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)

We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTX-insensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.
Cancer Metastasis Rev 1987
PMID:Biological and biochemical properties of new anticancer folate antagonists. 354 36

The methotrexate concentrations in the lungs or cutaneous metastases of patients with osteogenic or soft-tissue sarcoma were determined at different times after a high-dose methotrexate therapy. The levels in the metastases were 0.964 to 2.96 X 10(-7) molar six to nine days after the end of MTX infusion. They were thus 7.8 to 28 times higher than the corresponding serum levels. At the same time, an appreciable rise of dihydrofolate reductase activity was observed in the metastases. After chromatographic separation over Sephadex G15, MTX polyglutamates could be demonstrated in all tumor samples investigated so far; these amounted up to 68.3% of the total MTX. Taking into account the slower efflux of MTX polyglutamates compared to unchanged MTX, a new hypothesis for the principle of action of high-dose methotrexate therapy is discussed: the very high MTX doses lead to such high intracellular MTX concentrations even in transport-resistant tumor cells that at least part of the MTX is converted into MTX polyglutamates. Unchanged MTX flows relatively rapidly out of the cells, whereas the MTX polyglutamates only break down very slowly and thus can be cytostatically effective over a long period of time.
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PMID:Methotrexate and methotrexate polyglutamates in human sarcoma metastases after high-dose methotrexate therapy. 619 16

The stability of the mammalian genome depends on the proper function of G1 and G2 cell cycle control mechanisms. Two tumor suppressors, p53 and retinoblastoma (Rb), play key roles in progression from G1 into S-phase. We address the mechanisms by which these proteins mediate a G1 arrest in response to DNA damage and limiting metabolic conditions. Gamma-irradiation induced a prolonged, p53-dependent G1 arrest associated with a long-term increase in the levels of the cdk-inhibitor p21WAFl/Cipl (p21). Microinjection of linear plasmid DNA also caused a G1 arrest. The p53-dependent arrest induced by inhibitors of UMP biosynthesis was reversible and occurred in the absence of detectable DNA damage. Both arrest mechanisms contribute to limiting the formation and propagation of damaged genomes. Cells containing mutant p53 but wild-type Rb do not generate methotrexate (Mtx) resistant variants. However, pre-treatment with DNA damaging agents prior to drug selection resulted in resistant clones containing amplified dihydrofolate reductase (DHFR) genes, suggesting that DNA breakage is a rate limiting step for gene amplification. The Mtx-induced arrest did not occur in cells with non-functional Rb. Rb acts as a negative regulator of the E2F transcription factors, and Rb-deficient primary mouse embryo fibroblasts (MEFs) produced elevated levels of mRNA and protein for key E2F target genes. Failure to prevent entry into S-phase in Rb-/- MEFs exposed to DNA-damaging or nutrient limiting conditions caused apoptosis and correlated with p53 induction. Taken together, these findings indicate a link between p53 and Rb function and suggest that their coordination insures correct entry into S-phase, minimizing the emergence of genetic variants.
Cancer Metastasis Rev 1995 Mar
PMID:Genetic instability as a consequence of inappropriate entry into and progression through S-phase. 760 22

The expression of several resistance markers (P-glycoprotein, glutathione S-transferase-pi, thymidylate synthase, dihydrofolate reductase) was analyzed in matched primary tumors and lymph node metastases from 21 patients with lung cancer using immunohistochemistry. The analysis showed that expression of these resistance proteins is generally congruent in primary lung cancer and simultaneously resected lymph node metastases. This suggests that in general the resistance of a primary tumor predicts for the resistance of the metastases and vice versa.
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PMID:Detection of resistance proteins in matched primary lung tumors and lymph node metastases. 791 93

We investigated four mechanisms of intrinsic chemoresistance in a series of 67 human brain tumours including 31 gliomas (one grade I ganglioglioma, nine grade II and 10 grade III astrocytomas, 11 glioblastomas), 13 cerebral metastases, one medulloblastoma, one malignant teratoma, three ependymomas and 18 meningiomas. We studied four genes by northern blotting: multidrug-resistance (MDR 1), glutathione-s transferase (GST pi), dihydrofolate reductase (DHFR), and topoisomerase II (Topo II). The Topo II gene was absent in the normal adult brain (100%) and in 64% of the tumour samples tested. A second gene, GST pi, was found to be overexpressed in 38% of brain tumours. The two other chemoresistance-related genes were occasionally overexpressed in brain tumours (2% for MDR1, 9% for DHFR). Our results provide evidence that chemoresistance is intrinsic to the brain tissue and seems likely to be a multifactorial process.
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PMID:A study of the expression of four chemoresistance-related genes in human primary and metastatic brain tumours. 838 72

Methotrexate produced the first remission in leukemia and the first cure of a solid tumor, choriocarcinoma. Methotrexate tightly binds to dihydrofolate reductase (DHFR), blocking the reduction of dihydrofolate to tetrahydrofolic acid, the active form of folic acid. Methotrexate also directly inhibits the folate-dependent enzymes of de novo purine and thymidylate synthesis. Resistance to methotrexate may develop as a result of elevated DHFR activity or defective transport of methotrexate into malignant cells. Increased DHFR enzyme levels may also result from amplification of the DHFR gene, which is now clinically significant in selected patients. Methotrexate is an active drug in the first-line treatment of gestational trophoblastic disease (GTD) and in metastatic squamous cell carcinoma of the cervix. Since the introduction of methotrexate chemotherapy for malignant GTD, most hospitals have reported almost 100% cure rates for patients with nonmetastatic disease using single-agent regimens. Patients with low-risk metastatic disease have been treated with methotrexate and folinic acid and over 50% complete remission rates have been reported. Patients with metastatic GTD who had one or more high-risk factors benefited from initial multiagent chemotherapy, rather than waiting for acquisition of drug-resistance to single-agent therapy to start multiagent treatment. Using multiagent combination chemotherapy such as MAC (methotrexate, actinomycin D, cyclophosphamide) or EMA-CO (etoposide, methotrexate, actinomycin D and cyclophosphamide, vincristine), most investigators have reported remission in approximately 60 to 80% of patients with high-risk metastatic GTD. Although the role of chemotherapy in carcinoma of the cervix has been limited for several reasons, trial of combination chemotherapy including methotrexate has been reported. However, it is still impossible to draw definite conclusions as to whether methotrexate combined with another clearly active drug may yield a superior response rate and survival.
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PMID:[Methotrexate in gynecologic oncology]. 897 93

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

High-dose methotrexate is a major component of current protocols for the treatment of osteosarcoma, but some tumors seem to be resistant. Potential mechanisms of resistance include decreased transport through the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR). To investigate methotrexate resistance, tumors were obtained from 42 patients with high-grade osteosarcoma. RFC and DHFR mRNA expression were studied by semiquantitative reverse transcription-PCR. The RFC and DHFR genes were studied for deletions and amplification by Southern blot. Thirteen of 20 (65%) osteosarcoma samples were found to have decreased RFC expression at the time of initial biopsy. At definitive surgery and relapse, 10 of 22 (45%) were found to have decreased RFC expression. Seventeen of 26 (65%) samples with a poor response to chemotherapy had decreased RFC expression, whereas 5 of 14 (36%) samples with a good response had a decrease (P = 0.03). None of the samples had an RFC gene deletion. Two of 20 samples (10%) showed increased DHFR expression at initial biopsy. The frequency of increased DHFR expression was significantly higher in metastatic or recurrent tumors (62%, P = 0.014). None of the samples showed evidence of DHFR gene amplification. The high frequency of decreased RFC expression in the biopsy material suggests that impaired transport of methotrexate is a common mechanism of intrinsic resistance in osteosarcoma. Increased DHFR expression in the pulmonary metastases may be a mechanism of acquired methotrexate resistance or a difference between primary and metastatic lesions.
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PMID:Mechanisms of methotrexate resistance in osteosarcoma. 1010 Jul 15

We recently reported that forced overexpression of the transcription factor E2F-1 in human HT-1080 fibrosarcoma cells resulted in corresponding high levels of thymidylate synthase (TS) and resistance to 5-fluoropyrimidines (D. Banerjee et al., Cancer Res., 58: 4292-4296, 1998). Because colorectal metastasis to the lung has higher TS levels than liver metastasis and is less responsive to treatment with 5-fluorouracil (R. Gorlick et al., J. Clin. Oncol., 16: 1465-1469, 1998), it was, therefore, of interest to measure E2F-1 expression in these tumors. In contrast to marginally increased levels of dihydrofolate reductase and topoisomerase I in lung metastasis as compared with liver metastasis, lung tumors had a 5-fold increase in E2F-1 expression as compared with liver tumors, corresponding to the relative levels of TS in these metastases. These data indicate that there exists a close correlation between E2F-1 and TS levels and provide a rationale for targeting this transcription factor, ie., E2F-1, for the treatment of certain cancers.
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PMID:Levels of E2F-1 expression are higher in lung metastasis of colon cancer as compared with hepatic metastasis and correlate with levels of thymidylate synthase. 1081 Nov 10

Cellular drug resistance is one of the principal obstacles to the clinical efficacy of cancer chemotherapy. In this review, we describe the potential role for translational regulation as a novel mechanism for modulating chemosensitivity. The evidence for the translational control of thymidylate synthase, dihydrofolate reductase, and p53 will be presented, as will experimental data showing how disruptions in this important regulatory process can lead to the rapid emergence of cellular drug resistance.
Cancer Metastasis Rev 2001
PMID:Translational regulation as a novel mechanism for the development of cellular drug resistance. 1183 45


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