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)

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

Marimastat, a matrix metalloproteinese inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. Even with novel approaches such as molecular targeting of cancer chemotherapy, peritoneal dissemination of gastric cancer has little sensitivity to anticancer drugs, and it is impossible to inhibit its growth completely. Intraperitoneal injection of TMK-1 into nude mice at 5 x 10( 5) cells / body resulted in carcinomatous peritonitis that mimicked clinical cases. Continuous administration of marimastat (18 mg / kg / day) from 24 h after the tumor inoculation successfully inhibited the growth of peritoneal dissemination nodules. Combined administration of marimastat (18 mg / kg / day) and mitomycin C (MMC, 2 mg / kg) showed synergistic inhibition of growth of peritoneal dissemination, being superior to MMC alone (2 mg / kg). Although marimastat alone could not increase survival time with statistical significance, combined administration of marimastat and MMC had a survival benefit with statistical significance. The combination of marimastat and MMC increased the preventive effect on peritoneal dissemination. Marimastat seems to be a candidate for the prevention of peritoneal spread of gastric carcinoma.
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PMID:Matrix metalloproteinase inhibitor, marimastat, decreases peritoneal spread of gastric carcinoma in nude mice. 1214 50

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

Marimastat is a broad-spectrum matrix metalloproteinase (MMP) inhibitor that inhibits almost all major MMPs, key enzymes in gastric cancer invasion and metastasis. We investigated the ability of marimastat to inhibit tumor angiogenesis in the severe combined immuno-deficient (SCID) mouse/human gastric cancer model of peritoneal dissemination. A human stomach adenocarcinoma cell line, TMK-1, was injected intraperitoneally into SCID mice. On the 7th day after tumor inoculation, the administration of marimastat (27 mg/kg/day) was initiated and the treatment was continued for 2 weeks using subcutaneously-inoculating mini-osmotic pumps. On the 21st day, the mice were killed and the disseminated nodules were evaluated. Total weights, numbers, and the microvascular density of the disseminating nodules were significantly lower in mice treated with marimastat compared to the control group. Film in situ zymography demonstrated that net gelatinolytic activity in the tissues was weaker in treated-group nodules than in control-group nodules. Thus, our results suggested that marimastat inhibited peritoneal dissemination of human gastric cancer cells through inhibition of tumor angiogenesis, possibly involving the down-regulation of gelatinases, in SCID mice injected with human gastric cancer cells.
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PMID:Reduced angiogenesis in peritoneal dissemination of gastric cancer through gelatinase inhibition. 1452 32

Gastric cancer is most chemosensitive among gastrointestinal tumors. However, the role of chemotherapy in advanced disease and its advantage over best supportive care has been adequately addressed only in the last decade. First generation regimens, such as 5-Fluorouracil (5-FU), Doxorubicin, Mitomycin C (FAM) have been used until early 90's, when evidence from randomized studies came up in favour of second generation regimens, such as 5-FU, Doxorubicin, high-dose Methotrexate (FAMTX), which in turn was proven less active than a third generation regimen, such as epirubicin, cisplatin, continuous infusion 5-FU (ECF) in a randomized study. Newer treatment options came up over last years. The Swiss Group for Clinical Cancer Research has carried out a randomized three-arm phase II study with ECF or docetaxel, cisplatin (TC), or docetaxel, cisplatin, 5-FU (TCF) in advanced gastric cancer. TCF has been selected as the combination to be further evaluated in a formal comparison with ECF. Oxaliplatin is being tested in advanced gastric cancer. Two recently published phase II studies of biweekly infusional 5-FU, folinic acid, and oxaliplatin have shown a considerable therapeutic activity. Irinotecan is another drug under investigation in advanced gastric cancer, both as single agent and in combination. A randomized phase II-III study of irinotecan plus cisplatin or irinotecan plus folinic acid/5-FU has recently been completed; the latter arm was proven worth undergoing a formal comparison with a standard CF regimen. Oral fluoropyrimidines represent a suitable therapeutic option in selected groups of patients. Marimastat is a matrix metalloproteinase inhibitor, whose main toxicity is musculoskeletal. A randomized phase III study of marimastat versus placebo as maintenance therapy in advanced gastric cancer has shown a significant survival advantage for the marimastat arm, both in the total patient population and in the subgroup of patients who had previously received chemotherapy. Since a clear gold standard for advanced gastric cancer does not yet exist, the inclusion of patients in well designed clinical trials is to be considered the best treatment option.
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PMID:Gastric cancer. Treatment of advanced disease and new drugs. 1597 May 66