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

EAP (etoposide, doxorubicin, cisplatin), a chemotherapeutic combination given over 8 days, proposed by German investigators in cancer of the stomach, has been considered to be too toxic by others. A positive experience with a similar regimen (PAV) developed by the SAKK given over 3 days in small cell lung cancer led us to test it in gastric adenocarcinoma. 41 patients with metastatic gastric cancer were enrolled in the study and 38 were evaluable for response and toxicity. One complete response and 12 partial responses were recorded, giving a response rate of 34% (95% confidence interval (CI) 20-51%). Median progression-free and overall survival were 3.4 and 6.3 months, respectively. Haematotoxicity was the leading toxicity with 34 (90%) and 17 (45%) grade III-IV neutropenia and thrombocytopenia, respectively. Despite this high rate of granulocytopenia, only six episodes of non-fatal febrile neutropenia were observed. Other toxicities were relatively easy to manage with infrequent grade III-IV occurrences. We conclude that PAV is active in gastric cancer and seems to be better tolerated than EAP.
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PMID:Cisplatin, doxorubicin and etoposide (PAV) in advanced gastric carcinoma: the SAKK experience. Swiss Group for Clinical Cancer Research (SAKK). 1007 Mar 22

The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growth-inhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials.
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PMID:FK317, a novel substituted dihydrobenzoxazine, exhibits potent antitumor activity against human tumor xenografts in nude mice. 1008 92

Marimastat (BB-2516) is the first matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed phase I and II trials. Phase I studies involved healthy volunteers who received short courses of marimastat; these were well tolerated. Symptoms experienced by many patients with various malignancies included severe joint and muscle pain which were debilitating in >60% of patients at doses >50 mg bid. These symptoms were reversible on discontinuation of the drug, and their incidence has been decreased by using marimastat 10 mg bid, the dose used in current studies. Phase II studies involved the use of serum tumor markers as surrogate indicators of antitumor activity. Six studies in colorectal, ovarian, and prostate cancer have been completed and pooled analysis has demonstrated a dose-dependent biological effect (as defined by the authors); 58% of patients respond at doses >50 mg bid. Effects on tumor markers were associated with increased survival. Small phase II studies have suggested potential activity in pancreatic and gastric cancer and have demonstrated the safety of combining cytotoxic chemotherapeutic agents with marimastat. Ongoing phase III studies are investigating the effects of marimastat in addition to chemotherapy in the treatment of small cell lung cancer and pancreatic and gastric carcinoma.
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PMID:Marimastat (BB2516): current status of development. 1035 60

Recently, the PTEN/MMAC1 gene encoding a protein phosphatase (PP) and the PPP2R1B gene encoding a regulatory subunit of PP2A have been identified as being genetically altered in several types of human cancers, indicating that aberrations of intracellular signaling pathways via PPs are involved in human carcinogenesis. Here we report genetic alterations of the PPP1R3 gene located at chromosome 7q31, which encodes regulatory subunit 3 of PP1, in various types of human cancers. Mutations of the PPP1R3 gene were detected in 5 of 33 (15%) non-small cell lung cancer cell lines and 2 of 38 (5%) primary non-small cell lung cancers and were also observed in cell lines derived from a small cell lung cancer, an ovarian cancer, a colorectal cancer, and a gastric cancer. Mutations were widely dispersed in the coding region of the PPP1R3 gene. Three of the 11 detected mutations were nonsense mutations, whereas the remaining ones were missense mutations, most of which caused substitutions of evolutionarily conserved amino acids. These findings suggest that PPP1R3 alteration plays a role in the development of human cancers and that PPP1R3 could act as a tumor suppressor gene.
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PMID:Alterations of the PPP1R3 gene in human cancer. 1048 48

The camptothecins are a maturing class of anticancer agents. In this article, we review the pharmacology and antitumor activity of the camptothecin analogues that are approved for clinical use and those investigational agents undergoing clinical evaluation. Camptothecin is a naturally occurring cytotoxic alkaloid that has a unique intracellular target, topoisomerase I, a nuclear enzyme that reduces the torsional stress of supercoiled DNA during the replication, recombination, transcription, and repair of DNA. Topotecan and irinotecan are synthetic analogues designed to facilitate parenteral administration of the active lactone form of the compound by introducing functional groups to enhance solubility. They are now well-established components in the chemotherapeutic management of several neoplasms. Topotecan has modest activity in patients treated previously with ovarian and small cell lung cancer and is currently approved for use in the United States as second-line therapy in these diseases. Preliminary evidence of activity against hematological malignancies is also promising. Irinotecan is a prodrug that undergoes enzymatic conversion to the biologically active metabolite 7-ethyl-10-hydroxy-camptothecin. It is presently the treatment of choice when used in combination with fluoropyrimidines as first-line therapy for patients with advanced colorectal cancer or as a single agent after failure of 5-fluorouracil-based chemotherapy. Encouraging preliminary results suggest that irinotecan may have an increasing role in the treatment of other solid tumors, including small and non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer, and malignant gliomas. Several additional camptothecin analogues are in various stages of clinical development, including 9-aminocamptothecin, 9-nitrocamptothecin, 7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin, exatecan mesylate, and karenitecin. Efforts to further optimize therapeutic effectiveness through drug delivery strategies that prolong tumor exposure to these S phase-specific agents, such as improving oral bioavailability through structure modification and innovative formulation approaches, alternative parenteral dosage forms, and administration schedules, are being actively pursued. Combining camptothecins with other anticancer drugs and treatment modalities, as well as gaining a better understanding of the factors contributing to tumor sensitivity and resistance, continues to be the object of considerable interest.
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PMID:Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. 1189 91

Tumor angiogenesis is essential for tumor growth and metastasis formation. Luminex methodology was used to measure the levels of four angiogenic cytokines in cell culture medium and in the plasma of mice bearing human tumors. We obtained plasma and conditioned culture medium from 12 different human tumor cell lines. Tumor necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-beta) were determined by the Luminex FlowMetrix assay. VEGF, TNF-alpha, and bFGF were undetectable in non-tumor-bearing animals. HS746T gastric cancer and Caki-1 renal cell cancer cells in culture produced high levels of VEGF (1000 and 450 pg/10(6) cells, respectively). High levels of TGF-beta were produced by HS746T gastric carcinoma and Calu-6 non-small-cell lung carcinoma (3000 and 1000 pg/10(6) cells, respectively). Caki-1 renal cell carcinoma and Calu-6 non-small-cell lung carcinoma cells in culture produced high levels of bFGF (42 and 10 pg/10(6) cells, respectively). Caki-1, SW2 SCLC, HCT-116 and HT-29 colon tumors produced high plasma levels of VEGF (200, 220, 42, and 151 pg/ml, respectively) and TGF-beta (31, 36, 45, 32 pg/ml, respectively). A positive linear correlation was seen between tumor volume and VEGF in SW2 (r=0.87) and Caki-1 (r=0.47) tumors, and a moderate correlation in HCT116 tumors (r=0.3). Angiogenic profiles in the plasma of nude mice bearing human tumors may be useful to identify appropriate biomarkers for antiangiogenic therapy, as diagnostic and prognostic tools, and to monitor the responses of individual tumors to antiangiogenic therapy.
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PMID:Circulating angiogenic growth factor levels in mice bearing human tumors using Luminex Multiplex technology. 1272 60

Marimastat [BB 2516, TA 2516] is a second-generation anticancer drug originally developed with British Biotech in Europe and North America. It is an orally active metalloprotease inhibitor of the same class as batimastat, and is the first compound in this class to have completed a pivotal clinical trial. Marimastat also has collagenase- and angiogenesis-inhibiting properties. British Biotech and Schering-Plough have signed an agreement enabling the latter to develop and market marimastat in North America and Europe. Under the terms of the agreement, British Biotech will receive an up-front license fee of 4 million US dollars and a 4 million US dollars equity investment in British Biotech by Schering-Plough. Schering-Plough holds rights to marimastat in all countries other than the Far East and Japan. The two companies are considering asking the FDA for accelerated approval in gastric cancer based on the secondary endpoint of progression-free survival. Marimastat is licensed to Tanabe Seiyaku in Japan, where phase II clinical trials are underway for the treatment of advanced gastric cancer and lung cancer. Further phase II trials in other tumour types are planned. The commencement of phase II trials in Japan resulted in a milestone payment of 5 million US dollars to British Biotech from Tanabe Seiyaku. Tanabe Seiyaku also holds rights to marimastat in the Far East. Marimastat has been in pivotal phase III trials in glioblastoma, breast, ovarian and small and non-small cell lung cancer, but these trials have all been discontinued because marimastat failed to show superior efficacy over either standard chemotherapy or placebo. Results from the marimastat 131 trial in patients with glioblastoma, for example, indicated that marimastat was no better than placebo at prolonging survival in these cancer patients. In June 2000, when the results of this study were released, shares in British Biotech fell 21.6% to just 19 pence per share. The phase III trial in small cell lung cancer was discontinued when the results of study 140 were released in February 2001 showing that marimastat was not significantly more effective than placebo in prolonging the survival of small cell lung cancer patients. The results of this study were consistent with those reported in study 117. British Biotech has also conducted a phase III placebo-controlled study of marimastat as monotherapy in patients with inoperable gastric cancer at 37 centres throughout Europe. Results from this trial indicated that it did not achieve its primary endpoint of a statistically significant survival benefit over placebo. However, data collected during the follow-up period have shown increases in survival benefit in the treatment group in addition to a significant improvement in disease-free progression, the secondary endpoint of the trial. Development of marimastat for this indication is ongoing. In May 2001, British Biotech reported data from an interim analysis of results from the remaining phase III study in pancreatic cancer (study 183) that showed no patient benefit for marimastat recipients compared with gemcitabine. However, these results did not meet stopping criteria and the study continues under the guidance of Schering-Plough. The multicentre trials are being conducted in the US, Canada and the European Union. The phase III trial of marimastat in combination with carboplatin that was being conducted in patients with ovarian cancer was discontinued because British Biotech realised that the design of the trial was insufficient for registration in the US or Europe. Altogether, seven phase III studies have failed to meet their primary end-points, but the company has stated that the effectiveness of marimastat is more likely to be seen in patients with less advanced disease. Phase II trials in prostate and head and neck cancer are still underway in the US.
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PMID:Marimastat: BB 2516, TA 2516. 1275 9

On the basis of data of the Human Genome Project, it was embraced the newest information about the gene content of the human genome, the disease genes, the parasitic DNA, the single nucleotide polymorphisms, the repeat sequences, the cytoskeletons, the regulation of cell proliferation, and their medical consequences. The applicability of the acquaintance with the human genome in pathology is presented with a few examples of our own. The significance of the single nucleotide polymorphisms in susceptibility to, or protection from, a host of disease is illustrated by the example of the allele variation of Apo-E gene. The copy number of the N-myc gene in neuroblastomas and HER2/neu gene in breast carcinomas was determined with quantitative PCR techniques. The monoclonally increased abnormal p53 protein expression was found in small cell lung cancer (in 90% frequency), in oro-pharyngeal carcinomas (82%), in esophageal squamous cell carcinomas (59%) in stomach cancer (33%), in colon carcinomas (27%) and in soft tissue sarcomas (13%). These data advert to the fact that the mutation of the p53 gene is much more frequent in those tumors in which the basic tissue is directly exposed to with the environmental carcinogens. It is now known, that near the repetitive sequences, gene rearrangement can more easily be evolve. Finally, we have determined the conditions of the accomplishment of the molecular pathological diagnosis: (1) It is applicable, when the classic morphology does not eventuate a conclusive result. (2) Well known and validated gene alterations are admissible to diagnostic purpose. (3) Only standard methods are applicable along with positive and negative controls. (4) The result has to correlate with the morphological picture, the immunohistochemical profile and the clinical data. (5) It is necessary to be able to appropriately interpret the molecular biological result, which is then incorporated in the pathological report. (6) The ethical, legal and social consequences must be considered.
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PMID:[Effect of learning about the human genome on the development of pathology]. 1497 56

The pattern of inhibition of cell proliferation and cytotoxicity in vitro by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (Naph-DNB) was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the trypan blue (TB) dye exclusion assays in nine murine and human cell lines of different histologic origin. In our culture conditions Naph-DNB showed a good inhibiting activity against all cell lines tested, with IC(50)s varying within a narrow micromolar range of concentrations (2.0 +/- 0.2-14.3 +/- 2.3 microM). In particular, murine P388 (leukemia), human Jurkat (leukemia), A2780, PA-1 (ovarian carcinoma) and Saos-2 (osteosarcoma) cells showed the highest sensitivity to the inhibiting potential of Naph-DNB, while human A549 (non small cell lung cancer, NSCLC), MDA-MB-231 (breast cancer), HGC-27 (gastric cancer) and HCT-8 (colon carcinoma) were the least sensitive cell lines. Moreover, the analysis of cytotoxicity of Naph-DNB evaluated by the TB test showed that this compound was able to kill cells with IC(50)s ranging from 1.7 to 39.2 microM. The study of the induction of apoptosis was carried out by 4'-6-diamidine-2'-phenylindole (DAPI) staining of segmented nuclei, western blot of p53 protein and TdT-mediated dUTP-biotin nick end labeling (TUNEL) method, while the interaction with DNA was evaluated through the analysis of interstrand cross-link (ISCL) formation. Our data show that in all cell lines tested Naph-DNB was able to form ISCLs, to upregulate p53 oncosuppressor-protein and to induce apoptosis. Moreover, TUNEL analysis also suggested that Naph-DNB, similarly to other anticancer drugs, was able to block cells in the G (0)/ G (1) phase of the cell cycle. In conclusion our data suggest that Naph-DNB may be an effective novel lead molecule for the design of new anticancer compounds.
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PMID:Preliminary evaluation in vitro of the inhibition of cell proliferation, cytotoxicity and induction of apoptosis by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene. 1529 6

Notch signaling pathway maintains stem cells through transcriptional activation of HES/HEY family members to repress tissue-specific transcription factors. Here, comparative integromic analyses on HES/HEY family members were carried out. HES3 gene encodes two isoforms due to alternative promoters. Complete coding sequence of HES3 variant 2 was determined by curating CX755241.1 EST. Refined phylogenetic analysis using HES3 variant 2 instead of variant 1 revealed that mammalian bHLH transcription factors with Orange domain were grouped into HES subfamily (HES1, HES2, HES3, HES4, HES5, HES6, HES7) and HEY subfamily (HEY1, HEY2, HEYL, HESL/HELT, DEC1/BHLHB2, DEC2/BHLHB3). Eight amino-acid residues were added to the C-terminal WRPW motif in human HES3 due to lineage specific T to G nucleotide change at stop codon of chimpanzee, rat, and mouse HES3 orthologs. HES1 and HES3 were expressed in undifferentiated embryonic stem (ES) cells. HES1 was also expressed in fetal tissues, and regenerating liver. HES1, HEY1 and HEY2 were expressed in endothelial cells. HES1, HES4 and HES6 were expressed in gastric cancer, HES1 and DEC1 in pancreatic cancer, HES1, HES2, HES4, HES6 and DEC2 in colorectal cancer. HES6 was also expressed in other tumors, such as brain tumors, melanoma, small cell lung cancer, retinoblastoma, ovarian cancer, and breast cancer. Double NANOG-binding sites, CSL/RBPSUH-binding site and TATA-box in HES1 promoter, NANOG-, SOX2-, POU5F1/OCT3/OCT4-binding sites and TATA-box in HES3 promoter, double CSL-binding sites in HES5 promoter, SOX2-, POU-binding sites and TATA-box in HES6 promoter, and CSL-binding site in HEY1, HEY2 and HEYL promoters were evolutionarily conserved. However, double CSL-binding sites in mouse Hes7 promoter were not conserved in human HES7 promoter. Together these facts indicate that HES1 and HES3 were target genes of the ES cell-specific network of transcription factors, and that HES1, HES5, HEY1, HEY2 and HEYL were target genes of Notch signaling pathway.
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PMID:Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. 1761 4


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