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)

Administration of 2,3-dihydro-1H-pyrazole[2,3a]imidazole (IMPY, 150 mg/kg) followed 8 hr later by injection of deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine (dAdo/EHNA, 175 mg/17.5 mg/kg) on days 2, 3, 6, and 7 increased the mean survival time of L1210 tumor bearing mice (210%). The sequential treatment was more efficacious than the simultaneous administration of these drugs. Administration of IMPY or dAdo/EHNA, alone, at the same doses as in the combination, did not prolong the life-span of tumor bearing mice. To determine the basis for the increased survival due to the sequential treatment with IMPY and dAdo/EHNA, cell cycle analysis and deoxyribonucleoside triphosphate concentrations were measured. Cytotoxicity of IMPY and dAdo/EHNA is known to be achieved through the inhibition of ribonucleotide reductase. IMPY is a specific inhibitor of the nonheme-iron subunit of ribonucleotide reductase, whereas deoxyadenosine in the presence of the adenosine deaminase inhibition, EHNA, is converted to deoxyadenosine 5'-triphosphate (dATP), which is a specific inhibitor of the effector-binding-subunit of ribonucleotide reductase. Our studies showed that L1210 cells accumulated in early S-phase, whereas intracellular dATP and deoxyguanosine triphosphate (dGTP) pools were depleted 8 hr after IMPY administration. dAdo/EHNA administration 8 hr after IMPY injection caused an increase in the intracellular concentration of dATP while maintaining the depletion of the dGTP pool and prolonged the S-phase as compared to the administration of IMPY alone.
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PMID:Antineoplastic effect of the combination of 2,3-dihydro-1H-pyrazole[2,3a]imidazole plus deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine in mice with L1210 leukemia cells. 236 48

Experiments were carried out in vitro using DNA polymerase and ribonucleotide reductase inhibitors to investigate their cytotoxicity to P388 murine leukemia sensitive (P388/S) and resistant (P388/R) to adriamycin (ADR). DNA polymerase inhibitors such as cytosine arabinoside (ara-C) and aphidicolin elicited comparative inhibition of DNA biosynthesis in both parental and ADR-resistant tumor cells. However, ribonucleotide reductase inhibitors such as hydroxyurea (HU) and caracemide were collaterally more sensitive to P388/R cells. Inosine diglycolaldehyde (Inox) was ineffective in showing such a response. Pretreatment with HU significantly increased intracellular ADR levels and inhibition of RNA biosynthesis by ADR in P388/R cells while, in P388/S cells, sequential or concurrent treatment with HU did not enhance intracellular ADR levels. Mechanisms underlying such an effect, implications due to reduced intracellular ATP levels in drug-resistant cells, and the possible utility of using ribonucleotide reductase as a target in drug-resistant tumors for the therapeutic benefit are discussed.
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PMID:Differential effect of collaterally sensitive antimetabolites on P388 murine leukemia sensitive and resistant to adriamycin in vitro. 251 59

Naturally occurring tyrosine radicals from the M2 subunit of ribonucleotide reductase (RR) have been recorded by ESR in proliferating ordinary Ehrlich-ascites (EA) tumor cells of mice. Tyrosine radicals are stable in EA cells at room temperature for 2 h. Up to 500 mW no microwave saturation occurs. The relatively high stability and non-saturation of tyrosine radicals in EA cells suggests a suitable protein conformation in the M2 subunit enabling a close contact between the tyrosine radical and the antiferromagnetic iron complex. This facilitates an ESR study of functionally essential tyrosine radicals of RR in EA cells at low temperature and recommends this cellular system for studying such processes as inhibition and activation, which change the content of tyrosine radicals of the proliferation-linked RR. Oxygen treatment of non-proliferating (quiescent) EA cells reactivates tyrosine radicals 2-3 fold as found in strongly proliferating cells. We conclude that in quiescent cells, suffering from a lack of oxygen due to their high density in the peritoneal cavity, a reactivation of tyrosine radicals occurs by oxidation of non-radical tyrosine residues of inactive M2 subunits.
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PMID:Stability and reactivation of tyrosine radicals from ribonucleotide reductase in tumor cells studied by ESR. 253 45

The paramagnetic form of ribonucleotide reductase was detected by ESR method in human cervix tissues, especially in tumor ones. The magnetic relaxation rate was proved to be slower for this form than for that in normal animal tissues having a high level of proliferative activity or in Ehrlich tumor cells studied before.
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PMID:[Paramagnetic form of ribonucleotide reductase in human tissues]. 254 65

Iron (Fe) depletion with anti-transferrin (Tf) receptor monoclonal antibodies (MAbs), Fe chelators, or gallium (Ga) salts inhibits in vitro and in vivo growth of tumor cells. The present studies examined the cytotoxic effects of an IgA anti-human Tf receptor MAb, 42/6, combined with parabactin, a powerful Fe chelator, or Ga nitrate. Parabactin inhibited in vitro growth of human hematopoietic and solid tumor cells, and the rank order of their sensitivities to the Fe chelator was identical to their relative sensitivity to MAb 42/6 as demonstrated in previous studies. When the most parabactin and MAb 42/6-sensitive (HL60 leukemia) and -resistant (KB carcinoma) cells were incubated with various concentrations of parabactin, cell killing was time and dose dependent over the first 24 hours. Little additional cytotoxicity occurred, however, when cells were exposed to parabactin for 48 hours. HL60 cells were slightly more sensitive than KB cells to parabactin cytotoxicity. Addition of optimally effective concentrations of anti-Tf receptor MAb 42/6 to parabactin increased cytotoxicity to HL60 cells over a narrow parabactin dose range but had little effect on cytotoxicity to KB cells. Cell cycle analysis of cells treated with parabactin for 24 hours showed that doses causing variable cytotoxicity increased the percentage of cells in S phase, but higher parabactin concentrations consistently arrested cells in G1 phase or at the G1/S interface. MAb 42/6 also increased toxicity of parabactin to granulocyte/macrophage colony-stimulating factors and normal marrow granulocyte/macrophage progenitors. When HL60 or KB cells were treated with MAb 42/6 combined with Ga nitrate, MAb 42/6 increased cytotoxicity of Ga for HL60 cells but had little or no effect on Ga cytotoxicity to KB cells. In contrast, MAb 42/6 had minimal effects on cytotoxicity of the ribonucleotide reductase inhibitor, isoquinaldehyde thiosemicarbazone, to either HL60 or KB cells. Both hematopoietic and solid tumors were killed by Fe depletion, but the present studies suggested that hematopoietic cells are more sensitive than solid tumor cells to cytotoxic effects of Fe depletion. Combined Fe depletion therapy by the use of MAb 42/6 with an Fe chelator or Ga salt increased toxicity to MAb 42/6-sensitive cells, such as HL60, but was not more effective against MAb 42/6-resistant solid tumor cells. Combination Fe depletion therapy of hematopoietic cell tumors merits evaluation in experimental in vivo tumor systems.
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PMID:Combination iron depletion therapy. 266 76

A rapid elevation of ribonucleotide reductase activity was observed with BALB/c 3T3 fibroblasts within 1/2 to 1 hour treatment with 0.1 microM 12-O-tetradecanoylphorbol-13-acetate (TPA). This increase in activity was transient, and returned to about normal levels within 24 to 48 hours. Northern analysis of the two components of ribonucleotide reductase showed a slight transient elevation of M1 mRNA and a marked transient elevation of M2 mRNA after 1/2 hour TPA treatment. As a positive control, ornithine decarboxylase message levels were also observed to be transiently elevated following identical treatment with TPA. Western blot analysis with M1 and M2 specific monoclonal antibodies indicated that the increase in ribonucleotide reductase activity was primarily due to the transient elevation of the M2 but not the M1 protein during treatment with 0.1 microM TPA. This first demonstration that the tumor promotor, TPA, can cause rapid and transient alterations in ribonucleotide reductase suggests that the enzyme, particularly the M2 component, may play an important role in the critical events involved in the process of tumor promotion.
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PMID:Transient elevation of ribonucleotide reductase activity, M2 mRNA and M2 protein in BALB/c 3T3 fibroblasts in the presence of 12-O-tetradecanoylphorbol-13-acetate. 266 51

Although they are proliferatively quiescent, the cells in the intact adult rat liver express the gene coding for the M1 subunit of ribonucleotide reductase. But since they do not need deoxyribonucleotides, they promptly inactivate the 88 to 90 kDa M1 products and degrade them into 40 kDa fragments. Partial hepatectomy signals the remaining cells to start proliferating. Two hours before the onset of DNA replication, around 16 to 18 hr after partial hepatectomy, the cells start accumulating a large pool of functional ribonucleotide reductase M2 subunits. Near the end of the G1 build-up the cells step up M1 gene expression, stop inactivating, and reduce the degradation of the M1 products. The accumulating functional 88 to 90 kDa M1 subunits, each with more than one catalytic site, couple with functional M2 subunits to produce active ribonucleotide reductase holoenzyme which accumulates in the outer nuclear membrane from which they supply deoxyribonucleotide precursors to intranuclear replication enzymes. At the end of the S phase, the cell reduces M1 gene expression and resumes degrading 88 to 90 kDa M1 subunits. At least some of the 40 kDa M1 fragments are still active and can form partially active "holoenzymes" when mixed with a standard preparation of functional M2 subunits. The M1 control mechanism appears not to operate in hepatoma cells and Ehrlich ascites tumor cells, both of which maintain a pool of undegraded 88 to 90 kDa M1 components.
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PMID:Ribonucleotide reductase--new twists in an old tale. 269 42

Culture experiments on Ehrlich ascites tumor cells revealed that a low oxygen tension (about 20% in normoxic atmosphere) induced an increase in the length of the growth cycle. The relative growth of aerobic control cells after transfer to the second in vitro passage was 145% within 24 h, and reduced to 50% at 1% O2 and about 30% at 0.1% O2. The increase in protein and DNA content of these hypoxic cultures was equally impaired. Also, the cell cycle traverse as analyzed by flow cytometry was affected predominantly at the G1/early S stage. Uptake of labeled thymidine into acid-insoluble material of hypoxic cells was below that of controls whereas incorporation of uridine exceeded that of normoxic controls. Supplementation of cells cultured under 0.1 and 1% O2 with 0.1 mM uridine or 0.1 mM deoxycytidine + 0.01 mM deoxyadenosine and deoxyguanosine improved all growth parameters; deoxynucleosides were more effective than uridine in cells under 0.1% O2 whereas in cells cultured under 1% O2 similar effects of both were observed. This points to an insufficient supply of nucleic acid precursors even under moderate limitations of oxygen tension and not only under strict hypoxia. Whereas a 12-h cultivation time at 0.1% O2 hardly impaired cell growth after reoxygenation, a cultivation time of 24 h considerably reduced the cellular capability to recover. This was alleviated by addition of (deoxy)nucleosides from the beginning of hypoxic culture. The results are interpreted as supporting the concept that the biosynthetic pathway of pyrimidine (deoxy)nucleotides--because of two oxygen-dependent enzymes, dihydroorotate dehydrogenase and ribonucleotide reductase--is a potential transducer of environmental limitations in oxygen tension to the proliferative capacity of cells.
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PMID:The biosynthetic pathway of pyrimidine (deoxy)nucleotides: a sensor of oxygen tension necessary for maintaining cell proliferation? 272 99

The fluoropyrimidines, FUra and 5-fluoro-2'-deoxyuridine (FUdR), have been found to be more growth inhibitory and cytotoxic to both mouse and human tumor cells when grown in cell culture medium containing folinic acid. The increment in the activity of these drugs observed in folinate-containing medium was similar for a mouse leukemia cell line and for 4 human leukemia cell lines. This suggests that the mechanism of action of the fluoropyrimidines against these mouse and human cell lines is similar. The most probable mechanism of the interaction between folinic acid and the fluoropyrimidines is stabilization of thymidylate synthase (TS) in inactive complexes with 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and folate cofactor. Such trapping of enzyme in inactive form would negate the effects of the accumulation of the reaction substrate 2'-deoxyuridine-5'-monophosphate. It is suggested that the combination of FUra with folinic acid and, in addition, an inhibitor of ribonucleotide reductase such as hydroxyurea may be more effective than FUra and folinic acid alone.
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PMID:Biochemical rationale for the synergism of 5-fluorouracil and folinic acid. 296 29

The transforming potential of the herpes simplex virus type 2 (HSV-2) BamHI fragment E (map position 0.533-0.583) encoding the 140-kDa ribonucleotide reductase was assayed by transfection in established Rat-2 cells. Foci of refractile, morphologically distinguishable cells were induced at lower efficiency and after a longer incubation period as compared to the human tumor oncogene EJ-Ha-ras. Focus-derived BamHI fragment E-transformed cell lines formed medium-to-large (0.1-0.25 mm) colonies in soft agar and were tumorigenic in immunocompetent syngeneic rats. Southern blot analysis of normal rat DNA after EcoRI digestion revealed specific DNA segments homologous to HSV-2 BamHI fragment-E DNA. In BamHI fragment E-transformed and tumor-derived lines, about 8- to 30-fold amplification was detected in a subset of the specific HSV-related DNA segments. In addition, extrachromosomal DNA was isolated from transformed cells by plasmid rescue and contained the left-hand 70% of HSV-2 Bam HI fragment E fused to rat DNA. These results indicate the presence in normal cells of nonrepetitive DNA segments, related to the transforming HSV-2 fragment, that can be targeted for genetic alterations associated with neoplastic transformation.
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PMID:DNA amplification and neoplastic transformation mediated by a herpes simplex DNA fragment containing cell-related sequences. 300 67


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