Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemotherapy failure remains a significant medical problem in the treatment of neoplastic disease and is thought to be due to many different factors including membrane transport, p-glycoprotein in multidrug resistance, glutathione and its related enzymes, topoisomerase II and DNA repair. Glutathione is a major constituent of non-protein thiol and participates in detoxification of chemotherapy and radiation. Thus, glutathione concentration is correlated with sensitivity to alkylating agents and radiation, and increased in resistant cell lines. Buthionine sulfoximine (BSO) is an inhibitor of glutathione biosynthesis and may increase cytotoxicities of alkylating agents, including melphalan and cisplatin, and radiation in sensitive and resistant cell lines. We studied effects on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation by BSO treatment in human stomach cancer cell line (SNU-1) and ovarian cancer cell line (OVCAR-3). The results were as follow: 1) After BSO treatment of 1 mM and 2 mM for 2 days, the intracellular thiol concentration was depleted to 75.7% and 76.2% in SNU-1, and 74.1% and 63.0% in OVCAR-3, respectively. 2) The intracellular thiol concentration in SNU-1 was depleted to 33.4% after BSO 2 mM for only 2 hours incubation and 71.5% after small amount of BSO (0.02 mM) for 2 days. 3) The recovery of intracellular thiol concentration required more than 3 days after BSO removal. 4) BSO inhibited partially the growth of SNU-1 and OVCAR-3. 5) The cytotoxicities of cisplatin and carboplatin were markedly enhanced both in SNU-1 and OVCAR-3 by BSO treatment. 6) The cytotoxicities of radiation was increased in OVCAR-3 and SNU-1 by BSO treatment. Therefore, it is concluded that BSO can deplete effectively the intracellular thiol concentration and enhance the cytotoxicities of cisplatin, carboplatin and radiation.
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PMID:Effects of buthionine sulfoximine treatment on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation in human stomach and ovarian cancer cell lines. 130 72

Irinotecan hydrochloride (CPT-11), topotecan, sobuzoxane, NC-190, and IST-622 are unique topoisomerase inhibitors and are investigational in Japan. CPT-11 is a water-soluble, semisynthetic derivative of camtothecin. CPT-11 shows its anticancer activity by inhibiting topoisomerase I activity, now a target of anticancer agents with major interest. Recent clinical trials reveal that CPT-11 is very effective in the treatment of cancer including lung cancer, cervical cancer, ovary cancer, stomach cancer, colon cancer, and non-Hodgkin's lymphoma. Major dose limiting toxicities are leukopenia and diarrhea, and are dose related. Topotecan is an another semisynthetic derivative of camtothecin and is also topoisomerase I inhibitor. Topotecan has undergone phase I clinical evaluations in USA, europe, and recently in Japan. DLF are leukopenia and neutropenia. Topotecan is more hydrophilic than its parent compound and shows lesser protein binding. Renal excretion appears to be the major route of elimination. Sobuzoxane (MST-16) is a unique derivative of dioxopiperazine, an inhibitor of topoisomerase II. In phase II studies, definite anticancer effects are observed in patients with non-Hodgkin's lymphoma and adult T-cell leukemia/lymphoma. Responses are seen even in pretreated cases. Leukopenia is also dose-limiting. Non-hematologic toxicities are mild and include alopecia and G.I. toxicities. NC-190 is a novel benzophenazine derivative with excellent antitumor activities against murine tumors. NC-190 also inhibits topoisomerase II. Now the drug is an early clinical phase II studies in Japan. Toxicities include bone marrow suppression, transient mild to moderate liver enzyme elevation, alopecia and mild G.I. toxicities. Tumor responses are occasionally encountered. IST-622 is a semisynthetic derivative of chartreusin. The drug is an inhibitor of topoisomerase II (and I in high concentration). IST-622 shows excellent, broad anticancer activity against murine tumors. The drug is well absorbed from small intestine. IST-622 is now in phase I clinical trial in Japan.
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PMID:[Topoisomerase inhibitors developing in Japan]. 842 86

Genistein, an isoflavone, is a specific inhibitor of tyrosine kinase and topoisomerase II. However, its effect on cell growth is unknown. Therefore, we examined the effects of genistein on cell growth and cell cycle progression and compared its effects with other flavonoids. Genistein inhibited in a dose-dependent manner the growth of HGC-27 cells derived from human gastric cancer. Flow-cytometric analysis showed that genistein almost completely arrested the cell cycle progression at G2-M. This effect was reversible when genistein was removed from the culture medium. In contrast, other flavonoids such as flavone, luteolin, and the structurally similar daidzein arrested the cell cycle at G1. Consistent with the flow-cytometric analysis, microscopic observation showed that genistein did not increase the mitotic index, which supposes that genistein may arrest the cell cycle at G2 or early M. These results suggest that the G2-M arrest by genistein is a unique effect among flavonoids.
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PMID:Genistein arrests cell cycle progression at G2-M. 844 13

In contrast to intrinsic drug resistance, induced multidrug resistance in gastric cancer cells has not been well studied. Therefore, two doxorubicin-resistant cell lines, (SNU-1DOX, SNU-16DOX), were derived in vitro from gastric carcinoma cell lines (SNU-1, SNU-16) respectively, and their characteristics were investigated. These resistances were not associated with overexpression of mdrl, multidrug resistance associated protein 1 (MRP1), pi or liver class of glutathione S transferase (GST pi, GSTL), heat shock protein 70 (HSP70), p53 or transglutaminase C (TGC). Levels of p21WAF1 RNA and topoisomerase II protein were decreased in the SNU-16DOX, but not in SNU-1DOX. However, the subsequent enzyme activity of topoisomerase II in SNU-16DOX was not decreased, but rather increased in SNU-16DOX. Furthermore, both resistant cell lines showed lower uptake and higher efflux of doxorubicin and induced cross-resistance to etoposide and vincristine in addition to doxorubicin, indicating a multi-drug resistance phenotype. In summary, we report two gastric carcinoma cell lines exhibiting induced multidrug resistance phenotype and suggest that mdrl, MRP1, GST, TGC, HSP70 and p53 do not play important roles in induced drug resistance in these cell lines. The role of changes in topoisomerase II activity and/or protein is still inconclusive, and p21WAF1 is associated with induced multidrug resistance in the SNU-16DOX gastric carcinoma cell line.
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PMID:Characteristics of human gastric carcinoma cell lines with induced multidrug resistance. 941 98

6-N-Amino analogues of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione] (3b) were synthesized and tested with respect to topoisomerase inhibition, cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN-45 human stomach cancer cells implanted in mice than NB-506.
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PMID:Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino analogues of NB-506. 1034 Jun 2

TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c] quinolin-7-one dihydrochloride), a dual topoisomerase (topo) inhibitor, was developed as an anticancer agent by targeting topo I and topo II and has previously been shown to be effective against lung tumors. In this study, we investigated the cytotoxic activity of TAS-103 in various human cancer cell lines (including gastric, colon, squamous, lung, and breast cancer cells) and the induction of apoptosis by TAS-103. We next established stable transfectants of Bcl-2 in the gastric cancer cell line AZ521 and found that Bcl-2 blocked TAS-103-induced apoptosis. In addition, we demonstrated that the activities of ICE-like and CPP32-like proteases are involved in the signal transduction pathway of TAS-103-induced apoptosis. In summary, TAS-103 is a novel type of anticancer agent with a unique mechanism and could be useful as a lead compound for development of new drugs.
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PMID:A dual topoisomerase inhibitor, TAS-103, induces apoptosis in human cancer cells. 1042 63

Deoxynybomycin was identified as an inducer of p21the/WAF1 gene following screening using a reporter, p21/luciferase. The present study examined its anti-proliferative effect on human tumor cell lines. Deoxynybomycin selectively inhibited growth of human osteoblastic sarcoma Saos-2, gastric cancer TMK-1, and monocytic leukemia THP-1 cells, but did not affect survival of normal human fibroblasts at doses up to 5 microg/ml. Results from an assay system using a panel of 39 human cancer cell lines indicated that deoxynybomycin has selective cytotoxic activity against lung carcinoma cell lines. Deoxynybomycin induced apoptosis in Saos-2, TMK-1, and THP-1 cells as revealed by DNA fragmentation and TUNEL assays. It inhibited topoisomerase I but not topoisomerase II. These results suggest that deoxynybomycin may be useful in cancer chemotherapy.
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PMID:Deoxynybomycin is a selective anti-tumor agent inducing apoptosis and inhibiting topoisomerase I. 1099

Gastric cancer is poorly-responsive to widely used antitumour drugs, the efficacy of which is thought to be related to the capacity of triggering apoptosis. This process requires a series of gene products including a functional p53 protein. We tested the effects of two DNA topoisomerase II poisons, etoposide and doxorubicin, on gastric cancer cell lines with different genetic lesions. We characterised MKN74 and MKN28 cells for p53 gene status and for the expression of p53 and p21 proteins, as well as of topoisomerase II alpha and beta isoforms. After drug treatments, the cells were analysed for drug cytotoxicity, colony forming ability, cell cycle distribution and presence of apoptotic features. Our findings demonstrated that both etoposide and doxorubicin have a potent anti-proliferative effect on gastric cancer cells. Cell death kinetics was different in the two cell lines, MKN74 cells being more sensitive than MKN28 to the drugs. MKN74 cells, although harboring a wt p53 gene, were unable to undergo a massive apoptosis following etoposide treatment. The response of this cell line might be related to the topoisomerase II beta isozyme, the expression of which proved to be undetectable.
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PMID:Effects of topoisomerase II inhibitors on gastric cancer cells characterized by different genetic lesions. 1172 58

From the roots of Salvia prionitis a new tricyclic diterpene, saprirearine (1), a new anhydride-type compound, saprionide (2), a new 7,8-seco-abietane diterpene derivative, 7,8-seco-para-ferruginone (3), and two new 4,5-seco-5,10-friedo-abietane diterpenoids, 4-hydroxysaprorthoquinone (4) and 3-keto-4-hydroxysaprorthoquinone (5), were isolated. Their structures were established by spectroscopic methods and chemical transformation. Compound 3 showed antimicrobial activities against two Gram-positive organisms, Staphylococcus aureus and Micrococcus luteus, with MIC values of 20.0 and 15.0 microM, respectively. Compound 4 showed significant inhibition against topoisomerase Iota with an IC50 value of 0.8 microM. Compound 5 exhibited cytotoxic activities against HL-60 human leukemia and the SGC-7901 and MKN-28 stomach cancer cell lines, with IC50 values of 4.6, 0.2, and 0.3 microM, respectively.
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PMID:Bioactive abietane and seco-abietane diterpenoids from Salvia prionitis. 1214 63

A series of benz[f]indole-4,9-diones, based on the antitumor activity of 1,4-naphthoquinone, were synthesized and evaluated for their cytotoxic activity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer), and also for the inhibition of human DNA topoisomerases I and II activity in vitro. Several compounds including 2-amino-3-ethoxycarbonyl-N-methyl-benz[f]indole-4,9-dione showed a potential cytotoxic activity judged by IC50<20.0 microg/ml in the panel of cancer cell lines. Especially, 2-hydroxy-3-ethoxycarbonyl-N-(3,4-dimethylphenyl)-benz[f]indole-4,9-dione had potential selective cytotoxicity against lung cancer cells (IC50=0.4 microg/ml)) compared to colon (IC50>20.0 microg/ml) and stomach (IC50>20.0 microg/ml) cancer cells. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II activities were used. In a topoisomerase I-mediated relaxation assay using human placenta DNA topoisomerase I and supercoiled pHOTI plasmid DNA, 2-amino-3-ethoxycarbonyl-N-(4-fluorophenyl)-benz[f]indole-4,9-dione had the most potent inhibitory activity among the compounds tested. However, most of the compounds showed only weak inhibition of the DNA topoisomerase II-mediated KDNA (Kinetoplast DNA) decatenation assay, except for 2-amino-3-ethoxycarbonyl-N-(4-methylphenyl)-benz[f]indole-4,9-dione and 2-amino-3-ethoxycarbonyl-N-(2-bromoehtyl)-benz[f]indole-4,9-dione with a moderate inhibitory activity. These results suggest that several active compounds had relatively selective inhibitory activity against toposiomearse I compared to toposiomerase II. No obvious correlation was observed between the cytotoxicity of the individual compound and the inhibitory activity of DNA relaxation and decatenation by topoisomerase I and II, respectively, in vitro.
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PMID:Cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs. 1451 80


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