Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From January 1984 to June 1990, we observed 42 patients with meningeal carcinomatosis, 20 men and 22 women, aged 21 to 80 years (median age, 53 years). The two most common primary malignancies were lung cancer (50%) and breast cancer (31%). Sixty-four per cent was adenocarcinoma. On the first lumbar puncture, 86% had malignant cells in the cerebrospinal fluid. The findings of brain computed tomography were hydrocephalus (62%), contrast enhancement in the cerebral sulci or basal cisterns (31%), concomitant parenchymal metastases (15%) and normal scan (18%). In five out of seven cases, myelography showed irregular filling defects over the spinal cord or cauda equina. Treatment results were evaluated in 24 patients. Eight received radiation therapy (RT) alone, and 16 had combined therapy with RT plus intrathecal methotrexate (IT MTX). Of the patients who received RT alone, only one patient with lung carcinoma was stabilized clinically. Of the cases receiving combined therapy, seven improved clinically. Six of these were patients with breast carcinoma who received IT MTX via Ommaya reservoir. The latter had a median survival of 23 weeks. The follow-up period of the entire group of patients ranged from one day to 50 weeks. The median survival was four weeks. Based on this study, combined therapy with RT and IT MTX is indicated for breast carcinoma with meningeal carcinomatosis, but the therapeutic effects are uncertain for lung carcinoma and other malignancies.
 ...
PMID:Meningeal carcinomatosis from solid tumors: clinical analysis of 42 cases. 135 92

This report updates findings from two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials conducted to evaluate the worth of systemic therapy for the treatment of node-negative breast cancer patients. In trial B-13, 737 women with estrogen receptor (ER)-negative tumors treated by sequential methotrexate and fluorouracil (MTX----5-FU) followed by leucovorin were compared with a control group treated by surgery alone. Findings for all patients through 5 years of follow-up indicate a 27% reduction in treatment failure as a result of MTX----5-FU (76% vs 67%). While patients 49 years old or less and 50 years old or more benefited significantly from MTX----5-FU, the effect on disease-free survival (DFS) was greatest in those 50 years or older, where a 50% reduction in treatment failure occurred (86% vs 72%). A 69% reduction in mortality resulting from MTX----5-FU was observed in the older group (95% vs 84%). Trial B-14 compared placebo with tamoxifen (TMX) in 2844 patients with ER-positive tumors. As originally reported, findings through 5 years of follow-up indicate a significant reduction (36%) in treatment failure as a result of the TMX (82% vs 72%). Improvement in DFS was highly significant in both age groups. In patients 49 years old or younger, there was a 44% reduction in DFS (81% vs 66%) and, in those 50 years old or more, a 31% reduction (82% vs 74%). A Cox proportional hazards model failed to indicate a benefit from MTX----5-FU and TMX in all patient subgroups. Both therapies reduced local-regional and distant recurrence, as well as breast tumor recurrence following lumpectomy. Updated findings from trials B-13 and B-14 continue to support our conclusions that (a) no subgroups of node-negative patients that we examined have such a good outcome as to preclude the use of effective systemic therapy in their treatment and (b) despite the benefits observed from MTX----5-FU and TMX, no subgroup of patients was so affected as to preclude use of a particular subgroup in assessing other therapy regimens in additional clinical trials. The identification and evaluation of markers to determine which patients should receive systemic therapy are of the highest priority. At present, however, the use of markers for therapeutic decision making regarding individual patients is tenuous.
 ...
PMID:Systemic therapy in node-negative patients: updated findings from NSABP clinical trials. National Surgical Adjuvant Breast and Bowel Project. 162 17

We have studied the effects of methotrexate (MTX-Glu1) and the polyglutamate derivatives of methotrexate (MTXPGs) with 2, 3, 4, and 5 glutamyl residues on the catalytic activity of thymidylate synthase purified from MCF-7 human breast cancer cells and on the kinetics of the ternary complex formation by 5-fluoro-2'-deoxyuridine 5'-monophosphate, folate cofactor, and thymidylate synthase. MTX-Glu1 exhibited uncompetitive inhibition of thymidylate synthase when reaction kinetics were analyzed by either double reciprocal plots or a computerized mathematical model based on nonlinear least-squares curve fitting. The Ki for MTX-Glu1 inhibition was 13 microM and the I50 was 22 microM, irrespective of the degree of polyglutamation of the folate. In contrast, the polyglutamated derivatives of MTX all acted as noncompetitive inhibitors. The MTXPGs had 75-300-fold greater potency than MTX-Glu1 as inhibitors of thymidylate synthase catalytic activity, with Ki values from 0.17 to 0.047 microM for MTX-Glu2 to MTX-Glu5, respectively. Neither MTX-Glu1 nor MTXPGs promoted the formation of a charcoal-stable ternary complex with thymidylate synthase and 5-fluoro-2'-deoxyuridine 5'-monophosphate. CH2-H4PteGlu5 (where PteGlu represents pteroylglutamic acid) was found to be 40-fold more potent than CH2-H4PteGlu1 in participating in the formation of a ternary complex, and 10 microM MTX-Glu5 significantly inhibited the formation of a ternary complex containing this folate as cofactor. The inhibition was determined to be due to a reduction in the kon. The potency of this inhibition was markedly greater in the presence of CH2-H4PteGlu1 as compared to CH2-H4PteGlu5. This finding suggests that the degree of interference with complex formation in intact cells would depend on the state of polyglutamation of available folate cofactor. Ternary complex formation with H2PteGlu5 as the folate cofactor was also investigated, and a 50% reduction in complex formation was found in the presence of a 2 microM concentration of MTX-Glu5. These findings have significant implications regarding the mechanism of action of MTX-Glu1 and contribute to an understanding of the complex interactions of MTX-Glu1 and 5-fluorouracil.
 ...
PMID:Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. 241 Apr 16

Previous studies have demonstrated that insulin augments methotrexate transport and enhances its cytotoxicity to human breast cancer cells. We therefore investigated the effects of insulin on methotrexate polyglutamate synthesis and binding to dihydrofolate reductase (DHFR) in two human breast cancer cell lines, MCF-7 and MDA-MB-231. Cells were exposed to 2 microM [3H]MTX and varying insulin concentrations for the desired time before determination of the polyglutamate content by high-performance liquid chromatography (HPLC). DHFR-bound drug was separated from free intracellular drug by chromatography on DEAE-Sephacel minicolumns prior to HPLC analysis. Incubation of MCF-7 cells with 2.5 nM insulin for 48 h before exposure to 2 microM [3H]MTX for a further 24 h resulted in a significant increase in both total drug and total polyglutamates compared with control cells. Increasing the insulin concentration in the medium yielded further increases in polyglutamylation so that at 250 nM insulin and above total polyglutamates were increased by 64% compared with control cells. Further evaluation of the effects of physiologic insulin levels on polyglutamate synthesis revealed that 2.5 nM insulin caused an increase in the net glutamylation rate for each polyglutamate derivative during the final 12 h of a 24 h exposure to MTX. Analysis of the effects of insulin on polyglutamate binding to DHFR revealed that exposure to 2.5 nM insulin resulted in the preferential binding of higher polyglutamates to DHFR. In MDA-231 cells, a breast cancer cell line with a poor capacity for polyglutamate synthesis, insulin exposure resulted in an increase in the cellular accumulation of each polyglutamate derivative, with the greatest proportionate increases occurring in the cellular levels of higher polyglutamates. These data suggest that insulin augmentation of MTX polyglutamate synthesis may account for its previously observed ability to enhance MTX cytotoxicity.
 ...
PMID:Insulin effects on methotrexate polyglutamate synthesis and enzyme binding in cultured human breast cancer cells. 241 22

MTX and dipyridamole are synergistic in their toxicity towards the MDA.MB.436 human breast cancer cell line. Dipyridamole increases net MTX uptake into the cells and increases the intracellular levels of MTXG7 to G10, the highest molecular weight polyglutamyl derivatives of MTX detected. During a recovery period, after completion of exposure to MTX with and without dipyridamole, levels of MTXG7 to G10 remained elevated in dipyridamole treated cells by comparison with controls. Dipyridamole, which has no intrinsic effect on cell growth, transforms a cytostatic response of MDA.MB.436 cells towards MTX into a cytotoxic response. The effect of dipyridamole is not mediated through an increase in prostacyclin biosynthesis.
 ...
PMID:Enhancement of methotrexate cytotoxicity towards the MDA.MB.436 human breast cancer cell line by dipyridamole. The role of methotrexate polyglutamates. 242 77

A case of multifocal axonopathy associated with intrathecal methotrexate (IT MTX) and radiation therapy is presented. A 33-year-old woman suffering from meningeal carcinomatosis of breast cancer origin had developed prominent multifocal axonal degeneration in the cerebral white matter after treatment with IT MTX therapy and cranial irradiation. The principal features of this axonal degeneration were segmental hydropic swellings, macrophage infiltration of swollen axons, and scattered spheroid formation associated with reactive astrocytosis. These features were similar to those observed in our previous experimental study using cats treated with IT MTX alone. This "multifocal axonopathy" without necrotizing lesions seems to be different from disseminated necrotizing leukoencephalopathy, and, therefore, may be another form of MTX-related leukoencephalopathy. IT MTX and cranial irradiation seem to have exerted synergistic effects in producing the "multifocal axonopathy" in this case.
 ...
PMID:Methotrexate-related multifocal axonopathy. Report of an autopsy case. 260 40

The results of 63 patients with advanced malignant tumors treated by combined chemotherapy including high-dose cisplatin (HD-DDP) (single dose 50-100 mg/m2) are reported. The remission rates and duration of the remission for various malignant tumors were: 40% (10 PR out of 25 patients) and 3-8 months for non-small cell lung cancer (NSCLC) treated by PMFV (DDP, MMC, 5FU and VCR) regimen; 87% (4 CR and 9 PR out of 15) and 3-14 months for breast cancer treated by PCMF (DDP, CTX, MTX and 5FU) regimen; 100% (1 CR and 3 PR out of 4) and 3-10 months for testicular cancer treated by PPV (DDP, Pingyangmycin and VCR) regimen; 57% (1CR and 3 PR out of 7) and 5-12 months for malignant melanoma treated by PBDV (DDP, BCNU, DTIC and VCR) regimen; 33% (2 PR out of 6) and 5 months for esophageal cancer treated by PPV regimen. In 6 patients with other malignant tumors, the remission rate was 50% (3 PR). The results show that the combined regimens including HD-DDP in the treatment of breast cancer and NSCLC (remission rate 87% and 40%, respectively) are better than that including low-dose DDP (17% and 7%) (P less than 0.001, P less than 0.01) and that including adriamycin (30% and 13%) (P less than 0.001, P less than 0.05). In the treatment, obvious gastrointestinal reaction, leukopenia, thrombocytopenia and mild functional damage of the liver and kidney were observed.
 ...
PMID:[Evaluation of combined chemotherapy including high-dose cisplatin in the treatment of malignant tumors]. 282 Jun 83

From 1977 to 1982, 62 patients with various advanced malignant solid tumors were treated by HD-MTX-CFR therapy and totally 129 courses were given. Majority of the patients suffered from malignant lymphoma (10), osteogenic sarcoma (11), lung cancer (16), esophageal cancer (3), breast cancer (3) and malignant melanoma (4). All were confirmed by cytology or pathology except one primary liver cancer. There were clinically measurable lesions in 59 patients for evaluation of the treatment, and 3 osteogenic sarcoma patients without metastasis were given a postoperative adjuvant chemotherapy. 33 out of 62 had received chemotherapy and/or radiotherapy before. Dose of MTX ranged from 2 to 3 gm per course in most patients and dose of CF, from 9 to 12 mg every 6 hours for 3 days. 2 (3.4%) patients achieved complete remission (1 osteogenic sarcoma and 1 malignant lymphoma) and 8 (13.6%), partial remission (1 osteogenic sarcoma, 5 malignant lymphoma, 1 esophageal cancer and 1 breast cancer) with a total response rate of 15.9%. No response was observed in all 16 lung cancers. The main side effects of HD-MTX-CFR therapy were leukopenia, thrombocytopenia, elevation of SGPT, nausea, vomiting, mucositis, skin rash, fever and fatigue. All patients were followed more than 3 years. 4 patients are still alive (9, 9, 4 and 7 years, respectively), including 3 osteogenic sarcoma patients who received postoperative adjuvant chemotherapy and 1 mycosis fungoides.
 ...
PMID:[High-dose methotrexate with citrovorum factor rescue (HD-MTX-CFR) in the treatment of malignant solid tumors--clinical analysis of 62 patients]. 326 85

This paper reviews the data on the clinical studies of sequential methotrexate and 5-fluorouracil in advanced colorectal, gastric, head and neck, and breast cancer. To date, a lot of phase II studies have been conducted, but there are many distance in each clinical data concerning response rate and side effect by the difference between their clinical methods with respect to the interval between methotrexate and 5-fluorouracil, or the dosage of each drugs. There are several reports with high response rate in those phase II studies, but randomized controlled studies recently reported have not yet confirmed the sequential effect of MTX-5-FU treatment. Therefore, it is concluded that the randomized controlled studies with the most available methods must be performed to evaluate the true efficacy of sequential methotrexate and 5-fluorouracil treatment.
 ...
PMID:[Current studies of sequential methotrexate and 5-fluorouracil treatment in cancer chemotherapy]. 327 12

The effects of combination chemotherapy including mitoxantrone (MXN) "M-VEMFH" for advanced breast cancer were studied. The M-VEMFH regimen consisted of MXN 7 mg/m2, VCR 0.7 mg/m2, EX 333 mg/m2, MTX 13.3 mg/m2 i.v. on day 1, 5-FU 333 mg/m2 i.v. from day 1 to day 5 and pred. (H) 60 mg/m2 p.o. with tapering off in 2 weeks. In 7 cases heavily pretreated with combination chemotherapy including ADR, CR 2, PR 2, NC 2 and PD 1 were observed (response rate 57.1%). In 5 cases without prior ADR, PR 1, NC 2 and PD 2 were obtained. One case given 586 mg/m2 of prior ADR died of congestive heart failure after administration of 47 mg/m2 of NXN. One case died of sepsis. The other side effects were stomatitis, vulvitis, abnormal gustation, nausea, vomiting and alopecia. M-VEMFH is effective combination chemotherapy for advanced breast cancer resistant to ADR, but care must be exerted due to the accompanying cardiotoxicity and leukopenia.
 ...
PMID:[Effects of combination chemotherapy M-VEMFH including mitoxantrone in advanced breast cancer]. 405 16


1 2 3 4 5 6 Next >>