Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sequential chemotherapy with methotrexate and 5-fluorouracil (MTX/5-FU) for advanced gastric cancer was given 29 patients. The procedure consisted of weekly MTX 100 mg/m2 (i.v.) followed three hours later by 5-FU 600 mg/m2 (i.v.) with leucovorin rescue on each of the following two days. Nine of 28 patients (32.1%) showed partial response to this treatment. Response rates were 28.6% in the 21 cases with poorly differentiated adenocarcinoma and 42.9% in the 7 cases with well- or moderately-differentiated adenocarcinoma. This procedure was especially effective for primary lesions (PR 9/20: 45%) and lymphnode metastases (CR 4 + PR 4, 8/17: 47.1%). Side effects were mild leukopenia and G-I symptoms such as nausea, diarrhea and loss of appetite, except in 1 patient who died of severe myelosuppression with sepsis. We concluded that sequential MTX/5-FU therapy is fairly effective and the adjuvant chemotherapy of choice for advanced or recurrent gastric cancer with not only poorly differentiated adenocarcinoma but also well- or moderately-differentiated adenocarcinoma.
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PMID:[Sequential chemotherapy with methotrexate and 5-fluorouracil for advanced gastric cancer]. 953 Mar 60

We report here on treatment results of consecutive CCLSG NHL studies (NHL855, 1985-1989; NHL890, 1989-1996). The NHL855 protocol consisted of an induction phase of five drugs (VCR, PRD, CPM, DXR, and high-dose MTX) and a maintenance phase of 7 drugs. The probabilities of EFS at 7 years were 78% (SE, 10%) for the patients with localized disease, and 38% (SE, 7%) for those with advanced disease. In the NHL 890 protocol, the patients were assigned to two different treatment groups according to their histology and received different consolidation therapy; non-lymphoblastic subtype was treated almost identically to NHL855 while LASP and VP-16 were newly added for the lymphoblastic subtype. The 7-year EFS improved to 91% (SE, 6%) for localized disease, and 61% (SE, 6%) for advanced disease. A remarkable improvement was particularly evident for lymphoblastic type with mediastinal mass. Optional trial of high-dose sequential chemotherapy and peripheral blood progenitor cell auto grafting resulted in an unfavorable outcome. The 7-year EFS according to main histological subgroups were as follows: 84% (10%) for large cell type, 67% (11%) for Burkitt's-type, 58% (10%) for lymphoblastic type. Secondary cancer occurred in two of the 163 patients studied. Both patients were AML (M0/M4) and MLL rearrangement was detected in the M4 case.
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PMID:[Treatment of children with non-Hodgkin's lymphoma with CCLSG NHL 855/890 protocols long-term outcome and incidence of secondary malignancies]. 959 95

1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxyuridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihydrofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.
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PMID:5-fluorouracil: a pharmacological paradigm in the use of cytotoxics. 980 59

A novel monoclonal antibody has been developed that reacts strongly with human prostatic cancer, especially tumors of high grade. This antibody (7E11C-5) is currently in Phase 3 trials as an imaging agent for metastatic disease. We have cloned the gene that encodes the antigen that is recognized by the 7E11C-5 monoclonal antibody and have designated this unique protein prostate-specific membrane (PSM) antigen. PSM antigen is a putative class II transmembranous glycoprotein exhibiting a molecular size of Mr 94,000. Functionally, class II membrane proteins serve as transport or binding proteins or have hydrolytic activity. Preliminary studies have demonstrated binding of pteroylmonoglutamate (folate) to membrane fractions that also cross-reacted with the PSM monoclonal antibody. We observed substantial carboxypeptidase activity as folate hydrolase associated with PSM antigen. The purpose of our study was to demonstrate that human prostatic carcinoma cells expressing PSM antigen exhibit folate hydrolase activity using methotrexate triglutamate (MTXGlu3) and pteroylpentaglutamate (PteGlu5) as substrates. Isolated membrane fractions from four human prostate cancer cell lines (LNCaP, PC-3, TSU-Prl, and Duke-145) were examined for folate hydrolase activity using capillary electrophoresis. After timed incubations at various pH ranges and in the presence and absence of thiol reagents, separation of pteroyl(glutamate)n derivatives was achieved with an electrolyte of sodium borate and SDS, while absorbance was monitored at 300 nm. The results demonstrate clearly that LNCaP cells, which highly express PSM, hydrolyze gamma-glutamyl linkages of MTXGlu3. The membrane-bound enzyme is an exopeptidase, because it progressively liberates glutamates from MTXGlu3 and PteGlu5 with accumulation of MTX and PteGlu1, respectively. The semipurified enzyme has a broad activity from pH 2.5 to 9.5 and exhibits activity maxima at pH 5 and 8. Enzymatic activity is maintained in the presence of reduced glutathione, homocysteine, and p-hydroxymercuribenzoate (0.05-0.5 mm) but was inhibited weakly by DTT (>/=0.2 mm). By contrast to LNCaP cell membranes, membranes isolated from other human prostate adenocarcinoma cells (PC-3, Duke-145, and TSU-Pr1) did not exhibit comparable hydrolase activity, nor did they react with 7E11-C5 monoclonal antibody. After transfection of PC-3 cells with a full-length 2.65-kb PSM cDNA subcloned into a pREP7 eukaryotic expression vector, non-PSM antigen-expressing PC-3 cells developed immunoreactivity to 7E11-C5 monoclonal antibody and demonstrated folate hydrolase activities and optimum pH activity profiles identical to those of LNCaP cells. The membrane-bound enzymes from both LNCaP- and PC-3-transfected cells also have a capacity to hydrolyze an alpha-linked glutamyl moiety from N-acetyl-alpha-aspartylglutamate. We have identified that PSM antigen is a pteroyl poly-gamma-glutamyl carboxypeptidase (folate hydrolase) and is expressed strongly in human prostate cancer. Cancer cells that express this enzyme are resistant to methotrexate therapy. Those developing future therapeutic strategies in the treatment of prostate cancer that utilize folate antagonists need to consider this mechanism of resistance.
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PMID:Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. 981 19

Until the 1970s, the survival rate of osteosarcoma patients was less than 20%. By the 1990s, this had improved to 60% to 70%, and limb-sparing procedures have replaced amputation in many patients thanks to effective combination therapy. Neoadjuvant chemotherapy has become an accepted practice in the majority of institutions using protocols which include MTX, ADR, BCD and CDDP as the most active agents against this disease. Newer agents, particularly IFM and ETP, are increasingly incorporated into complex regimens. While several studies have reported multivariate analyses to identify prognostic factors, the histologic response to preoperative chemotherapy remains the most important prognostic factor. Pulmonary metastases are the primary cause of death in patients with osteosarcoma. Although current treatment regimens allow effective salvage therapy for the patients with pulmonary metastases, the actuarial survival rate is 30%. A more effective systemic treatment for those patients is needed. The current management of osteosarcoma is critically reviewed and a treatment strategy is proposed for discussion.
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PMID:[Combined multimodal therapy for osteosarcoma--neoadjuvant chemotherapy]. 1043 78

There have been few effective chemotherapeutic regimens for advanced gastric cancer with liver and intra-abdominal lymph node metastasis. A 78-year-old male patient was admitted to our hospital because of anorexia and abdominal discomfort. Gastroendoscopy showed a type 4 advanced gastric cancer in the antrum of the stomach. Histological study of biopsy specimens from the tumor revealed poorly differentiated adenocarcinoma. Examination by computed tomography and ultrasonography showed swollen paraaortic lymph nodes and liver metastasis. He was diagnosed as having advanced gastric cancer with liver and lymph node metastasis. This patient was treated weekly with an intraarterial 5-FU (500 mg) and MTX (100 mg) including AT-II by subcutaneously implanted port system placed into the celiac artery. Furthermore, he was administered tegafur/uracil (400 mg/day) 5 days weekly as pharmacokinetic modulating chemotherapy (PMC). After ten courses of treatment with PMC, the liver and lymph node metastases were reduced in size. This therapy was considered to be an effective treatment for advanced gastric cancer with liver and lymph node metastasis. The theoretical purpose of hypertensive chemotherapy used together with injection of angiotensin-II is to increase the delivery of anticancer drug to the target tumor tissue by increasing the blood flow in the tumor. We conclude that this chemotherapy is effective in cases of advanced gastric cancer with liver and lymph node metastasis from the viewpoints of toxicities, antitumor effect and QOL of the patient.
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PMID:[A case of advanced gastric cancer with liver and intra-abdominal lymph node metastasis treated by hypertensive selective chemotherapy with pharmacokinetic modulating chemotherapy]. 1293 72

We report a case of advanced gastric cancer that responded to docetaxel with low-dose 5-FU and cisplatin combination chemotherapy after becoming chemoresistant to M-FLP. A 52-year-old male was diagnosed with type 3 gastric cancer of angulus (poorly differentiated adenocarcinoma) with left neck, Virchow, mediastinal and abdominal lymph nodes metastases. The patient was treated with 5 courses of M-FLP (MTX + 5-FU + LV + CDDP), and the effect of this therapy was PR, but the tumor was chemoresistant to the sixth course of this therapy. After 7 courses of M-FLP, docetaxel (TXT) with low-dose FP (5-FU + CDDP) was administered to the patient as second-line chemotherapy. After 2 courses of TXT with low-dose FP, the gastric cancer and metastatic lymph nodes were remarkably reduced and the effect of this therapy was PR. The toxic events were anemia (grade 2) and leukopenia (grade 3), which were treated with G-CSF. CDDP and 5-FU based regimens are considered as the first-line chemotherapy for metastatic advanced gastric cancer in Japan; however, a second-line chemotherapy has not been established. As in this case, a TXT based regimen is effective and well tolerated therapy as a second-line chemotherapy for metastatic gastric cancer after prior exposure to CDDP and 5-FU.
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PMID:[A case of advanced gastric cancer that responded to docetaxel with low-dose 5-FU and cisplatin combination chemotherapy after becoming chemoresistant to M-FLP]. 1465 Sep 69

Alternative genetic pathways characterized by specific genetic profiles and exhibiting distinctive biological and clinical features have been proposed in colorectal carcinogenesis. Methotrexate (MTX) is a potent inhibitor of the dihydrofolate reductase (DHFR) enzyme, which is essential for DNA synthesis and cell growth. We have evaluated the association between different genetic features and the capacity to develop MTX resistance in colon cancer cell lines representative of alternative genetic pathways. Three aneuploid cell lines (HT-29, SW480, and SK-CO-1) showed pre-existing amplifications, but only one (HT-29) developed MTX resistance, showing amplification of the DHFR gene at 5q12-14 (>20-fold amplification and presence of extrachromosomal double minutes). Failure to develop resistance was attributed to the absence of two complete chromosomes 5 in SW480 and SK-CO-1 cells. Four near-diploid cell lines (LoVo, HCT116, DLD-1 and KM12C) and two aneuploid KM12C-derived metastases (KM12SM and KM12L4A) developed MTX resistance but none exhibited DHFR amplification. All resistant cells without DHFR gene amplification showed microsatellite instability. We conclude that chemoresistance capacity and the mechanism of chemoresistance are related with the genetic pathway and the karyotypic features of colon cancer cells.
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PMID:Genetic determinants of methotrexate responsiveness and resistance in colon cancer cells. 1600 55

We describe our experience with a patient who had undifferentiated gastric carcinoma with extensive lymph node metastasis, including para-aortic lymph-node metastasis, and had a complete response to induction therapy with methotrexate plus 5-fluorouracil (sequential therapy with MTX, 5-FU, and Leucovorin) and secondary treatment with oral TS-1. The patient was a 71-year-old woman with a massive gastric tumor (signet ring cell carcinoma), occupying most of the stomach. A computed tomographic (CT) scan revealed para-aortic, celiac, and common hepatic lymph-node metastases. Stage IV disease was diagnosed. Palliative total gastrectomy was performed to control bleeding and to improve oral intake of food. Two courses of induction therapy with MTX, 5-FU, and Leucovorin were started 3 weeks after surgery. A CT scan revealed residual lymph node metastasis. The response was assessed to be no change, but the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 improved from 7,028 ng/ml and 726 U/ml 3 weeks after surgery to 2,832 ng/ml and 281 U/ml, respectively. Secondary treatment with oral TS-1 was begun, and a CT scan showed distinct shrinkage of lymph-node metastases. There was no serious toxicity. The levels of CEA and CA19-9 decreased markedly to 2.9 ng/ml and 16 U/ml, respectively, about 6 months after surgery and remained at 3.7 ng/ml and 16 U/ml, respectively, about 1 year after surgery.
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PMID:[Stage IV gastric cancer patient who underwent palliative gastrectomy showing complete response to induction therapy with methotrexate plus 5-fluorouracil and secondary treatment with oral TS-1]. 1612 21

Curative resection is considered to be a standard therapy for gastric cancer with localized peritoneal metastases. For tumors with diffuse dissemination, chemotherapy may play a major role, however, the benefits of reduction surgery and standard chemotherapy have not yet been clarified. Median survival time after reduction surgery was reported to be 4-13 months for patients diagnosed by surgery and/or CT and 5-6 months for chemotherapy for those diagnosed by CT alone. Reduction surgery has a high risk, with a morbidity of 12-44% and a mortality of 3-14%. Palliative surgery should be indicated for stenosis or bleeding due to primary tumors. 5-FU, MTX-5-FU, TS-1, paclitaxel, and their combination are candidates for practice and clinical trials. It is important to evaluate the severity of peritoneal dissemination by diagnostic laparoscopy or laparotomy for decision making.
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PMID:[Treatment strategy for primary gastric cancer with peritoneal dissemination]. 1622 37


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