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 prevalence of herpes simplex virus type 2 (HSV-2) infections in the US has increased approximately 30%. Like HSV-1, which causes facial lesions, HSV-2 causes symptomatic lesions (at genital sites) and establishes latent infections of the sensory ganglia. However, the two viruses are biologically distinct, suggesting that they possess unique functions which are mediated by different viral genes. Unlike HSV-1, HSV-2 is a tumor virus. It causes neoplastic transformation of cultured human cells and tumors in animals. The oncogene is at the 5'-terminal of a chimeric gene that also codes for the large subunit of viral ribonucleotide reductase (RR1). It was captured from the cell and it codes for a novel growth factor receptor serine-threonine protein kinase (PK) the minimal genetic information of which can adapt to a relatively wide functional diversity due to the flexibile use of additional and alternate catalytic sites and protein interaction motifs which are organized in an efficient, almost superimposed fashion. By contrast to other growth factor receptor serine-threonine kinases studied so far, the HSV-2 oncoprotein (RR1 PK) activates the RAS signaling pathway, thereby providing a biological bridge to the tyrosine growth factor receptor kinases. Expression of the oncogene is required for neoplastic transformation and tumor growth in vivo is inhibited by antisense inhibition of oncogene expression. The virus conserved the captured oncogene because it provides a biological advantage for its survival. In cultured cells, RR1 PK is required for viral IE gene transcription. In vivo, RR1 PK is likely to be involved in latency reactivation.
 ...
PMID:Herpes simplex virus type 2: unique biological properties include neoplastic potential mediated by the PK domain of the large subunit of ribonucleotide reductase. 945 54

The ribonucleotide reductase (RR) gene has been associated with malignant transformation and metastatic potential. In this report, the significance of the expression of RR mRNA and enzymatic activity to the invasive potential was examined by Boyden chamber invasion assay. Our results suggest that overexpression of RR M2 mRNA and RR enzymatic activity correlates to an increase in cell invasive potential. The drug-induced HURs clone expressed a higher level RR M2 mRNA and enzyme activity which contributes significantly to the 3-fold increase in invasive potential of the cells observed relative to the KB wild-type control. On the contrary, the HUr revertant clone decreased the RR M2 mRNA level and enzymatic activity, concomitantly decreasing their invasive potential. This phenomenon is most likely due to the return of RR to levels comparable to that of the KB wild-type cells. To confirm that this observation was not of a drug-resistance phenotype associated with multiple gene alterations, the panel of RR transfectants (M1-D transfected M1 subunit cDNA, M2-D transfected M2 subunit cDNA, X-D transfected M1/M2 cDNA) characterized in a previous study were also tested in the invasion assay. The M2-D clone expressed 6-fold higher RR M2 mRNA and RR activity and also demonstrated 6-fold higher invasive potential in vitro than either the parental or vector only transfected cell line (KB-V). The X-D clone demonstrated 3-fold higher M2 mRNA expression and revealed 4-fold higher invasive potential than control cells. The M1-D clone, in contrast, expressed a baseline level of RR M2 mRNA and higher M1 mRNA. In contrast to the X-D and M2-D cells, the invasive potential of M1-D reached an even lower level in the invasive assay than the control. These results, therefore, suggest that RR M2 overexpression plays an important role in a tumor's invasiveness.
 ...
PMID:Overexpression of transfected human ribonucleotide reductase M2 subunit in human cancer cells enhances their invasive potential. 950 76

Herpes simplex viruses type 1 (HSV-1) with an inactivated viral ribonucleotide reductase (Hsrr, ICP6) were designed to target tumor cells with upregulated mammalian ribonucleotide reductase (mRR), an enzyme whose expression is regulated by the p16/pRB tumor suppressor pathway. A recombinant HSV-1 was generated by knock-out of Hsrr and insertion of the rat CYP2B1 transgene responsible for the bioactivation of the prodrugs, cyclophosphamide and ifosfamide. The mutant virus replicated selectively in rat and human tumor cells that express mRR. Addition of cyclophosphamide potentiated oncolytic effects against cultured tumor cells and subcutaneous tumor xenografts established in athymic mice.
 ...
PMID:An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy. 959 92

Recently, it was demonstrated that bradykinin (BK) enhances intracarotid delivery of herpes simplex virus type I (HSV) vectors to rat brain tumors, and that gene transfer takes place predominantly in the tumor periphery. The aim of the present study was to apply these findings to the treatment of experimental rat brain tumors. The HSV mutant, hrR3, which is disrupted in the ribonucleotide reductase gene, was injected intra-arterially with titers of 1 x 10(8), 1 X 10(9), and 1 x 10(10) plaque-forming units (pfu) both with and without BK into Fischer 344 rats with intracerebral, syngeneic 9L tumors. Starting on day 3 after vector administration, animals were treated by intraperitoneal injection of 60 mg/kg/day ganciclovir (GCV) or placebo. 1 x 10(10) pfu hrR3 in combination with BK and GCV treatment was able to eradicate tumors in 80% of the animals; 1 x 10(9) pfu cured 40% of the rats, and 1 x 10(8) pfu achieved an extension of survival time but no tumor cures. Control groups had 100% mortality within 30 days after injection of tumor cells, with the exception of the group with injection of 1 x 10(10) pfu of virus and GCV treatment, which had one long-term survivor. No apparent complications of this novel type of brain tumor gene therapy were encountered. In conclusion, intra-arterial injection of attenuated HSV vectors with blood-tumor barrier modification and subsequent systemic GCV application appears to be a promising approach for the treatment of malignant brain tumors.
 ...
PMID:Long-term survival in a rodent brain tumor model by bradykinin-enhanced intra-arterial delivery of a therapeutic herpes simplex virus vector. 962 99

Ribonucleotide reductase is the rate limiting enzyme of de novo DNA synthesis; its activity is significantly increased in tumor cells related to the proliferation rate. Therefore the enzyme is considered to be an excellent target for cancer chemotherapy. In the present study we tested the in vitro and in vivo antitumor effects of a drug combination using trimidox (3,4,5-trihydroxybenzamidoxime), a novel inhibitor of ribonucleotide reductase with adriamycin, a widely used anticancer drug. This combination was selected because adriamycin generates free radicals being responsible for cardiotoxic side effects; trimidox has been shown to be a good free radical scavenger. The in vitro cytotoxic effect of the drug combination was examined in L1210 mouse leukemia cells employing a MTT chemosensitivity assay. Incubation of these cells with adriamycin and trimidox together yielded less than additive cytotoxic effects compared to either drug alone. These effects were not caused by the involvement of p-glycoprotein mediated drug efflux. However, when the effect of trimidox and adriamycin in combination was examined in L1210 leukemia bearing mice antitumor effects of adriamycin could be enhanced by the presence of trimidox. Our data indicate, that the in vivo combination of adriamycin together with trimidox might be beneficial for the treatment of malignancies.
 ...
PMID:Enhanced effects of adriamycin by combination with a new ribonucleotide reductase inhibitor, trimidox, in murine leukemia. 971 80

The influence of pre-existing anti-herpes simplex type 1 (HSV-1) immunity on HSV-1 vector-mediated gene transfer to glioma cells was analyzed in this gene marking study using intracranial D74 gliomas in syngeneic Fischer rats. The HSV-1 mutant virus used, hrR3, is defective in ribonucleotide reductase and bears the marker genes E. coli lacZ and HSV-1 thymidine kinase (HSVtk). Initial marker gene expression in tumors 12 h after direct virus injection was reduced in immunized animals to about 15% of that in nonimmunized animals. Marker gene expression in both sets stayed at initial levels for 2 days after intratumoral injection and declined markedly on day 5. Inflammatory infiltrates in the tumor were more prominent in HSV-1-immunized, as compared with nonimmunized animals, at 12 and 24 h, but appeared similar at 2-5 days after injection. By day 10, the immune reaction had subsided in immunized animals and macrophages remained only in nonimmunized animals. In conclusion, gene transfer to brain tumors using a HSV-1 vector was greatly reduced, but not completely abolished, under pre-immunization conditions. Pre-existing antibodies to HSV-1 may also serve a positive role in providing an increased margin of safety in intracranial application of HSV-1 vectors by limiting spread of the virus within the brain and to other tissues.
 ...
PMID:Pre-existing herpes simplex virus 1 (HSV-1) immunity decreases, but does not abolish, gene transfer to experimental brain tumors by a HSV-1 vector. 974 61

(E)-2'-deoxy-2'-(fluoromethylene) cytidine (MDL101,731) is a new deoxycytidine analog which shows potent antitumor activity against several human tumor models. We previously showed that MDL101,731 inhibited human ribonucleotide reductase (RNR) in HeLa S3 human cervical carcinoma cells. Recently, it has been reported that another deoxycytidine analog, 2'-deoxy-2'-methylidenecytidine (DMDC) which also inhibits RNR from Escherichia coli, does not inhibit RNR in intact L1210 murine leukemia cells. MDL101,731 was designed as an inhibitor of RNR, so it is important to know the contribution of the RNR inhibitory activity of the drug on its antitumor efficacy in vivo. Therefore, we examined the relationship between the antitumor activity and RNR inhibitory activity of MDL101,731 using LX-1 human lung carcinoma which was highly sensitive to this drug. MDL101,731 showed strong inhibition of RNR activity in LX-1 lung carcinoma by both i.v. and p.o. administration. Administration of 15 mg/kg i.v. and 30 mg/kg p.o. of MDL101,731, doses which showed almost the same degree of antitumor activity against LX-1 lung carcinoma on a daily 5 day schedule, caused a similar degree and similar kinetics of inhibition of RNR in LX-1 lung carcinoma at least for 12 h after administration. On the other hand, DMDC as well as 1-beta-D-arabinofuranosyl-cytosine (ara-C), which is a well-known deoxycytidine analog and inhibits DNA polymerase alpha, did not inhibit RNR in LX-1 lung carcinoma at doses demonstrating antitumor activity. These results indicate that MDL101,731 exhibited antitumor activity through inhibition of RNR activity in tumor cells in vivo and the mechanism of antitumor action of MDL 101,731 might be different from those of DMDC and ara-C, at least in part.
 ...
PMID:The relationship between the antitumor activity and the ribonucleotide reductase inhibitory activity of (E)-2'-deoxy-2'-(fluoromethylene) cytidine, MDL 101,731. 977 10

Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. human C33-A cervix cancer and U-87 MG glioblastoma xenografts. FMdC given once daily has a dose-dependent antitumor effect. The maximum tolerated dose in the mice was reached with 10 daily i.p. administrations of 10 mg/kg over 12 days. In the case of radiotherapy (RT) alone (10 fractions over 12 days), the radiation dose required to produce local tumor control in 50% of the treated C33-A xenografts was 51.0 Gy. When combined with FMdC, the radiation dose required to produce local tumor control was reduced to 41.4 and 38.2 Gy, at respective doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation. The corresponding enhancement ratios (ERs) were 1.2 and 1.3, respectively. In U-87 MG xenografts, when 5-20 mg/kg FMdC combined with 30 or 40 Gy of RT, the combination treatment produced a significantly increased growth delay as compared with RT alone (P < or =0.002). The ERs of 5, 10, and 20 mg/kg FMdC at a dose of 30 Gy were 2.0, 1.4, and 1.8, respectively. At the 40-Gy level, ERs of 10 and 20 mg/kg FMdC were 1.4 and 1.7. When FMdC was combined with 50 Gy of RT, an increased long-term remission rate of 80-88.9% was observed, as compared with 25% for RT alone (P <0.05). FMdC produced moderate myelosuppression in the mice bearing cervix cancer, whereas leukocytosis occurred in the mice bearing glioblastoma at a low dose. Slightly increased skin toxicity (only with U-87 MG tumor) was observed, as compared with RT alone. In conclusion, FMdC is a potent cytotoxic agent and able to modify the radiation response of C33-A and U-87 MG xenografts.
 ...
PMID:(E)-2'-deoxy-2'-(fluoromethylene) cytidine potentiates radioresponse of two human solid tumor xenografts. 985 73

Eight analogues of 1-[5-halogenosalicylidene]-2-[2'-pyridinoyl]hydrazine and -[2'-pyridyl]hydrazine, four of 1-[pyridoxylidene]-2-[2'-pyridinoyl]hydrazine, seven of 1-[pyridoxylidene]-2-[2'-pyridyl]hydrazine, and one each of 1, 2-bis[pyridoxylidene]diaminoethane and bis[pyridoxylidenehydrazino]phthalazine were synthesized. Their solutions in DMF were assayed for activity against the metalloenzyme ribonucleoside diphosphate reductase (RdR), prepared from a subcutaneously growing murine tumor (sarcoma 180) implanted in B6D2F3 male mice. The 14C-labeled CDP reductase was assayed by the modified method of Takeda and Weber, in which [14C]cytidine was separated from deoxycytidine by thin-layer chromatography (TLC) on cellulose foil. Distribution of radioactivity was assessed with an automatic TLC linear analyzer. Of the 31 compounds tested, 13 were essentially inactive, 7 were highly active against RdR, and the remaining 20 were slightly more active than hydroxyurea (used as a reference compound). The mechanism of inhibition is discussed in terms of three alternative pathways, initiated by sequestration of iron embedded in the R1 subunit of the metalloenzyme to form a C-centered chelate radical (via redox cycling). Alternatively, the latter could either reduce the tyrosyl radical or intercept radicals generated in the reduction process.
 ...
PMID:Domain-structured N1,N2-derivatized hydrazines as inhibitors of ribonucleoside diphosphate reductase: redox-cycling considerations. 992 29

Tumor cell resistance to certain chemotherapeutic agents may result in cross-resistance to related antineoplastic agents. To study cross-resistance among inhibitors of ribonucleotide reductase, we developed hydroxyurea-resistant (HU-R) CCRF-CEM cells. These cells were 6-fold more resistant to hydroxyurea than the parent hydroxyurea-sensitive (HU-S) cell line and displayed an increase in the mRNA and protein of the R2 subunit of ribonucleotide reductase. We examined whether HU-R cells were cross-resistant to gemcitabine, a drug that blocks cell proliferation by inhibiting ribonucleotide reductase and incorporating itself into DNA. Contrary to our expectation, HU-R cells had an increased sensitivity to gemcitabine. The IC50 of gemcitabine was 0.061 +/- 0.03 microM for HU-R cells versus 0.16 +/- 0.02 microM for HU-S cells (P = 0.005). The cellular uptake of [3H]gemcitabine and its incorporation into DNA were increased in HU-R cells. Over an 18-h incubation with radiolabeled gemcitabine (0.25 microM), gemcitabine uptake was 286 +/- 37.3 fmol/10(6) cells for HU-R cells and 128 +/- 8.8 fmol/10(6) cells for HU-S cells (P = 0.03). The incorporation of gemcitabine into DNA was 75 +/- 6.7 fmol/10(6) cells for HU-R cells versus 22 +/- 0.6 fmol/10(6) cells for HU-S cells (P < 0.02). Our studies suggest that the increased sensitivity of HU-R cells to gemcitabine results from increased drug uptake by these cells. This, in turn, favors the incorporation of gemcitabine into DNA, resulting in enhanced cytotoxicity. The increased sensitivity of malignant cells to gemcitabine after the development of hydroxyurea resistance may be relevant to the design of chemotherapeutic trials with these drugs.
 ...
PMID:Increased sensitivity of hydroxyurea-resistant leukemic cells to gemcitabine. 1003 95


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