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)

Epidemiological and experimental data suggest that fatty acids may modulate the growth of tumor cells. We have analyzed the effect of different types of fatty acids, bound to serum proteins in physiological conditions, on the lipid composition and growth of human neoplastic B and T-cell lines and compared their effect on normal lymphocyte proliferation. Fatty acids with 0 to 2 unsaturations (stearic, oleic, and linoleic), at concentrations up to 50 or 100 microM did not significantly affect the proliferation of leukemic cells. However, long-chain polyunsaturated fatty acids (PUFA), and mainly docosahexaenoic (22:6, n-3), were cytotoxic at concentrations greater than or equal to 20 microM after 48-72 h in culture. Simultaneous supplementation with vitamin E restored normal cell growth. The amount of end-products of lipid peroxidation in cells correlated with the observed toxicity but the amount of superoxides did not. Fatty acid supplementations increased cell triacylglycerol content but did not affect the degree of unsaturation of phospholipids, cholesterol/phospholipids molar ratio, or membrane fluidity. Glutathione-S-transferase activity was low in Raji and CEM cells, moderate in lymphocytes and high in Ramos cells and did not increase with supplementations. The proliferation of normal lymphocytes, which produced lower amounts of end-products of lipid perodixation, was not inhibited, but in some cases stimulated, by PUFA (with the exception of 30 microM 22:6). The extension of these results to situations in vivo could lead to use of PUFA for delaying leukemia progression or in adjuvant chemotherapy.
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PMID:Increased cytotoxicity of polyunsaturated fatty acids on human tumoral B and T-cell lines compared with normal lymphocytes. 132 Jul 13

Twenty-two patients with advanced head and neck carcinoma were treated with 5FU 400 mg-2 m-1 week and folinic acid 500 mg m-2 week-1 plus CDDP in escalating doses from 20 to 40 mg m-2 week-1 without forced diuresis. Reduced glutathione at the dose of 1.5 g m-2 was employed to protect patients from CDDP-related nephrotoxicity. The aims of the study were: a) to evaluate the therapeutic efficacy of this schedule, and b) to evaluate reduced glutathione as uroprotector. Out of 20 evaluable patients 14 (70%) had a major objective response. A CR with a mean duration of 9.0+ months was achieved in 15% of the patients, a PR of 5.8+ months in 55% of the patients, while 3 patients had stable disease and 4 progressed. It was possible to escalate CDDP up to 35 mg m-2 week-1, but at the dose of CDDP 40 mg m-2 week-1 the occurrence of grade 2 renal toxicity provoked a severe reduction of dose-intensity. Overall, this treatment has been very well tolerated by most patients with few cases of grade 3 gastrointestinal or hematological toxicity. In conclusion, the schedule seems effective and may be safely given to patients with advanced head and neck cancer on outpatient basis. Reduced glutathione seems to be able to reduce, at least partially, CDDP-related nephrotoxicity permitting the delivery of higher CDDP doses.
Med Oncol Tumor Pharmacother 1992
PMID:Weekly 5-fluorouracil and folinic acid plus escalating doses of cisplatin with glutathione protection in patients with advanced head and neck cancer. 134 59

Platinum-based chemotherapy has led to an improvement in complete response rates and duration of median remission, but has only given a modest improvement in overall survival in patients with advanced ovarian cancer. Chemotherapy will in the future focus upon: (1) improving the complete remission rate with new induction regimens; (2) identifying strategies capable of converting partial remission into complete remission; (3) preventing or delaying recurrences in patients who do achieve a complete remission; (4) identifying mechanisms of antineoplastic drug resistance and pharmacologic techniques capable of reversing drug resistance. Among the treatment approaches being utilized are high-dose chemotherapy with autologous bone marrow transplantation, development of new chemotherapeutic regimens which include Taxol and hexamethylmelamine, and intraperitoneal chemotherapy. In addition, our understanding of the mechanisms of antineoplastic drug resistance has led to the development of novel therapeutic approaches. It has been demonstrated that resistance to platinum and alkylating agents is associated with both increased concentrations of cellular glutathione (GSH) as well as an increased capacity of tumor cells to repair damage to DNA. Inhibition of GSH biosynthesis with buthionine sulfoximine (BSO), a synthetic inhibitor of the enzyme gamma glutamyl cysteine synthetase, has led to the potentiation of alkylating agent activity in vitro and in vivo. A phase I trial of BSO plus melphalan is currently in progress and a trial of BSO plus carboplatin is planned. Inhibition of the DNA repair process with aphidicolin potentiates the cytotoxicity of cisplatin in drug-resistant tumor cells. Clinical trials of aphidicolin plus cisplatin await the completion of ongoing phase I trials of aphidicolin.
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PMID:Role of chemotherapy in the future treatment of ovarian cancer. 135 5

Mechanisms of tumor resistance to 4-hydroperoxycyclophosphamide (4-HC) were studied by using a panel of human medulloblastoma cell lines either passaged in the laboratory for resistance to 4-HC or established from tumors showing clinical resistance to cyclophosphamide. Multiple distinct mechanisms of resistance were demonstrated. Daoy (4-HCR), a line that was 6-fold more resistant than Daoy, contained elevated levels of aldehyde dehydrogenase (ALDH). Most of the difference in sensitivity between the Daoy (4-HCR) and Daoy cell lines was abolished when 4-HC was replaced with phenylketocyclophosphamide, a 4-HC analogue that cannot be detoxified by ALDH. Thus, elevated levels of ALDH appear to play a role in the resistance of Daoy (4-HCR). Several of the cell lines [D283 Med (4-HCR), D341 Med (4-HCR), Daoy (4-HCR), D458 Med] contained elevated levels of glutathione (GSH). No changes in glutathione-S-transferase activity or isozyme pattern were observed, but in two of these three lines, the elevation in GSH was accompanied by elevated levels of gamma-glutamyl transpeptidase. To confirm the role of elevated GSH content in 4-HC resistance, the sensitivity of the cell lines to 4-HC was repeated after depletion of GSH by treatment with L-buthionine-S,R-sulfoximine. In medulloblastoma cell lines without other mechanisms of resistance, a linear relationship was seen between GSH content and resistance to 4-HC. Moreover, cells with GSH content greater than 5 nmol/mg protein and no other overriding mechanism of resistance could be sensitized to 4-HC treatment with L-buthionine-S,R-sulfoximine. Finally, D283 Med (4-HCR) cells had mild elevations in both ALDH and GSH content, but were resistant to phenylketocyclophosphamide and were not significantly sensitized by L-buthionine-S,R-sulfoximine. This cell line appears to demonstrate a third mechanism of resistance to 4-HC. These results suggest that 4-HC resistance in medulloblastoma can be multifactorial.
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PMID:Cyclophosphamide resistance in medulloblastoma. 135 17

Tumors that formerly were uniformly fatal can now be cured by cancer chemotherapy. However, successful anticancer therapy is faced by many obstacles, such as excessive normal tissue toxicity and drug resistance. Tumor drug resistance may be either intrinsic or acquired. The multidrug resistance (MDR) is a unique phenomenon and is characterized by tumor resistance to various structurally unrelated drugs. Known mechanisms for MDR include overexpression of a membrane P-glycoprotein 170 and elevated cellular levels of reducing agents, such as glutathione (GSH). Currently available strategies for overcoming drug resistance include competitive inhibitors of the P-glycoprotein 170, inhibitors of GSH synthesis, and adjuvant therapy with hyperthermia. Development of drug resistance is analogous to a physiological detoxification mechanism and may continue to limit the effectiveness of cancer chemotherapy in the near future.
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PMID:Tumor cell drug resistance and its reversal. 136 8

Clinical success in the treatment of tumors with chemotherapy has significantly improved over the past several years. However, treatment failures due to drug resistance of cancer cells has remained a major problem. The classical form of multiple drug resistance is perhaps also the most common type of drug resistance, and represents the overexpression of a transmembrane glycoprotein pump (P-170) that mediates the efflux of a spectrum of structurally and functionally unrelated drugs. Here, we discuss recent evidence that support the concept that the total phenomenon of multiple drug resistance (MDR) involves several other mechanisms in addition to that underlying "classical" MDR. These include the action of other energy-dependent membrane efflux pumps, elevated levels of GSH for drug conjugation and detoxification to facilitate export, enhanced DNA repair facility, gene amplification and oncogene activation. The combination of mechanisms used by any particular cell line is variable and suggests that many of these mechanisms are independent. Successful reversal of drug resistance appears to require the identification of relevant operative resistance mechanisms. An example is the competitive inhibition of P-170 with verapamil, quinine and tamoxifen. A broadly successful strategy for killing drug-resistant cancer cells, however, could be based on either selective energy depletion of cancer cells or the permeabilization of tumor cells with an effective bypass of efflux pumps, since many mechanisms of drug resistance entail the energy-dependent export of toxins. The latter approach may be achieved via membrane lipid modifications or the introduction of membrane pores by biological or physical (electroporation) means.
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PMID:Multidrug resistance: prospects for clinical management. 137 33

Selenium is increasingly recognized as a versatile anticarcinogenic agent. Its protective functions cannot be solely attributed to the action of glutathione peroxidase. Instead, selenium appears to operate by several mechanisms, depending on dosage and chemical form of selenium and the nature of the carcinogenic stress. In a major protective function, selenium is proposed to prevent the malignant transformation of cells by acting as a "redox switch" in the activation-inactivation of cellular growth factors and other functional proteins through the catalysis of oxidation-reduction reactions of critical SH groups of SS bonds. The growth-modulatory effects of selenium are dependent on the levels of intracellular GSH and the oxygen supply. In general, growth inhibition is achieved by the Se-mediated stimulation of cellular respiration. Selenium appears to inhibit the replication of tumor viruses and the activation of oncogenes by similar mechanisms. However, it may also alter carcinogen metabolism and protect DNA against carcinogen-induced damage. In additional functions of relevance to its anticarcinogenic activity, selenium acts as an acceptor of biogenic methyl groups, and is involved in the detoxification of metals and of certain xenobiotics. In its interactions with transformed cells at higher concentrations, it may induce effects ranging from metabolic and phenotypical changes, and partial renormalization to selective cytotoxicity owing to reversible or irreversible inhibition of protein and DNA synthesis. Selenium also has immunopotentiating properties. It is required for optimal macrophage and NK cell function. Its protective effects are influenced by synergistic and antagonistic dietary and environmental factors. The latter include a variety of toxic heavy metals and xenobiotic compounds, but they are also influenced by essential elements, such as zinc. The exposure to antagonistic factors must be minimized for the full expression of its anticarcinogenic potential.
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PMID:Selenium. Mechanistic aspects of anticarcinogenic action. 137 60

Treatment of isolated mitochondria from rat hepatoma tumor cells (AS-30D) with the oxidant, t-butyl hydroperoxide (tBuOOH, 1 or 5 mumol/ml) resulted in the oxidation of glutathione (GSH to GSSG) and the formation of protein-glutathione mixed disulfides (ProSSG). The GSSG was retained inside of the hepatoma mitochondria. In the presence of ADP+succinate (5 or 10 mM), or ketoglutarate (10 mM) or malate (5 mM), the GSSG was reduced to GSH, but the amount of ProSSG stayed constant. With saline or ADP+glutamate (10 mM)/malate (0.1 mm) no reduction of GSSG to GSH occurred. The presence of antimycin (5 micrograms/ml) with ADP+succinate inhibited reduction. At a concentration of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, 0.5 mM) which inhibited a major portion of the glutathione reductase activity, the reduction of GSSG to replenish GSH was also inhibited. NADPH may play a critical role as well, for the addition of 2.4 mM NADPH to permeabilized hepatoma mitochondria fostered the reduction of GSSG after tBuOOH treatment. Therefore, hepatoma mitochondria possess a glutathione reductase-dependent system to reduce GSSG to GSH. The reaction only occurs with actively respiring mitochondria.
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PMID:Glutathione disulfide reduction in tumor mitochondria after t-butyl hydroperoxide treatment. 139 20

In vitro studies have suggested that elevated levels of the thiol glutathione (GSH) may be associated with acquired alkylating agent resistance, but there is currently little data on the relationship between elevated GSH and glutathione S-transferase levels and clinical alkylating agent resistance. In this study, GSH and glutathione S-transferase levels have been determined in 23 human ovarian tumor samples obtained prior to the onset of combination chemotherapy, and in 23 samples obtained after the development of acquired chemoresistance. GSH levels were 10-fold greater in human ovarian tumor cells obtained after alkylating agent resistance developed, than in biopsy samples obtained prior to treatment. No significant changes in the expression of total glutathione S-transferases were seen in relation to prior drug exposure.
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PMID:Cellular glutathione (GSH) and glutathione S-transferase (GST) activity in human ovarian tumor biopsies following exposure to alkylating agents. 139 40

The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole body irradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio.
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PMID:Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. 141 40


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