more effective than either treatment alone. Local chemotherapy may also be of benefit to patients who have previously received maximal cranial irradiation but suffer an intracranial recurrence.
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PMID:Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. 891 60

Tissue-specific expression of human UGT1A6, a UDP-glucuronosyltransferase isoform conjugating a wide variety of planar phenols, has been studied using a reverse transcriptase-polymerase chain reaction. Use of intron-overlapping forward and reverse primers from exon 1 and 2 and of a "hot start" modification led to selective amplification of a UGT1A6 mRNA fragment. In addition, homologous competitor mRNA was synthesized, reverse transcribed, and coamplified to allow quantitation of UGT1A6 mRNA. Using these methods UGT1A6 mRNA could be demonstrated in liver, kidney, duodenum, and lung. Cell-specific regulation of UGT1A6 by TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) was studied in various cell systems. TCDD induction was found in the human colon carcinoma cell line Caco-2 and in hepatocyte primary cultures. In contrast, in lung carcinoma A549 cells this isoform was constitutively expressed and not induced by TCDD.
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PMID:Tissue-specific 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible expression of human UDP-glucuronosyltransferase UGT1A6. 891 52

New 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3- diones with substituents at the 4, 8, 9, 10, and 11 positions were synthesized. Diazonium salts prepared from aminoazonafides were key intermediates for many of the analogues. Six of the new compounds were more potent than azonafide in a panel of tumor cells including human melanoma and ovarian carcinoma and murine L1210 leukemias. Three of these compounds, the 10-OCH3, 10-OC2H5, and 10-F analogues, had better ratios of cardiotoxicity to tumor-cell toxicity than azonafide. Eight compounds were not cross-resistant with MDR L1210 leukemia, and the 10-CN analogue was more potent against solid tumor cells than leukemia cells. The 9-OH, 10-CN, and 10-F analogues had high potency against both sensitive and resistant cell lines of MFX 7 breast carcinoma and WiDr colon carcinoma and sensitivity A599 lung carcinoma. Advantages of the 10-Cl, 10-NH2, and 10-CN analogues over azonafide were apparent in P388 leukemia in mice, and the 10-CN analogue was more effective than doxorubicin in this assay. Quantitative structure-activity relationship studies revealed statistically significant correlations between DNA binding strength of 8- and 10-substituted azonafides, as measured by deltaTm, and toxicity to tumor cells. There also were correlations between substituent size, as measured by MR, and cytotoxicity for 9- and 10-substituted azonafides and between MR and deltaTm for 4- and 11-substituted azonafides. Lipophilicity of substituents (pi) correlated with cytotoxicity for 9-, 10-, and 11-substituted azonafides. These results lend support to a model in which DNA binding strength influences cytotoxic potency, and lipophilicity increases DNA binding whereas large substituents decrease it.
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PMID:2-[2'-(Dimethylamino)ethyl]-1,2-dihydro- 3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at positions 4, 8, 9, 10, and 11. Synthesis, antitumor activity, and quantitative structure-activity relationships. 896 May 58

The antitumor activities of several glucuronide methyl esters of podophyllum derivatives were tested in vitro against two human tumor cell lines and their drug resistant sublines. The most active compound studied was methyl (4'-carbobenzoxy-4'-demethyl-epipodophyllotoxin-D-glucopyranoside)uronat e 19. Compound 19 was as potent in a colon carcinoma model and was twice as potent in a lung carcinoma model as etoposide 6. In vivo, however, in a mouse leukemia P388 model, it had only marginal activity, with a maximum T/C% value of 125 at 37 mg/kg (iv).
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PMID:Studies in sugar chemistry. VII. Glucuronides of podophyllum derivatives. 939 86

The lymphoid-specific protein tyrosine kinase, p56lck which is essential for both T cell development and function, is aberrantly expressed in colon and small lung carcinoma lines. In this paper, we demonstrate p56lck is also expressed in colon tumour biopsies due predominantly or exclusively to the use of the lck type I promoter. In T leukaemia lines, the lck type I promoter requires binding sites for both Ets- and Myb-related transcription factors. In contrast, in colon tumour lines the activation of the lck type I promoter requires the Ets but not the Myb binding site. In these lines, a consensus binding site for HMG-related transcription factors, AACAAAG, is required for efficient lck type I promoter activity. Sox-4 is a candidate transcription factor for binding and activating the lck type l promoter in colon carcinoma cells. Co-expression of Ets-1 and Sox-4, but neither protein alone, was sufficient to activate the lck type l promoter in HeLa cells which do not normally express lck transcripts. These results suggest that aberrant expression of p56lck from the lck type l promoter in colon carcinoma arises from transcriptional activation mediated by Ets- and HMG-related transcription factors.
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PMID:An alternative pathway for expression of p56lck from type I promoter transcripts in colon carcinoma. 941 36

A set of friedelane triterpenoids has been isolated from the stem bark exudates of Maytenus macrocarpa. It includes a new friedelan triterpene (1), together with the known compounds friedelin, 3-oxo-29-hydroxyfriedelane, 3-oxofriedelan-25-al, and canophyllol. The structures of these compounds were elucidated by spectroscopic and chemical evidence. Complete 1H and 13C assignments were achieved by 2D NMR spectroscopy. The new compound showed weak activity against aldose reductase. It did not display antitumor activity against P-388 lymphoid neoplasm, A-549 human lung carcinoma, HT-29 human colon carcinoma, or MEL-28 human melanoma cell lines.
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PMID:Friedelane triterpenoids from Maytenus macrocarpa. 946 56

Transcriptional regulation of human UGT1A6, a UDP glucuronosyltransferase isoform conjugating a wide variety of planar phenols, has been studied using transfection experiments with plasmids containing its 3-kb 5' upstream region and chloramphenicol acetyltransferase as reporter gene. Previously, two modes of expression of the isoform have been described: in colon carcinoma Caco-2 cells UGT1A6 was found to be TCDD-inducible, whereas in lung carcinoma A549 cells it was constitutively expressed. Therefore functional analysis of UGT1A6 regulation was carried out using these two cell lines. In the upstream region of human UGT1A6 one xenobiotic-responsive element (XRE) was found between-1498 and -1502 bp. In Caco-2 cells the reporter gene activity of the entire plasmid and of deletion mutants containing the XRE were TCDD-inducible, in contrast to experiments with a deletion mutant which did not contain the XRE. TCDD induction was marginal in transfection studies with A549 cells. Gel mobility shift analysis indicated that the aryl hydrocarbon receptor and its partner Arnt bind to the XRE. Furthermore, primer extension studies suggest cell-specific use of multiple TATA boxes. Hence, regulation of human UGT1A6 appears to be cell-specific including both constitutive and aryl hydrocarbon receptor-controlled expression.
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PMID:Aryl hydrocarbon receptor-inducible or constitutive expression of human UDP glucuronosyltransferase UGT1A6. 946 22

A new oral type of 5-fluorouracil (5-FU) derivative possessed of both potent antitumor activity and less gastrointestinal (GI) toxicity was investigated and developed in the form of a combination of tegafur (FT), a masked form of 5-FU, and its two peculiar biochemical modulators. One is 5-chloro-2,4-dihydroxypyridine (CDHP), a new potent inhibitor of 5-FU degradation in vivo, and another is potassium oxonate (Oxo), a characteristic inhibitor of 5-FU phosphorylation, which distributes much higher in GI tract after p.o. administration. 5-FU levels in blood of rats following administration of FT, were markedly elevated and persisted for a long-time by co-oral CDHP corresponding to over 0.4 molar ratio to FT, like the case in continuous infusion of 5-FU, which resulted in an augmentation of antitumor efficacy in Yoshida sarcoma-bearing rats, although severe GI toxicity simultaneously occurred. To reduce 5-FU-induced toxicities such as diarrhea and body weight loss and to maintain the augmented antitumor activity, 0.5 to 2 molar Oxo was orally given to rats with one molar FT plus 0.4 molar CDHP. As a result, both severe GI injury and body weight loss were markedly inhibited by coadministration of 0.5 to 1.0 molar Oxo while high antitumor efficacy (about 90% inhibition of tumor growth) was maintained. However, such almost complete antitumor effect was reduced to about 50% inhibition of tumor growth by over 2 molar Oxo combined with one molar FT plus 0.4 molar CDHP. Based on these results, a novel 5-FU derivative, named S-1, was composed of one molar FT, 0.4 molar CDHP and one molar Oxo. S-1 showed an antitumor activity over 3-fold stronger than UFT (one molar FT plus 4 molar uracil) against Yoshida sarcoma and Sato lung carcinoma in rats and human colon carcinoma (KM12C) xenografted in nude rats when its minimum toxic dose was administered. Co-oral Oxo also significantly reduced the incidence of diarrhea and stomatitis induced by administration of FT-CDHP in beagle dogs. These results suggest that high antitumor activity and less GI toxicity of S-1 was brought about by the elevation in blood and tumor tissues and by selective decrease of 5-fluoronucleotides, an active metabolite of 5-FU, in GI tract.
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PMID:[Invention of a tumor-selective 5-fluorouracil derivative named S-1 by biochemical modulation of 5-fluorouracil]. 949 31

Previous studies have identified and characterized both murine in vivo and human in vitro T cell responses reflecting specific mutations in the ras proto-oncogenes at codon 12, 13, or 61. In an attempt to determine whether peptide epitopes reflecting point mutations in the ras oncogenes are immunogenic in humans for the production of CD4+ and/or CD8+ T cell responses, a phase I clinical trial was initiated in metastatic carcinoma patients whose primary tumors harbor mutations in the K-ras proto-oncogenes at codon 12. The peptides used here as immunogens, which were administered in Detox adjuvant, spanned the ras sequence 5-17 and reflected the amino acid substitution of glycine (Gly) at position 12 to aspartic acid (Asp), cysteine (Cys), or valine (Val). Three of eight evaluable patients have demonstrated peptide-specific cell-mediated immunity, as determined by the production of T cell lines resulting from the vaccination. First, an antigen (Ag)-specific, major histocompatibility complex (MHC) class II (DP)-restricted CD4+ T cell line was established in vitro from postvaccination lymphocytes of a non-small cell lung carcinoma patient whose primary tumor contained a Cys12 mutation when cultured on the immunizing peptide. Moreover, CD4+ proliferation was inducible against the corresponding mutant K-ras protein, suggesting productive T cell receptor recognition of exogenously processed Ag. Second, an Ag-specific, MHC class I (HLA-A2)-restricted CD8+ cytotoxic T lymphocyte (CTL) line was established in vitro from postvaccination lymphocytes of a colon carcinoma patient whose primary tumor contained an Asp12 mutation. To that end, a 10-mer peptide, nested within the 13-mer immunizing peptide, was identified [i.e., ras5-14(Asp12)], which was shown to bind to HLA-A2 and display specific functional capacity for expansion of the in vivo primed CD8+ CTL precursors. Third, both Ag-specific, MHC class II (DQ)-restricted CD4+ and MHC class I-restricted (HLA-A2) CD8+ T cell lines were generated from a single patient with duodenal carcinoma whose primary tumor contained a Val12 mutation when cultured on the immunizing 13-mer peptide or a nested 10-mer peptide [i.e., ras5-14(Val12)], respectively. Evidence is thus provided that vaccination with mutant ras oncogene peptides in adjuvant may induce specific anti-ras cellular immune responses, with no detectable cross-reactivity toward normal proto-ras sequences. Moreover, we have identified for the first time human HLA-A2-restricted, CD8+ CTL epitopes reflecting specific point mutations in the K-ras oncogenes at codon 12 which, in concert with the activation of the CD4+ T cell response, may have important implications for both active and passive immunotherapies in selected cancer patients.
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PMID:Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations. 951 98


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