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)

There is no chemotherapy considered to be standard treatment for advanced gastric cancer worldwide, and there is no consensus as to whether combination or single agent therapy is preferred. In the phase I portion, a dose-escalation study of cisplatin (CDDP) combined with TS-1, new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). TS-1 was given orally at 40 mg/m2 bid for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg/m2, depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg/m2, because 33.3% of patients (2/6) developed DLTs; mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg/m2. In the phase II portion, 19 patients including 6 patients of the RD phase I portion were evaluated. The median administered courses was 4 (range: 1-8). The incidence of haematological and non-haematological toxicities (> or = grade 3) was 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95%) confidence interval: 54.9 (90.6%), and the median survival days were 383. This regimen is considered to be active against AGC with acceptable toxicity. In addition, currently, a randomized phase III study (JCOG 9912) for AGC patients not treated previously with chemotherapy is underway in Japan. It compares three arms: 5-FU alone, TS-1 alone and CPT-11 with CDDP therapy. We also initiated a randomized phase III study comparing TS-1 alone, and with CDDP for AGC. From those two phase III studies, we may be able to evaluate the clinical benefit of TS-1 in combination with CDDP versus TS-1 single, or 5-FU combined with CDDP therapy in terms of survival benefits and improving the QOL for AGC patients.
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PMID:[Combination chemotherapy of TS-1 +cisplatin for inoperable gastric cancer]. 1557 Sep 20

The effectiveness of chemotherapy for metastatic gastric cancer has been already revealed. But a standard chemotherapy has not been established yet. New agents such as TS-1, CPT-11 and taxanes are improving the response rates and also the survivals for gastric cancer. Including these new drugs, several randomized phase III trials are ongoing in Japan. In the near future, the candidate for standard resume will be sent abroad. In this article, we described the current state of CPT-11 combined chemotherapy for gastric cancer. Among various CPT-11- combined chemotherapy, CPT-11 + TS-1 is the most effective and less toxic treatment.
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PMID:[CPT-11 combined chemotherapy for metastatic gastric cancer]. 1557 Sep 23

Epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. In the experiments described here using AGS gastric cancer cells, SN38 (the active metabolite of CPT-11) induced tyrosine phosphorylation of EGFR within 5 min, and this was followed by the induction of transcripts and/or proteins of heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-alpha, and interlukin-8 (IL-8). SN38 also activates nuclear factor-kappaB and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib (Iressa, ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.
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PMID:Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. 1572 19

The epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. The findings reported here demonstrate that SN38 (the active metabolite of CPT-11) induces the tyrosine phosphorylation of EGFR within 5 min, followed by the induction of transcripts and/or proteins of the heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-alpha, and interlukin-8 (IL-8) in AGS gastric cancer cells. SN38 also activates nuclear factor-kappa B and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib ("Iressa", ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.
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PMID:Gefitinib ("Iressa", ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. 1572 63

With the availability of new chemotherapeutic agents such as S-1 and paclitaxel (TXL) for advanced gastric cancer, the development of a strategy for a third-line chemotherapy is urgently needed. We treated a patient with recurrent gastric cancer using TXL, irinotecan hydrochloride (CPT-11) and cisplatin (CDDP) as a third-line chemotherapy. The patient was a 46-year-old man who had undergone total gastrectomy for advanced gastric cancer with lymph node metastases. For postoperative recurrence, he was first treated with S-1 as an outpatient; however, tumor markers increased, and para-aortic lymph node metastasis was revealed by thoracic and abdominal CT scan. A second-line therapy with weekly TXL and CDDP was then added, but resulted in PD. Therefore, combination chemotherapy with TXL, CPT-11 and CDDP was started biweekly as a third-line chemotherapy. TXL (80mg/m2) was infused over 1 hour after short premedication, followed by CPT-11 (25mg/m2) and CDDP (15mg/m2) over 30 min. After 6 courses of this therapy, the serum AFP and TPA returned to normal, and the size of the metastatic para-aortic lymph nodes reduced. The effect of this therapy was judged as PR and the toxicity of this regimen was tolerable. The patient has undergone 10 courses of this therapy and is maintaining a clinical PR. The patient was able to resume his full social activities. TXL, CPT-11 and CDDP combination chemotherapy may be useful and safe for patients with recurrent gastric cancer, even after first-or second-line therapy with S-1 or taxanes.
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PMID:Third-line chemotherapy with paclitaxel, irinotecan hydrochloride and cisplatin for recurrent gastric cancer: a case report. 1578 61

A 58-year-old man with gastric cancer who had undergone distal gastrectomy on February 8, 2001 was revealed to have anorexia, and was diagnosed with a local recurrence in anastomosis by upper GI examination in August 2003. In September 2003, he was given combination chemotherapy with TS-1 50 mg/m2 (days 1-14) and CPT-11 80 mg/m2 (days 1, 8) every 3 weeks. A complete response (CR) was confirmed by endoscopy in December 2003. At present, he has been receiving chemotherapy with only TS-1 50 mg/m2 as a maintenance therapy and continuing CR. However, a trial of combination therapy with TS-1 plus CPT-11 is ongoing, and this combination chemotherapy may well achieve a high response rate. Because the adverse events of this chemotherapy have been mild and tolerable in some of our cases, this regimen is considered very useful.
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PMID:[Complete response of recurrent gastric cancer to chemotherapy with TS-1 and CPT-11--a case report]. 1598 29

We report a case of a 59-year-old man with advanced gastric cancer. Distal gastrectomy with lymph node dissection (D1) was performed. Pathological staging was IV (T3N1CY1), and the operation resulted in curability C. The serum CA19-9 level before the operation was 201 U/ml, and it did not normalize 3 months after the operation. Postoperative chemotherapy (TS-1, 100 mg/day) was performed. Because the tumor markers such as CEA and CA19-9 level elevated 5 months after the operation, triweekly docetaxel therapy and TS-1 administration (days 1-14) were performed. We disbontinued this therapy after 2 courses due to adverse reactions, such as leukopenia (grade 4) and liver dysfunction (grade 2). Peritoneal dissemination was diagnosed by the appearance of ascites and thickness of the peritoneum 11 months after the operation. So the patient was treated with a biweekly combination chemotherapy of irinotecan (CPT-11 60 mg/m2) and cisplatin (CDDP 30 mg/m2). Eight courses of this therapy induced partial remission and normalization of the serum CEA level. No major adverse reaction to this therapy was observed. The partial remission and good patient's QOL were achieved during follow-up 7 months after the administration of CPT-11 plus CDDP. This case suggests that patients with recurrent peritoneal dissemination of gastric cancer could benefit from CPT-11 with CDDP combination therapy as a second-line or third-line treatment.
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PMID:[A case of peritoneal dissemination of gastric cancer successfully treated by irinotecan combined with cisplatin]. 1598 30

The interaction between CPT-11 and oxaliplatin, a new platinum derivative that has a great antitumor activity against colon cancer, has not been determined in gastric cancer cells. In this study, we investigated in vitro cytotoxic activity of oxaliplatin alone or in combination with SN-38, an active metabolite of CPT-11, using different exposure schedules in three human gastric cancer cell lines (AZ-521, MKN-45, and NUGC-4). Cytotoxicity was determined by WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation was evaluated by flow cytometry. In 24-h exposure, simultaneous administration of oxaliplatin and SN-38 showed a synergistic effect in AZ-521 and NUGC-4 cells, and an additive effect in MKN-45 cells. Greater than additive effects were observed in all of the cell lines when cells were treated with oxaliplatin followed by SN-38, whereas such effects were observed only in NUGC-4 cells in the reverse sequence. Flow cytometric analyses at IC(50) indicated that apoptosis was most prominent in simultaneous exposures with accumulation of cells in both G(0)/G(1) and S phases. These results suggest that SN-38 may kill the cells recovering from the G(1) block produced by oxaliplatin as they progress into the S phase. Simultaneous administration appears most active in gastric cancer cell lines. These results may provide important information for a clinical trial of oxaliplatin and CPT-11 combination for patients with gastric cancer.
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PMID:Synergistic interaction between oxaliplatin and SN-38 in human gastric cancer cell lines in vitro. 1607 75

Chemotherapies for recurrent gastric cancer have not yet been established. Here we report a case of type 4 gastric cancer associated with lymphangitis carcinomatosis which became refractory to the previous chemotherapies. The case was a 40-year-old woman. She had been diagnosed with gastric cancer after a Krukenberg tumor operation. Chemotherapies (TS-1 plus CDDP as first-line, and TS-1 plus taxanes as second-line) were performed, and a partial response was achieved. Disease activity has been well controlled until this time. Since recurrence of left pleural effusion and lymphangitis carcinomatosis was recognized, we changed the chemotherapy TS-1 plus CPT-11. Pleural effusion decreased and lymphangitis carcinomatosis improved. The serum CA 19-9 level rose transiently after CPT-11 administration, and tended to fall at the second week of chemotherapy. However, the patient died 2 years 4 months after the onset. TS-1 plus CPT-11 combination chemotherapy would be effective for lymphangitis carcinomatosis and also useful as third-line chemotherapy for recurrent gastric cancer.
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PMID:[A case of advanced gastric cancer with lymphangitis carcinomatosa after operation of Krukenberg tumor treated by TS-1 plus CPT-11 as third-line chemotherapy]. 1612 22

The patient was a 66-year-old female with Borrmann's type 4 gastric cancer complicated by metastasis to the liver and invasion of the head of the pancreas. Radical resection was not indicated, and only gastrojejunostomy was performed to bypass an existing pyloric obstruction. One course of chemotherapy was defined as 3 weeks of drug administration(TS-1 100 mg/body/day po for 21 days + CDDP 9 0 mg/body/day by iv drip on day 8), followed by a 2-week rest period. Chemotherapy was started 13 days after the operation, and it was possible to continue it for 7 courses. TS-1/CDDP therapy improved the patient's general condition. The tumor marker levels were also decreased. However, the efficacy of treatment began to decline,and ascites gradually developed during the fourth course of therapy. The treatment regimen was then switched to TS-1 100 mg/body/day po for 14 days, followed by a 14-day rest period, combined with PTX 9 0 mg/body/day iv drip on day 1 and day 15, while the ascites was being controlled. The ascites decreased significantly after the change in regimen, and the new regimen was continued for 6 courses. However, PTX was switched to CPT-11 because of gradual progression of peripheral neuropathy as a side effect of chemotherapy, and the patient subsequently died without any improvement in symptoms. This report describes a case of advanced gastric cancer treated by combination chemotherapy with TS-1 as a key drug, which resulted in a long survival (1 year and 5 months)and improvement in quality of life.
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PMID:[Effective treatment of unresectable advanced gastric cancer by TS-1-based chemotherapy with a sequential combination of cisplatin (CDDP) and paclitaxel (PTX)]. 1622 47


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