Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-FU is metabolized to FUTP and FdUMP in tumor cells and exhibits RNA- and DNA-directed cytotoxicity. Biochemical modulation of the intracellular metabolic pathways of 5-FU result in either selective enhancement of the antitumor effect or protection of the host. 1. Administration of pro-drugs of the active intermediates of 5-FU (FO-152, FF-705, TK-117, T-506) 2. Increase in PRPP level by inhibition of the de novo purine synthetic pathway, and greater production of cytotoxic 5-FU-containing nucleotides (MTX, MMPR) 3. Lowering of intracellular UTP pools by inhibition of de novo pyrimidine biosynthesis and enhancement of antitumor activity of 5-FU (PALA, Acivicin) 4. Increase in the UTP level and protection against 5-FU toxicity in normal host tissue (Uridine, Uridine + BAU, Cytidine) 5. Enhanced and prolonged inhibition of thymidylate synthetase by FdUMP (Leucovorin, MTX) 6. Inhibition of 5-FU degradation and increase in the 5-FU tissue level (Thymidine, Uracil)
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PMID:[In vivo distribution and activation of 5-FU--with special reference to biochemical modulation of intracellular metabolism]. 338 39

Effects of Methotrexate (MTX) alone and sequential combination chemotherapy of MTX and Bleomycin (BLM) were evaluated in 29 primary cases of squamous cell carcinoma of the oral cavity. MTX 50mg or 500 mg was administered intravenously once a week for a total dose of 100 to 200 mg in 10 cases and 1000 mg in 19 cases. In the cases of MTX 500 mg, CF (Leucovorin) rescue was given subsequently. BLM 15 mg was also administered intravenously twice a week for a total dose of 45-90 mg in 25 cases, so that 4 patients received MTX alone, 6 were transferred from BLM to MTX treatment and 19 were transferred from MTX to BLM. Objective response rate to MTX in cases of single and prior administration was 12/23 (52.2%). Treatment was found to be effective clinically in cases of exophytic growth type and histologically in cases of well differentiated types of tumor cells and well defined types of tumor-host borderline. Objective response rate to MTX treatment followed by BLM was 12/19 (57.9%) while that of BLM switched to MTX was 3/6 (50.0%). Side-effects, such as myelosuppression and anorexia, were observed in 12/29 cases given MTX, while, in only one case given BLM, skin reaction was observed. With respect to side-effects and the general preoperative condition of patients, the MTX to BLM course seemed to be better than that in which BLM was switched to MTX. Moderate-dose MTX: CF rescue + small-dose BLM therapy for oral cancer was, therefore, concluded to be useful as a preoperative adjuvant chemotherapy.
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PMID:[MTX-BLM therapy for squamous cell carcinoma of the oral cavity]. 621 51

Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance (t1/2 in mice of 45 minutes). Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The Ki,slope for inhibition of the human enzyme was 4 X 10(-11) M. A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. A new, stable and highly water-soluble formulation of trimetrexate has been developed. Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.
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PMID:Biochemical pharmacology of the lipophilic antifolate, trimetrexate. 623 75

5-Fluorouracil (5-FU), when preceded by methotrexate (MTX), results in synergistic tumor cell kill both in vitro and in vivo in mice. Since MTX concentrations 10 microM or greater maximize the synergy in vitro, we administered sequential MTX-5-FU as follows: MTX 125-250 mg/m2 i.v. followed 1 hr later by 5-FU 600 mg/m2 i.v. Leucovorin (LV) rescue 10 mg/m2 i.v. was given at hr 24, then 10 mg/m2 p.o. every 6 hr for 5 doses. One-hour and 24-hr serum MTX levels were monitored and 24-hr serum creatinine levels obtained. A weekly schedule was adhered to where possible, although most patients had at least one course delayed during the first month of treatment because of toxicity. Maintenance was every 2 wk. Since our initial report (Proc Am Soc Clin Oncol 21:473, 1980), a total of 35 squamous cell head and neck cancer patients, 12 with de novo and 23 with recurrent or metastatic disease, have been treated. Overall response rate is 71%, 65% in recurrent patients, 83% in de novo patients. Complete response rate was 11%. Median response duration for recurrent patients was 3.6 mo. With all deaths scored as disease-related and a minimum follow-up of 18 mo in all patients, a median survival of 11.5 mo for the 23 recurrent and 12 mo for the de novo patients was seen. Pretreatment performance status affected survival with Eastern Cooperative Oncology Group (ECOG) 0-1 patients living significantly longer than bedridden patients (p less than 0.001). Toxicity was either hematologic or gastrointestinal, with diarrhea, the limiting toxicity, accounting for the one drug-related death. The MTX/5-FU combination sequence may provide significant long-lasting palliation in patients with recurrent squamous head and neck cancer.
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PMID:Methotrexate and 5-fluorouracil in sequence in squamous head and neck cancer. 634 97

Since 1973 75 patients with carcinoma of the oropharynx were treated with regional cytostatic chemotherapy as an initial step of a combined therapy which consists of an follow-up operation and/or radiation. Methotrexate was used in intraarterial short infusions with Leucovorin rescue. The tumor response to i.a. chemotherapy was definite in 80% of the cases, without any negative side effects in the patients who are usually in a reduced general condition. After i.a. chemotherapy to reach a partial remission of the tumor and to create better conditions for the following therapy, we always tried to perform an operation and radiation. With this combination-therapy we reached, in the 1 year NED results as well as in the 3 year survival rate, with 60% resp. 54% better results than in patients who were only radiated after i.a. chemotherapy (43% 1 year NED results resp. 43% 3 year survival rate). A chemotherapy of oropharynx carcinoma is only justified, if other therapy forms follow up, if possible, composed of an operation and radiation. Because of the high rate of response of tumors seen in our patients, the low rate of side effects and the noticeable remission of the tumor-caused complaints it seems to us that the i.a. infusion therapy with methotrexate is a suitable form of chemotherapy for carcinoma of the oropharynx.
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PMID:[Intra-arterial chemotherapy as a part of a combination-therapy in carcinoma of the oropharynx]. 698 33

Recent in vitro and animal tumor studies suggest that sequential methotrexate (MTX) and 5-fluorouracil (5-FU) may be much more tumoricidal than either drug when used alone or in conventional combinations. Seventeen evaluable female patients with advanced carcinoma of the breast were treated with MTX 200 mg/M2I.V. followed one hour later with 5-FU 600 mg/M2I.V. Leucovorin 10 mg/M2 was begun orally 24 hours later and continued every six hours for six doses. Thirteen of these patients had not responded to prior drug treatment. Of the 17 patients, 11 responded to therapy, 9 had an objective response of greater than 50% tumor regression, and 2 had a minimal response of less than 50% tumor regression. The greatest number of responses was seen in skin and soft tissue. Disease-free interval, hormonal status, and prior therapy, with the exception of MTX and 5-FU containing drug regimens, did not appear to affect response rates. Toxicity was minimal and not life threatening. Based on these results it is believed that large trials with this drug sequence are warranted.
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PMID:Preliminary report on the efficacy of sequential methotrexate and 5-fluorouracil in advanced breast cancer. 702 Sep 15

Clinical and pharmacologic effects of dichloromethotrexate (DCM) were reevaluated by an intermittent intravenous large dose schedule in patients with advanced malignancies. DCM was tolerated without Leucovorin (calcium folinate) in man, even when the initial immunoassayable DCM level approached 10(-3) M. Hepatic dysfunction occurred more frequently at high doses. Hematologic toxicity was not dose-limiting. Plasma decay of DCM was comparable to that of methotrexate (MTX). Of 50 patients treated, five including two with hepatic metastasis from colon carcinoma, responded with more than 50% regression of tumor. In vitro comparison of DCM and MTX in Molt 3 cells revealed that DCM was slightly more inhibitory than MTX on an equimolar basis. In the presence of 2.5 g/dl of human serum albumin (HA), however, inhibitory effects of DCM decreased markedly. The decreased biologic effects of DCM compared to those of MTX are due to much higher binding to HA by DCM. This phenomenon appears to explain all of the clinical and pharmacologic characteristics of DCM.
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PMID:Clinical and laboratory reevalution of dichloromethotrexate. 744 49

Mice bearing subcutaneously implanted EMT6 mammary adenocarcinoma were treated with leucovorin or folic acid by continuous subcutaneous infusion or bolus intraperitoneal injection. (6R)-5,10-Methylenetetrahydrofolate pools in cytosolic extracts of the tumor, marrow, and gut were measured by analysis of the ternary complex with thymidylate synthase (5,10-methylenetetrahydrofolate: dUMP C-methyltransferase, EC 2.1.1.45) and 5-fluoro-2'-deoxyuridylate, and the polyglutamate distribution in the (6R)-5,10-methylenetetrahydrofolate pool was analyzed by native gel electrophoresis. Bolus intraperitoneal administration of either leucovorin or folic acid caused dose-dependent expansion of the (6R)-5,10-methylenetetrahydrofolate pool in the tumor, but not in the marrow or gut. For example, the AUC (0-5 hr) in the tumor increased from a baseline value of 8.2 to 20 nmol/mg protein.hr after a bolus dose of 1.5 mmol/kg of leucovorin or folic acid, whereas the increase in marrow and gut was 2- to 4-fold lower. Continuous subcutaneous infusion at the same total dosage over 3 days gave AUC (0-96 hr) values of 134 nmol/mg protein.hr for controls as compared with 347 nmol/mg protein.hr for the leucovorin group and 254 nmol/mg protein.hr for the folic acid group. In contrast to bolus treatment, the increase in (6R)-5,10-methylenetetrahydrofolate in the marrow and small intestine with both leucovorin and folic acid infusion was similar to the increase in the tumor. Thus, intraperitoneal bolus injection was tumor selective, but subcutaneous continuous infusion was not. Longer-chain polyglutamates of (6R)-5,10-methylenetetrahydrofolate in the tumor after bolus treatment with 0.375 and 0.75 mmol/kg of leucovorin or folic acid increased relative to controls. At higher doses of 1.5 and 2.25 mmol/kg, an increase was observed only in the mono/diglutamate fraction. In marrow, on the other hand, the mono/diglutamate fraction, but not the longer-chain polyglutamates, increased at all doses. In the constant infusion regimen, longer-chain polyglutamates increased in all three tissues, though in gut and marrow the mono/diglutamate fraction increased more than in tumor. Leucovorin and folic acid were converted to (6R)-5,10-methylenetetrahydrofolate more efficiently but less selectively during a 3-day subcutaneous infusion than after an intraperitoneal bolus. Longer-chain polyglutamates were selectively increased in tumor by both regimens of leucovorin administration.
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PMID:Leucovorin and folic acid regimens for selective expansion of murine 5,10-methylenetetrahydrofolate pools. 753 77

The prognosis for patients with advanced (stage III and IV) hepatocellular carcinoma (HCC) remains poor. Liver resection and liver transplantation have limited effects on overall survival. Our study was carried out to assess a novel therapeutic approach, which includes transarterial locoregional chemotherapy and in vivo locoregional dual immunostimulation, in patients with unresectable HCC. A group of 20 patients with stage III and IV hepatocellular carcinoma had 10 courses (once per day) of transarterial targeted locoregional immunotherapy with interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), emulsified in a Lipiodol-Urografin mixture. The target organs were the spleen and the liver tumor itself. One course of intrahepatic locoregional targeting transarterial chemotherapy was given 10 days after completion of immunotherapy (mitomycin C, carboplatin, Farmorubicin, Leucovorin, 5-fluorouracil, and IFN-gamma). This was followed after 2 months by another course of transarterial targeted locoregional immunotherapy-chemotherapy. All patients survived the operation and had a mean survival time of 18 months (4-22 months). There was a decrease in the tumor size of 14 of the 20 patients. Serum alpha-fetoprotein (AFP) levels declined in 14 patients, reaching normal levels in 12 patients. These preliminary results indicate that combined locoregional immunotherapy-chemotherapy is a promising therapeutic approach in patients suffering from advanced nonresectable HCC and merits further evaluation.
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PMID:Combined transarterial targeting locoregional immunotherapy-chemotherapy for patients with unresectable hepatocellular carcinoma: a new alternative for an old problem. 754 32

Leucovorin (LV or 5-CHOFH4) has had long-standing clinical use as a rescue agent from the systemic toxic effects of methotrexate (MTX). Because the mouse has been the animal model most used to investigate MTX therapy, direct tissue assessment of LV and its reduced-folate metabolites was undertaken in the plasma, intestinal epithelium, and intraperitoneal L1210 cells of MTX-pretreated mice using a ternary-complex-based assay method. The results show that total folate accumulation and depletion in tissues is closely related to plasma levels, with somewhat greater persistence occurring in tissues, presumably due to polyglutamylation. Examination of individual folates in plasma showed that the combined 5,10-methylenetetrahydrofolate (CH2FH4) plus tetrahydrofolate (FH4) pool was the most extensively elevated pool other than that of the parent compound [S]-5-formyltetrahydrofolate ([S]-5-CHOFH4). The dihydrofolate (FH2) also became elevated, whereas the 5-methyltetrahydrofolate (5-CH3FH4) remained unchanged. Individual folates that were elevated in tissues were generally the same as those elevated in plasma, the exception being a significant accumulation of 10-formyltetrahydrofolate (10-CHOFH4) in both intestinal epithelial and L1210 cells. The elevation of FH2 in L1210 cells was greater and persisted longer than that in intestinal epithelium, whereas the opposite was true for CH2FH4 + FH4. This differential effect in tumor versus epithelial tissue is consistent with the selective rescue of normal tissue by LV.
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PMID:Disposition of leucovorin and its metabolites in the plasma, intestinal epithelium, and intraperitoneal L1210 cells of methotrexate-pretreated mice. 792 54


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