pyrimidinones and Stomach-Neoplasms

Metastatic progression of tumors is driven by genetic alterations and tumor-stroma interaction. To elucidate the mechanism underlying the oncogene-induced gastric tumor progression, we have developed an organoid-based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN-p53KO) organoids and KRAS

Topics: Animals; Disease Models, Animal; Epithelial-Mesenchymal Transition; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Stomach Neoplasms; Tumor Hypoxia; Tumor Microenvironment; Tumor Suppressor Protein p53

Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated.. Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined.. In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the WEE1 inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the WEE1 inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells.. Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of WEE1 inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Proteins; Cell Line, Tumor; DNA-Binding Proteins; Drug Synergism; Endonucleases; HEK293 Cells; Humans; Immune Checkpoint Inhibitors; Membrane Proteins; Mice; Nucleotidyltransferases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones; Signal Transduction; Stomach Neoplasms

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 13-23% of all GC cases and patients with HER2 overexpression exhibit a poor prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is an effective agent to treat HER2-amplified breast cancer but it failed in gastric cancer (GC) clinical trials. However, the molecular mechanism of lapatinib resistance in HER2-amplified GC is not well studied.. We employed an unbiased, genome-scale screening with pooled CRISPR library on HER2-amplified GC cell lines to identify genes that are associated with resistance to lapatinib. To validate the candidate genes, we applied in vitro and in vivo pharmacological tests to confirm the function of the target genes.. We found that loss of function of CSK or PTEN conferred lapatinib resistance in HER2-amplified GC cell lines NCI-N87 and OE19, respectively. Moreover, PI3K and MAPK signaling was significantly increased in CSK or PTEN null cells. Furthermore, in vitro and in vivo pharmacological study has shown that lapatinib resistance by the loss of function of CSK or PTEN, could be overcome by lapatinib combined with the PI3K inhibitor copanlisib and MEK inhibitor trametinib.. Our study suggests that loss-of-function mutations of CSK and PTEN cause lapatinib resistance by re-activating MAPK and PI3K pathways, and further proved these two pathways are druggable targets. Inhibiting the two pathways synergistically are effective to overcome lapatinib resistance in HER2-amplified GC. This study provides insights for understanding the resistant mechanism of HER2 targeted therapy and novel strategies that may ultimately overcome resistance or limited efficacy of lapatinib treatment for subset of HER2 amplified GC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Mice; Mice, Inbred NOD; Mice, SCID; Pyridones; Pyrimidines; Pyrimidinones; Quinazolines; Receptor, ErbB-2; Stomach Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Although substantial evidence has shown that the mammalian target of rapamycin (mTOR) pathway is an important therapeutic target in gastric cancer, the overall response rates in patients to mTOR inhibitor everolimus have been less than initially expected. We hypothesized that the limited efficacy of everolimus in gastric cancer is due to the activation of extracellular signal-regulated kinase (ERK).. ERK activation was investigated using western blot. The effects of dual inhibition of ERK and mTOR via genetic and pharmacological approaches were determined using cellular assays and xenograft mouse model.. We observed the decreased phosphorylation of mTOR, rS6, and 4EBP1 and increased phosphorylation of ERK and p90RSK in gastric cancer cells exposed to everolimus at clinically relevant concentration. Using both in vitro cell culture assays and in vivo xenograft mouse model, we found that trametinib overcame everolimus resistance by either effectively targeting resistant cells or further enhancing everolimus' efficacy in sensitive cells. Mechanism studies confirmed that trametinib overcame everolimus resistance via specifically inhibiting ERK and regulating ERK-mediated Bcl-2 family proteins in gastric cancer cells.. Inhibition of mTOR pathway can induce "paradoxical" activation of ERK in gastric cancer, and this activation can be reversed by trametinib. Since both drugs are clinically available, our findings might accelerate the initiation of clinical trials on gastric cancer using everolimus and trametinib combination.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Resistance, Neoplasm; Everolimus; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Stomach Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Given the poor prognosis of unresectable advanced gastric cancer (GC), novel therapeutic strategies are needed. The mitogen-activated protein kinase (MAPK) signaling cascade, the most frequently activated pathway in GC, plays an important role in tumorigenesis and metastasis. The MAPK/extracellular signal-regulated kinase (ERK) pathway is an attractive therapeutic target for GC. In this study, trametinib, a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor, reduced the p-ERK level and significantly increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in GC cells, resulting in reduced sensitivity to trametinib. Physapubescin B (PB), a steroidal compound extracted from the plant Physalis pubescens L., inhibited the proliferation and induced the apoptosis of GC cells by suppressing STAT3 phosphorylation. The combination of PB and trametinib suppressed the STAT3 phosphorylation induced by trametinib, and synergistically suppressed gastric tumor growth in vitro and in vivo. Together, these results indicate that inhibition of both MEK and STAT3 may be effective for patients with MAPK/ERK pathway-addicted GC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Withanolides

There is a wide variety of pancreatic neoplasms identified, but the great majority of them are of primary origin. Metastatic disease in the pancreatic parenchyma is quite rare (2-5% of pancreatic malignancies) and most often is quite difficult to differentiate from other primary lesions. Most of the imaging studies fail to give certain discriminating features for metastatic pancreatic neoplasms, contrary to endoscopic ultrasound and tissue sampling, which can provide an accurate diagnosis. In this report, we present a case of a male middle aged man who was admitted to our hospital with painless jaundice and finally was diagnosed with a cutaneous scalp melanoma dispersedly metastasized to the pancreas and upper gastrointestinal tract (stomach and duodenum).

Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cholangiopancreatography, Endoscopic Retrograde; Cranial Irradiation; Duodenal Neoplasms; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Endoscopy, Digestive System; Endosonography; Humans; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Oximes; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Skin Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

Topics: Antineoplastic Agents; Cell Movement; Cell Proliferation; Drug Discovery; High-Throughput Screening Assays; Humans; Isoenzymes; Molecular Structure; p21-Activated Kinases; Protein Kinase Inhibitors; Pyrimidinones; Signal Transduction; Stomach Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

To determine the role of BRAF

Topics: Aged; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Neuroendocrine; Cell Line, Tumor; Colorectal Neoplasms; Exons; Female; Follow-Up Studies; G1 Phase Cell Cycle Checkpoints; Humans; Imidazoles; Intestinal Neoplasms; Male; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Neuroendocrine Tumors; Oximes; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Stomach Neoplasms; Survival Analysis; Tissue Array Analysis; Vemurafenib; Xenograft Model Antitumor Assays

THIS ARTICLE WAS WITHDRAWN BY THE PUBLISHERS IN NOVEMBER 2020.

Topics: Apoptosis; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasm Invasiveness; Pyrimidinones; Stomach Neoplasms; Transfection; Wnt Signaling Pathway

The role of KRAS, when activated through canonical mutations, has been well established in cancer

Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Esophageal Neoplasms; Gene Amplification; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Piperidines; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidines; Pyrimidinones; Stomach Neoplasms

Targeting poly ADP-ribose polymerase (PARP) has been recently identified as a promising option against gastric cancer (GC). However, PARP inhibitors alone achieve limited efficacy. Combination strategies, especially with homologous recombination (HR) impairment, are of great hope to optimize PARP inhibitor's efficacy and expand target populations but remains largely unknown. Herein, we investigated whether a WEE1/ Polo-like kinase 1 (PLK1) dual inhibitor AZD1775 reported to impair HR augmented anticancer activity of a PARP inhibitor olaparib and its underlying mechanisms.. GC cell lines and in vivo xenografts were employed to determine antitumor activity of PARP inhibitor combined with WEE1/PLK1 dual inhibitor AZD1775. Western blot, genetic knockdown by siRNA, flow cytometry, Immunohistochemistry were performed to explore the underlying mechanisms.. AZD1775 dually targeting WEE1/PLK1 enhanced effects of olaparib on growth inhibition and apoptotic induction in GC cells. Mechanistic investigations elucidate that WEE1/PLK1 blockade downregulated several HR-related proteins and caused an accumulation in γH2AX. As confirmed in both GC cell lines and mice bearing GC xenografts, these effects were enhanced by AZD1775-olaparib combination compared to olaparib alone, suggesting that disrupting HR-mediated DNA damage repairs (DDR) by WEE1/PLK1 blockade might be responsible for improved GC cells' response to PARP inhibitors. Given the DNA damage checkpoint as a primary target of WEE1 inhibition, our data also demonstrate that AZD1775 abrogated olaparib-activated DNA damage checkpoint through CDC2 de-phosphorylation, followed by mitotic progression with unrepaired DNA damage (marked by increased pHH3-stained and γH2AX-stained cells, respectively).. PARP inhibitor olaparib combined with WEE1/PLK1 dual inhibitor AZD1775 elicited potentiated anticancer activity through disrupting DDR signaling and the DNA damage checkpoint. It sheds light on the combination strategy of WEE1/PLK1 dual inhibitors with PARP inhibitors in the treatment of GC, even in HR-proficient patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; DNA Damage; DNA Repair; Drug Synergism; Female; Humans; Mice; Nuclear Proteins; Phthalazines; Piperazines; Polo-Like Kinase 1; Poly(ADP-ribose) Polymerase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines; Pyrimidinones; Stomach Neoplasms; Xenograft Model Antitumor Assays

Based on the mechanisms by which Wee1 inhibitor and cisplatin played their own role, a promising strategy of Wee1 inhibitor combined with cisplatin was proposed, which was investigated in gastric cancer (GC). Either Wee1 inhibitor AZD1775 or cisplatin alone had a certain inhibitory effect on

Topics: Animals; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cisplatin; DNA Damage; Enzyme Inhibitors; Mice; Nuclear Proteins; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Rabbits; Stomach Neoplasms

Resistance to trastuzumab, which specifically target HER2-positive breast and gastric cancer, can develop ultimately in cancer patients. However, the underlying mechanisms of resistance in gastric cancer have not been fully elucidated. Here, we established trastuzumab-resistant MKN45 and NCI N87 gastric cancer sublines from their parental cells. The resistant cells exhibited characteristics of epithelial-mesenchymal transition (EMT) and acquired higher migratory and invasive capacities. To exploit the activated pathways and develop new strategies to overcome trastuzumab resistance, we investigated MKN45 and MKN45/R cells via label-free quantitative proteomics, and found pathways that were altered significantly in MKN45/R cells, with the Wnt/β-catenin pathway being the most significant. We further confirmed the activation of this pathway by detecting its key molecules in MKN45/R and NCI N87/R cells via Western blot, in which Wnt3A, FZD6, and CTNNB1 increased, whereas GSK-3β decreased, manifesting the activation of the Wnt/&-catenin pathway. Correspondingly, inhibition of Wnt/β-catenin pathway by ICG-001, a specific Wnt/&-catenin inhibitor, preferentially reduced proliferation and invasion of trastuzumab-resistant cells and reversed EMT. Concurringly, CTNNB1 knockdown in stable cell lines potently sensitized cells to trastuzumab and induced more apoptosis. Taken together, our study demonstrates that the Wnt/β-catenin pathway mediates trastuzumab resistance, and the combination of Wnt/β-catenin inhibitors with trastuzumab may be an effective treatment option.

Topics: Antineoplastic Agents, Immunological; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Neoplasm Invasiveness; Proteomics; Pyrimidinones; Stomach Neoplasms; Trastuzumab; Wnt Signaling Pathway

ICG-001, a small molecule, binds CREB-binding protein (CBP) to disrupt its interaction with β-catenin and inhibits CBP function as a co-activator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin signaling pathway, ICG-001 has been used in some tumor types to exert its anticarcinogenic effect. Here, we examined ICG-001 and its potential role as a therapeutic in gastric cancer (GC).. The gastric cancer cell lines SGC-7901, MGC-803, BGC-823 and MKN-45 were used in vitro and in vivo. The abilities of cell proliferation, tumor sphere formation, metastasis, tumorgenesis and chemoresistance to chemotherapy drugs in vitro were evaluated by MTT assay, colony formation assay, flow cytometry, migration and invasion assay, and tumor spheres culture. The in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. Alterations at RNA and protein levels were followed by qRT-PCR, western blot, coimmunoprecipitations and immunofluorescence assay.. In this study, we showed that ICG-001 significantly inhibited growth and metastasis of multiple GC cell lines, induced cell apoptosis, and augmented in vitro tumor spheres suppression when used in combination with chemotherapy drugs probably through robustly blocking association of β-catenin with CBP and N-cadherin, but promoting association of β-catenin with P300 and E-cadherin, instead of altering the distribution and expression of β-catenin.. Our findings suggest that ICG-001 suppresses GC cell line growth, metastasis and reduces its stem cell-like properties and chemoresistance, indicating that ICG-001 is a potentially useful small molecule therapeutic for GC.

Topics: Animals; Apoptosis; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; E1A-Associated p300 Protein; Epithelial-Mesenchymal Transition; Humans; Mice; Neoplastic Stem Cells; Pyrimidinones; Stomach Neoplasms; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Chemotherapeutic insensitivity is a main obstacle for effective treatment of gastric cancer (GC), the underlying mechanism remains to be investigated. Metastasis-associated in colon cancer-1 (MACC1), a transcription factor highly expressed in GC, is found to be related to chemotherapy sensitivity. Monocarboxylate transporter 1 (MCT1), a plasma membrane protein co-transporting lactate and H

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Survival; Cisplatin; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Monocarboxylic Acid Transporters; Multivariate Analysis; Prognosis; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Stomach Neoplasms; Symporters; Thiophenes; Trans-Activators; Transcription Factors

Wee1 is a member of the Serine/Threonine protein kinase family and is a key regulator of cell cycle progression. It has been known that WEE1 is highly expressed and has oncogenic functions in various cancers, but it is not yet studied in gastric cancers. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in gastric cancer. At first, higher expression levels of WEE1 with lower survival probability were determined in stage 4 gastric cancer patients or male patients with accompanied lymph node metastasis. To determine the function of WEE1 in gastric cancer cells, we determined that WEE1 ablation decreased the proliferation, migration, and invasion, while overexpression of WEE1 increased these effects in gastric cancer cells. We also validated the clinical application of WEE1 targeting by a small molecule, AZD1775 (MK-1775), which is a WEE1 specific inhibitor undergoing clinical trials. AZD1775 significantly inhibited cell proliferation and induced apoptosis and cell cycle arrest in gastric cancer cells, which was more effective in WEE1 high-expressing gastric cancer cells. Moreover, we performed combination treatments with AZD1775 and anti-cancer agents, 5- fluorouracil or Paclitaxel in gastric cancer cells and in gastric cancer orthotopic-transplanted mice to maximize the therapeutic effect and safety of AZD1775. The combination treatments dramatically inhibited the proliferation of gastric cancer cells and tumor burdens in stomach orthotopic-transplanted mice. Taken together, we propose that WEE1 is over-expressed and could enhance gastric cancer cell proliferation and metastasis. Therefore, we suggest that WEE1 is a potent target for gastric cancer therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Mice; Mice, Nude; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Transplantation; Nuclear Proteins; Paclitaxel; Phenotype; Prognosis; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Stomach Neoplasms

Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEK1 gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1‑mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.

Topics: Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Humans; Lapatinib; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mutation; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quinazolines; Receptor, ErbB-2; Stomach Neoplasms

The histamine H2-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day po. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 mg/kg/day po treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a dose-related and time-dependent neuroendocrine ECL-cell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 21-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 mg/kg SK&F 93479 po. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat.

Topics: Animals; Carcinogens; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Hydrogen-Ion Concentration; Hyperplasia; Imidazoles; Male; Mice; Omeprazole; Pyrimidinones; Rats; Stomach Neoplasms

Imidazole and isocytosine-furan derivatives inhibited H2 receptor activity in HGT-1 cells, in accordance with the following relative potencies (IC50 = 2.3 microM cimetidine as reference): SKF 93479 = cimetidine = 100 greater than metiamide = 62 greater than SKF 92408 = 2 greater than SKF 91581 = 0.07). The Schild plot for cimetidine was linear (slope = 0.97) with a pA2 value of 6.72 +/- 0.12 (Ki = 0.18 microM cimetidine), suggesting competitive inhibition. Preincubation of HGT-1 cells for 10 min with H2 antagonists at 2 microM concentration resulted in 90-100% inactivation (SKF 93479 and oxmetidine) and 65% inactivation (ranitidine) which persisted for 30 min, even after a washout period. Accordingly, the kinetics of 2 microM [3H] SKF 93479 binding to HGT-1 cells revealed a half-time for association of 10 min and a dissociation half-time of 120 min. There was a good correlation between the kinetics and relative potencies of cimetidine and SKF 93479 in inhibiting H2 receptor activity in purified plasma membranes (40 nM) as well as in intact HGT-1 cells preincubated for 2 hr with SKF 93479 before histamine addition (45 nM). Chronic treatment of HGT-1 cells for 6 days with 2 microM SKF 93479 specifically blocked H2 receptor activity since cyclic AMP generation induced by other hormones and agents such as VIP, glucagon, GIP and sodium fluoride was unaltered. In contrast, short term and chronic treatment by cimetidine was readily reversible. The isocytosine-furan derivative SKF 93479 differs from the imidazole analogue cimetidine by its apparent irreversible action, due to the slow onset of association from HGT-1 cells. The isocytosine ring in SKF 93479 and oxmetidine seems to play a preponderant role in their apparent long-lasting, irreversible actions.

Topics: Cell Line; Cimetidine; Cyclic AMP; Histamine; Histamine H2 Antagonists; Humans; Kinetics; Pyrimidinones; Receptors, Cell Surface; Receptors, Histamine; Receptors, Histamine H2; Receptors, Vasoactive Intestinal Peptide; Stomach Neoplasms; Structure-Activity Relationship; Vasoactive Intestinal Peptide

Topics: Aged; Cimetidine; Gastric Acid; Histamine H2 Antagonists; Humans; Middle Aged; Nitroso Compounds; Pyrimidinones; Ranitidine; Stomach Neoplasms

Homologous loss of histamine H2-receptor activity (cAMP generation) was observed after short-term (10-20 min) or chronic treatment (6 days) of cultured HGT-1 cells with histamine (desensitization) or the H2-receptor antagonist SKF 93479. This inactivation process was not observed when HGT-1 cells were exposed to the classical H2-antihistamine cimetidine. The data show: (1) that the compound SKF 93479 has a very prolonged inhibitory action on histamine receptor activity, suggesting an irreversible interaction between the antagonist and the receptor; (2) that cimetidine is a reversible H2-receptor antagonist which can be removed without changing the the efficacy and the potency of histamine on gastric cells; (3) that the H2-receptor antagonists cimetidine and SKF 93479 specifically block histamine H2-receptor activity in HGT-1 cells since cAMP generation induced by other hormones such as vasoactive intestinal peptide (VIP), glucagon or gastric inhibitory peptide (GIP) was unchanged after treatment; (4) the first evidence for time-dependent (half-life: 20 min) desensitization of gastric H2-receptors.

Topics: Cell Line; Cimetidine; Histamine; Histamine H2 Antagonists; Humans; Pyrimidinones; Receptors, Histamine; Receptors, Histamine H2; Stomach Neoplasms; Vasoactive Intestinal Peptide

Topics: Adult; Aged; Female; Fluorouracil; Furans; Humans; Lymphatic Metastasis; Male; Middle Aged; Preoperative Care; Pyrimidinones; Stomach; Stomach Neoplasms; Tegafur