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)

Thionitrites are spontaneous nitric oxide (NO) donors in neutral aqueous solutions. Consequently, they inhibit ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis, from Escherichia coli and murine adenocarcinoma TA3 cells. They also inhibit tumor cell proliferation. Reaction of thionitrites with protein R1, the large subunit, results in the nitrosation of cysteines, as shown from the formation of a chromophore with a characteristic absorption at 340 nm. EPR spectroscopy both on whole murine R2-overexpressing L1210 cells and on the pure protein showed that the tyrosyl radical of protein R2, the small subunit, reversibly couples to the NO radical, presumably leading to nitrosotyrosine adducts. Both molecular events might be at the origin of the inhibition of ribonucleotide reductase by NO, since a number of cysteines and the tyrosyl radical are essential for catalysis. These results identify NO donors as a new class of inhibitors of ribonucleotide reductase with potential applications as anticancer or antiviral chemotherapy agents.
 ...
PMID:Inhibition of ribonucleotide reductase by nitric oxide derived from thionitrites: reversible modifications of both subunits. 772 99

Most mechanisms of drugs which are used in brain tumor chemotherapy are well characterized: alkylation of DNA components (nitrosoureas), binding with tubulin protein resulting in metaphase arrest (vincristine), chromatid breaks and chromosome translocations (procarbazine), or inhibition of ribonucleotide reductase (hydroxyurea) [1]. These drugs exert their effects mainly during certain cell cycle phases of proliferating cells, particularly when DNA is synthesized. From this it can be assumed that the efficacy of these drugs depends on the fraction of proliferating cells. Thus it would be of great importance to estimate the proliferation rate of brain tumors which could guide chemotherapy in individual patients. Positron emission tomography (PET) measures quantitatively the in vivo tissue uptake of tracer substances. In tumors, the uptake appears to be altered in a characteristic way determined by biochemical properties of tumor tissue. Some aspects of brain tumor metabolism which are theoretically related to proliferation have been investigated with PET. In the following, the literature is reviewed with regard to: 1) tracer substances whose uptake has been thought to reflect tumor malignancy (11C-methionine, 18F-fluoro-deoxyglucose), and 2) tracers which theoretically could reflect mechanisms specifically related to DNA synthesis (11C-putrescine, ligands for peripheral benzodiazepine receptors).
 ...
PMID:PET: brain tumor biochemistry. 776 Jan 7

Survival of rats harboring cerebral 9L gliosarcomas can be significantly extended by an intratumoral inoculation with a herpes simplex virus vector, designated as hrR3. This vector, which bears the lacZ reporter gene, is defective in the gene encoding ribonucleotide reductase, allowing for replication in dividing tumor cells but not in postmitotic neural cells. It also possesses an intact viral thymidine kinase (TK) gene, which confers chemosensitivity to ganciclovir. In this study, the ability of ganciclovir to potentiate the antitumor effect of hrR3 was evaluated. In culture, there was a 23% decrease in the growth of 9L cells treated with hrR3 plus ganciclovir compared to hrR3 alone (P < 0.01). The combination of hrR3 plus ganciclovir led to the long-term survival of 48% of rats harboring intracerebral 9L gliosarcomas compared to 20% survival in the hrR3 group (P < 0.05). Ganciclovir treatment had no effect on the growth of tumor cells in vitro or in vivo when a herpes simplex virus vector with a defective TK gene was used. Immunocytochemistry confirmed selective expression of the TK gene in cells within the tumor. These findings indicate that the TK gene can potentiate the antitumor effect of the hrR3 herpes simplex virus vector and provide the basis for placing additional therapeutic genes in the genome of hrR3.
 ...
PMID:Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. 795 93

Herpes simplex virus (HSV) mutants kill dividing tumor cells but spare non-proliferating, healthy brain tissue and may be useful in developing new treatment strategies for malignant brain tumors. Two HSV mutants, a thymidine kinase deficient virus (TK-) and a ribonucleotide reductase mutant (RR-), killed 7/7 human tumor cell lines in tissue culture. The TK-HSV killed Rat RG2 glioma and W256 carcinoma lines but not the rat C6 glioma in culture. TK-HSV replication (12 pfu/cell) was similar to wild-type HSV (10 pfu/cell) in rapidly dividing W256 cells in tissue culture, but was minimal (< 1 pfu/cell) in serum-starved cells, suggesting that the proliferative activity of tumor cells at the site and time of TK-HSV injection may influence efficacy in vivo. Subcutaneous W256 tumors in male Sprague-Dawley rats were injected with TK-HSV or free inoculum. A significant effect of TK-HSV therapy on W256 tumor growth was demonstrated compared to controls (p = 0.002). Complete regression was observed in 4/9 experimental tumors, with no recurrence over 6 months. Tumor growth in the remaining 5/9 animals was attenuated during the first 3 to 5 days after treatment, but not beyond 5 days compared to 9 matched control animals; no tumor regression was observed in any of the control animals. These results suggest that HSV mutants are potentially useful as novel therapeutic agents in the treatment of tumors in immunocompetent subjects.
 ...
PMID:Mutant herpes simplex virus induced regression of tumors growing in immunocompetent rats. 796 89

Increased ribonucleotide reductase (RR) activity has been linked with malignant transformation and tumor cell growth. Therefore, this enzyme is considered to be an excellent target for cancer chemotherapy. We have examined the effects of a newly patented RR inhibitor, trimidox (3,4,5-trihydroxybenzohydroxamidoxime). Trimidox inhibited the growth of human promyelocytic leukemia HL-60 cells with an IC50 of 35 mumol/L. Incubation of HL-60 cells with 50 mumol/L trimidox for 24 hours decreased deoxyguanosine triphosphate (dGTP) and deoxycytidine triphosphate (dCTP) pools to 24% and 39% of control values, respectively. Incubation of HL-60 cells with 20 to 80 mumol/L trimidox even up to a period of 4 days did not alter the distribution of cells in different phases of cell cycle. Sequential incubation of HL-60 cells with trimidox (25 mumol/L) for 24 hours and then with 10 mumol/L tiazofurin (an inhibitor of inosine monophosphate dehydrogenase) for 4 days produced synergistic growth inhibitory activity, and the cell number decreased to 16% of untreated controls. When differentiation-linked cell surface marker expressions were determined in cells treated with trimidox and tiazofurin, a significantly increased fluorescence intensity was observed for the CD 11b (2.9-fold). CD 33 (1.9-fold), and HLA-D cell surface antigens. Expression of the transferrin receptor (CD71) increased 7.3-fold in cells treated with both agents, compared with untreated controls. Our results suggest that trimidox in combination with tiazofurin might be useful in the treatment of leukemia.
 ...
PMID:Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells. 799 48

In vitro and in vivo studies have established gallium nitrate as an effective chemotherapeutic agent against human medulloblastoma. In vitro, gallium nitrate reduced cell proliferation and DNA synthesis of medulloblastoma Daoy. Gallium inhibits the availability of 59Fe to ribonucleotide reductase and has a direct effect on the enzyme itself. In vivo, gallium demonstrated similar effects on the medulloblastoma Daoy cell line in nude mice. Tumor growth rate and actual size were decreased; however, severe nephrotoxicity and mortality were observed. In our study, intradermal injections of medulloblastoma Daoy cells were given to nude mice and then tumors were allowed to grow. Tumor-bearing mice received a 15-day gallium (50 mg/kg/day) regimen, 20-day rest, 7-day gallium (66.5 mg/kg/day) dose escalation regimen beginning when tumor size exceeded 8-10 mm in diameter. All treated and control mice received saline hyperhydration during both treatment sessions. Our study resulted in the prevention of severe toxicity and an inhibition of tumor growth. No toxicity occurred with gallium nitrate at 50 mg/kg/day. Severe morbidity and mortality were observed at the higher gallium dose level (66.5 mg/kg/day), suggesting that the 50 mg/kg/day dose is the appropriate level when investigating gallium nitrate as a chemotherapy agent in nude mice.
 ...
PMID:Prevention of gallium toxicity by hyperhydration in treatment of medulloblastoma. 806 Apr 23

A series of substituted 2-acylpyridine-alpha-(N)-hetarylhydrazones was prepared and studied for their effects on mammalian ribonucleotide reductase activity using a highly purified enzyme preparation from Ehrlich tumor cells and on mouse leukemia L1210 cell growth in culture. Pyridine-2-aldehyde-2-pyridylhydrazone (PH 22), ethyl-2-pyridylketone-I-phthalazinylhydrazone (PH 22-25) and pyridine-2-aldehyde-2'-quinolylhydrazone (PQ 22) inhibited purified ribonucleotide reductase activity and inhibited L1210 cell growth in culture. PH 22-25 inhibited [3H]thymidine incorporation into DNA and inhibited ribonucleotide reductase activity in situ (as measured bvy [14C]cytidine metabolism and as a result inhibited DNA synthesis. There was no effect on RNA synthesis. These data indicate that these substituted hydrazones are potent inhibitors of tumor cell growth through the inhibition of ribonucleotide reductase.
 ...
PMID:Substituted 2-acylpyridine-alpha-(N)-hetarylhydrazones as inhibitors of ribonucleotide reductase activity and L1210 cell growth. 807 87

The R2 gene of ribonucleotide reductase is elevated in BALB/c 3T3 fibroblasts treated with the tumor promotor, 12-O-tetradecanoylphorbol-13-acetate (TPA). TPA treatment increased the half-life of the R2 message by 3-fold, showing that TPA regulates R2 gene expression by a post-transcriptional mechanism(s). A 20-nucleotide (nt) TPA-responsive region was found within the R2 mRNA 3'-untranslated region (3'UTR). Ultraviolet cross-linking detected a novel 45-kDa protein-R2 mRNA complex migration band that bound selectively to the 20-nt fragment and did not bind to the 5'UTR or the coding region of the R2 message, or to the 3'UTRs of mRNA from several other genes, or to the homopolymer poly(A) sequence. The-45 kDa protein-R2 mRNA binding activity observed in unstimulated cells was markedly down-regulated after TPA treatment. Deletion of a 201-nt region, containing the 20-nt sequence, from the 3'UTR caused stabilization of hybrid chloramphenicol acetyltransferase mRNA in the absence of TPA treatment. Furthermore, in vitro decay reaction mixtures supplemented with the 20-nt sense RNA transcript resulted in stabilization of R2 message. A model is presented of R2 message regulation in which a cis-element within the 20-nt sequence of the 3'UTR interacts with a cytosolic protein to form a 45-kDa protein-mRNA binding complex. The TPA-induced alteration of R2 message stability is at least in part due to the down-regulation of the 45-kDa protein-mRNA binding activity which is linked to a reduction in the rate of R2 mRNA degradation.
 ...
PMID:Phorbol ester modulation of a novel cytoplasmic protein binding activity at the 3'-untranslated region of mammalian ribonucleotide reductase R2 mRNA and role in message stability. 812 29

(E)-2'-Deoxy-2'-(fluoromethylene)cytidine (MDL 101,731) is a mechanism-based inhibitor of ribonucleoside diphosphate reductase (J. Stubbe, personal communication), an enzyme involved in DNA synthesis and therefore a potential target for cancer chemotherapy. In the present report, we show that MDL 101,731 inhibits the proliferation of several human breast cancer cell lines, including the estrogen-dependent cell line, MCF-7, and the estrogen-independent cell lines MDA-MB-231, MDA-MB-468, and MDA-MB-435 in vitro at nanomolar concentrations (50% inhibitory concentration, 15-26 nM). Administration of MDL 101,731 caused marked regression of tumors which formed after s.c. inoculation of all four of the cell lines in athymic (nude) mice. MDA-MB-231 tumors were found to be most sensitive to MDL 101,731 with a 90-100% cure rate at doses of MDL 101,731 between 2 and 20 mg/kg, given as once daily i.p. injections, 5 days/week for as little as 3 weeks. Almost complete cessation of MDA-MB-231 tumor growth was obtained with a dose of 0.5 mg/kg MDL 101,731 following the same dosing regimen. MDA-MB-468, MDA-MB-435, and MCF-7 tumors were not as sensitive as MDA-MB-231, but tumor regression of 50, 65, and 80%, respectively, was obtained after 5-6 weeks of treatment. The effects of MDL 101,731 on spontaneous metastasis of MDA-MB-435 cells from the mammary fat pad to the lung was also examined, and it was found that the number of lung metastases was significantly decreased if mice received MDL 101,731 while the primary tumors were growing and after primary tumors were surgically excised. Additionally, preliminary evidence raises the possibility that MDL 101,731 may induce apoptosis in MDA-MB-231 tumors. Our data suggest that the use of MDL 101,731 for the treatment of breast cancer and possibly other solid tumors should be pursued.
 ...
PMID:Regression of human breast tumor xenografts in response to (E)-2'-deoxy-2'-(fluoromethylene)cytidine, an inhibitor of ribonucleoside diphosphate reductase. 813 52

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC50) at 5 microM, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC50 of 500 microM. Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with trimidox at 7.5 microM, a concentration that inhibits cell proliferation by 50% (IC50) or at 100 microM for 2 h; these concentrations resulted in a decrease in enzyme activity to 22% and 50% of the control value, respectively. Trimidox and hydroxyurea were cytotoxic to L1210 cells with IC50 values of 7.5 and 50 microM, respectively. Versus ribonucleotide reductase, trimidox and hydroxyurea yielded IC50 values of 12 and 87 microM, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing L1210 leukemia (by 82% in male mice and 112% in female mice). The anti-tumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and potent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.
 ...
PMID:Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase. 817 4


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