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

The postulation that the activity of key enzymes that reveal marked increases should be potential targets for anticancer chemotherapy (47) was supported by new evidence on the alterations of CDP reductase, CTP synthetase and OMP decarboxylase in hepatoma 3924A cell cultures. Inhibitors of these enzymes (VF-122, acivicin, pyrazofurin) and that of IMP dehydrogenase (tiazofurin) efficiently killed hepatoma 3924A cells in culture, as demonstrated by the clonogenic assay. Acivicin, pyrazofurin, tiazofurin and VF-122 were lethal against tumor cells in the exponential phase of growth with IC50 of 1.5, 5, 10 and 4.5 microM, respectively. All these antimetabolites exhibited cytotoxicity preponderantly against exponential-phase cultures, indicating that all the four drugs belong to Class II (phase-specific agents) in the Kinetic Classification of Anticancer Agents (38). Dibromodulcitol, a bifunctional alkylating agent, revealed cycle-specific cytotoxicity (Class III agent) against hepatoma 3924A, yielding IC50 values of 2.3 and 5.5 microM for exponentially and stationary growing cells, respectively. Using isobologram analysis on the survival data of 3924A cells, synergistic interaction was observed when DBD in combination with acivicin, pyrazofurin and tiazofurin was examined. DBD in combination with VF-122 exhibited additive lethality against hepatoma cells in culture. The synergistic and additive cytotoxicity in combinations of DBD with these antimetabolites was accompanied by the concurrent depletion of ribonucleotide and/or deoxyribonucleotide pools. The synergistic biological results of drug combinations of acivicin with DBD can be accounted for by the action of acivicin in inhibiting CTP synthetase, resulting in a synergistic decrease in CTP content, and by inhibition of DNA synthesis caused by DBD. The synergistic and additive depletion of UTP, CTP, dTTP and dCTP pools in the combinations of DBD with pyrazofurin may be responsible for the synergistic lethality of these combinations. Synergism, in terms of pool depletion, was observed for GTP and dCTP; summation was detected for dGTP when DBD and tiazofurin were given concurrently. The synergistic cytotoxicity of this drug combination may be a consequence of these alterations. The additive lethality of DBD-VF-122 drug combinations was reflected in the additive elevations of the ribonucleoside diphosphate concentrations. These observations indicate that treatments based on the Kinetic Classification and on the biochemical targeting of the drug should have an impact on the design of in vivo chemotherapy.
 ...
PMID:Potentiation of antimetabolite action by dibromodulcitol in cell culture. 383 19

Ribonucleotide reductase is a key enzyme in DNA replication and, as such, has been a target for antitumor agents. This enzyme is composed of two nonidentical protein subunits which can be specifically and independently inhibited. Combinations of drugs directed at the effector-binding and non-heme iron subunits of ribonucleotide reductase resulted in the synergistic inhibition of L1210 cell growth and synergistic L1210 cell kill. These combinations included dAdo/EHNA/IMPY/Desferal; dAdo/EHNA/hydroxyurea/Desferal (the EHNA was required to protect dAdo from deamination while Desferal modulated the effects of IMPY or hydroxyurea); 2-F-araA/IMPY/Desferal and 2-F-2'-dAdo/IMPY/Desferal (EHNA was not required to protect 2-F-araA or 2-F-2'-dAdo from deamination); and dGuo/8-AGuo/IMPY/Desferal (8-AGuo was required to protect dGuo from phosphorolysis). Although thymidine alone inhibited L1210 cell growth, it was not possible to potentiate the effects of thymidine with the pyrimidine nucleoside phosphorylase inhibitors, acyclothymidine, 5-chlorouracil and 2,6-dihydroxypyridine. Combinations of drugs directed at the ribonucleotide reductase and DNA polymerase sites were studied for their effects on L1210 cell growth. With these combinations, no synergistic inhibition of L1210 cell growth was observed. The combinations of aphidicolin and IMPY/Desferal and aphidicolin and dAdo/EHNA inhibited L1210 cell growth in an additive manner; the combinations of IMPY/Desferal and BuAU or IMPY/Desferal and BuPdG resulted in antagonistic inhibition of L1210 cell growth. From these results it is clear that combination chemotherapy directed at independent sites of the same key target enzyme can result in strong synergistic inhibition of cell growth and cytotoxicity offering a clear therapeutic advantage. In contrast, the combinations directed at sequential key enzymes (e.g. ribonucleotide reductase and DNA polymerase) did not result in synergistic inhibition of cell growth. The utility of combinations of drugs directed at specific but independent sites of the target enzyme (e.g. ribonucleotide reductase) has been demonstrated in tumor cell systems in culture and now must be demonstrated in vivo.
 ...
PMID:The utility of combinations of drugs directed at specific sites of the same target enzyme--ribonucleotide reductase as the model. 390 3

It would be expected that drugs directed at the rate-limiting step in a key metabolic pathway in tumor cell proliferation would provide a useful basis for therapy of neoplasms. Ribonucleotide reductase catalyzes the rate-limiting step in the de novo synthesis of dNTP's for DNA synthesis. Further, ribonucleotide reductase is composed of two non-identical protein subunits (non-heme iron and effector-binding subunits) which can be specifically and independently inhibited. As a result, combinations of drugs specifically directed at each of the subunits of ribonucleotide reductase have been shown to cause synergistic inhibition of L1210 cell growth in culture and synergistic cell kill. This approach offers a novel basis for the design of combination chemotherapy.
 ...
PMID:Combination chemotherapy directed at the components of nucleoside diphosphate reductase. 391 43

Ribonucleotide reductase catalyzes the rate-limiting step in DNA synthesis. It represents a key metabolic site at which specific inhibitors have been directed as potential antitumor agents. Several different classes of ribonucleotide reductase inhibitors have been generated and studied. Because of the nature of the DNA polymerase reaction in which all four dNTPs are required, the initial velocity vs dNTP concentration curve gives sigmoidal rather than hyperbolic kinetics. As a result, a 50 per cent decrease in ribonucleotide reductase activity causes a decrease in DNA polymerase activity of 75 per cent or greater depending on the ratio of [dNTP] to its Km. This has been demonstrated with theoretical calculations, actual DNA polymerase determinations and precursor studies in intact tumor cells. The structural requirements for a compound to serve as a specific inhibitor of ribonucleotide reductase, either as the non-heme iron or effector-binding subunit, are stringent. Each protein subunit comprising the active enzyme can be specifically and independently inhibited. When combinations of agents, each directed at one of the subunits of ribonucleotide reductase, are used, strong synergistic inhibition of L1210 cell growth and synergistic cytotoxicity result.
 ...
PMID:Drug action on ribonucleotide reductase. 391 89

Mechanism of cytotoxicity of 5-fluorouracil (5-FU) in relation to impairment of RNA metabolism was studied. 5-FU depressed the levels of ribonucleotide reductase and thymidine kinase, which are two key enzymes in DNA synthesis, in solid AH-130 tumor when given intraperitoneally at a dose of 60 mg/kg, and this inhibition seemed to be very toxic against cells. But this dose of 5-FU exceeded the amount that could be degraded by the liver, which was much higher than the clinical dose. We concluded that the impairment of RNA metabolism caused by 5-FU played a minor role in its anti-tumor actions.
 ...
PMID:[Studies on the mechanism of cytotoxicity of 5-fluorouracil--through impairment of metabolism]. 634 31

Mammalian ribonucleotide reductase catalyzes the rate-limiting for the de novo synthesis 2'-deoxyribonucleoside 5'-triphosphates. There is some suggestion that this step may also be the rate-limiting step of DNA synthesis. It is apparent that the level of the enzyme, ribonucleotide reductase, varies through the cell cycle and is highest in those tissues with the greatest proliferation rate. This increase in activity is associated with increased protein synthesis. The purified enzyme has been shown to be subject to strict allosteric regulation by the various nucleoside triphosphates and it has been proposed that allosteric regulation plays an important role in the level of ribonucleotide reductase activity which is expressed. All experimental data relating to this point, however, do not support the role of deoxyribonucleoside triphosphates as a major factor in determining cellular reductase activity during normal cell division. Several naturally occurring factors have been isolated from cells which lower ribonucleotide reductase activity in vitro. These factors have been found in tissues of low growth fraction and appear to be absent or low in tissues or high growth fraction such as tumor, regenerating liver and embryonic tissues. The expression of intracellular ribonucleotide reductase activity is therefore controlled at various levels and by various factors and the prevailing mode of regulation may vary throughout the cell cycle transverse and also in the various types of cells.
 ...
PMID:Regulation of ribonucleotide reductase activity in mammalian cells. 635 95

The objective of this investigation was to examine the relationship between levels of ribonucleotide reductase activity and transformation of two human cell strains. Enzyme activity levels were elevated by 3.2- to 3.5-fold in transformed cells compared directly to the normal human fibroblast strains from which they were derived. There did not appear to be a general correlation between elevated ribonucleotide reductase and increased proliferation abilities as has been previously observed with some rodent tumor cell lines. In keeping with the rise in reductase activity, human transformed cells were relatively more resistant to the cytotoxic effects of hydroxyurea, an antitumor agent whose site of action is ribonucleotide reductase. This indicates that an important point to be considered during drug therapy aimed at the reductase, is the greater sensitivity of normal compared to transformed cells due to differences in enzyme activity. The results of this investigation support the view that an increased ability to reduce ribonucleotides is an important step towards the development of a neoplastic program in human cells.
 ...
PMID:A comparison of ribonucleotide reductase activities in normal human fibroblast strains with their transformed counterparts. 639 12

Caracemide, a new antitumor agent now in clinical trial, was tested against partially purified ribonucleotide reductase from rat Novikoff tumor. It was found to be an active inhibitor, about one-ninth as effective as hydroxyurea.
 ...
PMID:Inhibition of ribonucleotide reductase by caracemide. 639 52

The metabolism of deoxycytidine (dCyd) and dCyd nucleotides in Yoshida ascites sarcoma (YS) cells and the host rat liver was investigated with reference to the increased excretion of urinary dCyd. Incorporation of [14C]orotic acid into the livers of rats at the fifth day after the transplantation of YS cells, the time when the amount of excretion of dCyd in urine was near maximal, was 2 times higher than that into the normal rat livers. After the injection of [14C]orotic acid, the ratio of the specific radioactivity of cytidylate to uridylate moieties of the host liver RNA was measured and found to be higher than that of normal rat liver RNA and to be similar to that of YS cell RNA. When [14C]orotic acid was injected into rats followed by the transplantation of YS cells, the radioactivities present in the livers disappeared more rapidly than those in the control rat livers. The activities of pyrimidine de novo synthesis enzymes, such as cytidine triphosphate synthetase (EC 6.3.4.2) and cytidine diphosphate reductase (EC 1.17.4.1), in YS were higher than those in both rat ascites hepatoma AH 7974 and Walker 256 carcinosarcoma, the transplantations of which did not induce increased excretion of dCyd into urine of the hosts. The activities of dCyd kinase (EC 2.7.1.10) and dCyd deaminase (EC 3.5.4.5) in YS cells were lower than those in the other two tumors investigated. The activities of cytidine triphosphate synthetase and cytidine diphosphate reductase in the livers of YS-bearing rats were elevated compared with those in the livers of rat ascites hepatoma AH 7974- or Walker 256 carcinosarcoma-bearing rats and normal rats, while the activities of dCyd kinase, 5'-nucleotidase (EC 3.1.3.5), and dCyd deaminase were similar between normal rat livers and tumor-bearing rat livers. These results suggest that the increased excretion of urinary dCyd in YS-bearing rats could be caused by both the stimulation of the synthesis of dCyd nucleotides and the low activity of dCyd deaminase in YS cells as well as in the host liver.
 ...
PMID:Origin of increased deoxycytidine excretion into urine of rats bearing Yoshida ascites sarcoma. 672 78

Cytotoxicity and perturbations of the deoxyribonucleoside triphosphate pools caused by thymidine were studied in thymidine-sensitive and -resistant human tumor cells. Incubation with 1 mM thymidine reduced cell viability by more than 90% in the three sensitive cell lines (two melanomas and one adrenal carcinoma) and reduced the growth rate without decreasing the viability of resistant LO melanoma cells. Thymidine (1 mM) greatly increased the ratio of the deoxythymidine 5'-triphosphate to deoxycytidine 5'-triphosphate pools in the sensitive cells compared to LO cells and also caused larger relative increases in the pool sizes of deoxyguanosine 5'-triphosphate and deoxyadenosine 5'-triphosphate in the sensitive compared to the resistant cells. 3-Deazauridine, known to inhibit synthesis of deoxycytidine 5'-triphosphate and cytidine 5'-triphosphate in other cell lines, potentiated the cytotoxicity of thymidine for thymidine-sensitive BE melanoma and LO cells. In LO cells, 3-deazauridine (50 microM) decreased the intracellular pool of deoxycytidine 5'-triphosphate to the level obtained with 1 mM thymidine. Lower concentrations of deoxycytidine as compared to cytidine were required to protect BE and LO cells against the cytotoxicity of thymidine plus 3-deazauridine. Deoxycytidine also was more effective than was cytidine in preventing loss of cell viability after exposure to thymidine or to 3-deazauridine individually. In these human melanoma cells, ribonucleotide reductase may be a major site of action of thymidine, of 3-deazauridine, and of both drugs in combination. These results indicate that in human tumor cells the cytotoxic effect of thymidine correlates with greater perturbations of the pyrimidine deoxyribonucleoside 5'-triphosphate pools and that thymidine and 3-deazauridine, which independently reduce the intracellular levels of deoxycytidine 5'-triphosphate, act synergistically against human tumor cells.
 ...
PMID:Cytotoxic and biochemical effects of thymidine and 3-deazauridine on human tumor cells. 672 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>