Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Mutant herpes simplex virus induced regression of tumors growing in immunocompetent rats. 796 89

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.
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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

Gemcitabine is a novel antimetabolite drug that acts by multiple mechanisms, including inhibition of ribonucleoside diphosphate reductase, of dCMP deaminase and of dCTP incorporation into DNA and RNA. Here, we report that gemcitabine induces cytotoxic and clonogenic death of 12 human malignant glioma cell lines at clinically relevant concentrations around 1 microM. Gemcitabine is thus approximately 100-fold more active than the congener drug, cytarabine. Gemcitabine cytotoxicity of glioma cells does not require wild-type p53 activity: (i) there was no difference in the susceptibility to gemcitabine between cell lines with wild-type p53 and cell lines with mutant or deleted p53; (ii) ectopic expression of a temperature-sensitive p53 protein either at wild-type (32.5 degrees C) or at mutant (38.5 degrees C) conformation had no significant influence on gemcitabine-induced cell death. Gemcitabine cytotoxicity was unaffected by the antioxidants, N-acetylcysteine and phenyl-N-tert-butyl-alpha-phenylnitrone. There was no correlation between the susceptibility to gemcitabine and the endogenous expression of the B cell lymphoma-2 (BCL-2)-family proteins BCL-2, BCL-XL, myeloid cell leukemia-1 (MCL-1), BCL-2-associated X protein (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-XS. Ectopic expression of BCL-2 moderately attenuated gemcitabine-induced cell death. Similarly, preexposure to the synthetic steroid, dexamethasone, which is commonly used to control cerebral edema in brain tumor patients, reduced gemcitabine cytotoxicity. We conclude that the clinical evaluation of gemcitabine for the adjuvant chemotherapy of malignant glioma is warranted.
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PMID:Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone. 998 15

Deletion of the gamma34.5 gene coding for virulence markedly reduces cytotoxicity mediated by herpes simplex virus type 1 (HSV-1) (J. M. Markert et al., Neurosurgery 32:597-603, 1993; N. S. Markovitz et al. , J. Virol. 71:5560-5569, 1997). To target lytic virulence to tumors, we have created a novel HSV-1 mutant, designated Myb34.5. This viral mutant is characterized by a deletion of the gene for infected cell polypeptide 6 (ICP6; also known as UL39 or ribonucleotide reductase) and of the two endogenous copies of the gamma34.5 gene (RL1) and by reintroduction of one copy of gamma34.5 under control of the E2F-responsive, cellular B-myb promoter. On direct intracerebral inoculation in BALB/c mice, the 50% lethal dose (LD(50)) for Myb34.5 was 2.7 x 10(7) PFU while that for HSVs with mutations in the gamma34.5 gene could not be technically achieved with available viral stocks and it was estimated as >1 x 10(7) PFU. The LD(50) for an HSV with a single defect in ICP6 function was 1.3 x 10(6) PFU. Conversely, Myb34.5's oncolytic efficacy against a variety of human glioma cells in culture and in vivo was enhanced compared to that of HSVs with gamma34.5 mutations, and in fact, it was comparable to that of the wild-type F strain and of viral mutants that possess a wild-type gamma34.5 gene. The characteristic shutoff of host protein synthesis, occurring after infection of human SK-N-SH neuroblastoma cells by gamma34.5 mutant viruses (J. Chou and B. Roizman, Proc. Natl. Acad. Sci. USA 89:3266-3270, 1992), was not present after infection with Myb34.5. There was an increase of almost 3 logarithmic units in the production of progeny virus in arrested fibroblasts compared to that in cycling fibroblasts infected with Myb34.5. These results suggest that transcriptional regulation of gamma34.5 by cell cycle-regulated promoters can be used to target HSV-1 virulence toward tumors while maintaining the desirable neuroattenuated phenotype of a gamma34.5 mutant.
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PMID:B-myb promoter retargeting of herpes simplex virus gamma34.5 gene-mediated virulence toward tumor and cycling cells. 1043 45

A number of thiosemicarbazones have been tested previously and herein are included three bis(thiosemicarbazones) for comparison to the previous derivatives. In general the uncomplexed thiosemicarbazones were more potent in the cytotoxic screens than the bis(thiosemicarbazone) except in the murine L1210 and the human colon SW480 screens. Mode of action studies have only demonstrated slight differences in the effects of the two types of compounds on nucleic acid metabolism. The symmetrical and unsymmetrical bis(thiosemicarbazones) complexes of copper, nickel, zinc, and cadmium have been examined to compare them to the heterocyclic N(4)-substituted thiosemicarbazones metal complexes. These new derivatives demonstrated excellent activity against the growth of suspended lymphomas and leukemias although it should be pointed out that generally they were not as active as the copper complexes of N(4)-substituted thiosemicarbazones. Nevertheless, selected bis(thiosemicarbazones) complexes were active against the growth of human lung MB9812, KB nasopharynx, epidermoid A431, glioma UM-86, colon SW480, ovary 1-A9, breast MCK-7, and osteosarcoma Saos-2. In human HL-60 promyelocytic leukemia cells the complexes preferentially inhibited DNA and purine syntheses over 60 min. The regulatory enzyme of the de novo purine pathway, IMP dehydrogenase, appeared to be a major target of the complexes. However, minor inhibition of the activities of DNA polymerase alpha, PRPP-amido transferase, ribonucleotide reductase, and nucleoside kinases occurred over the same time period. No doubt these effects of the complexes on nucleic acid metabolism were additive since the d[NTP] pool levels were reduced after 60 min as was DNA synthesis. The symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes did not cause as severe DNA fragmentation as the heterocyclic N(4)-substituted thiosemicarbazone metal complexes; furthermore, their metabolic effects in the tumor cell were more focused on a single synthetic pathway.
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PMID:The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells. 1096 96

The 3,5-pyrazolidinediones proved to be potent cytotoxic agents against the growth of a number of murine and human tumor cell lines, e.g. human THP-I monocytic leukemia, Hut-78 lymphoma, MCF-7 breast effusion, A549 lung carcinoma, U87MG glioma, Hela uterine and A431 epidermoid skin cancer. In human Tmolt4 cell leukemia, the agents substantially suppressed DNA and RNA syntheses after 60 min at 100 microM. The de novo purine biosynthetic pathway appeared to be the major target of the agents with the inhibition of both PRPP-amido transferase and IMP dehydrogenase (IMPDH) activities. Suppression of IMPDH activity was due to the inhibition of both the Type I and II isoforms through an uncompetitive mechanism; however, the Type II isoform was preferentially inhibited at lower concentrations of compounds tested (>50-150 microM). Therefore IMPDH Type II activity, which predominates in cancer cells, was selectively inhibited over the Type I isoform (208-312 microM). The activities of other enzymes examined were inhibited which added to the overall suppression of DNA synthesis, i.e., ribonucleotide reductase, dihydrofolate reductase and nucleoside kinases. The agents caused Tmolt4 DNA strand scission but the DNA molecule itself did not appear to be a target of the compounds since there was no induced cross-linking of the DNA, intercalation between base pairs or alkylation of the DNA bases.
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PMID:Cytotoxicity and mode of action of 1-(1-cyclohexenyl) and 1-unsubstituted 3,5-pyrazolidinediones in human Molt4 T cell leukemia. 1149 69

3-Ethoxycarbonyl-5-phenyl-1, 3a, 4, 5, 6, 6a-hexahydropyrrolo[3,4-c]pyrazole-4, 6-dione, 2, 2, 6, 6-tetraethyl-1H, 5H-pyrazole[1, 2-a]pyrazole-1, 3, 5, 7-[2H, 6H]-tetraone and 6-ethoxycarbonyl-3-phenyl-3-azabicyclo[3.1.0] hexane-2, 4-dione demonstrated potent cytotoxic activity in the human Tmolt3, Tmolt4 and HL-60 leukemia screens, HuT-78 lymphoma and HeLa suspended uterine carcinoma cell lines. Most notable was the finding that these compounds were significantly more active than the standard cytotoxic agents examined in the MCF-7 breast (ED50 0.2-1.0 microg/ml) and U87MG glioma (ED50 1.3-2. 6 microg/ml) tumor screens. The agents inhibited Tmolt4 leukemia DNA and RVA syntheses after 60 min at 100 microM Multiple enzymes involved with nucleic acid metabolism appeared to be targeted including inhibition of RNA polymerases, ribonucleotide reductase and nucleoside kinase activities, however, inhibition of de novo purine synthesis at the key regulatory enzyme IMP dehydrogenase appeared to be the primary target. The predominant IMPDH isoform (Type II) detected in a number of human cancers, such as leukemias, ovarian and breast, was inhibited by the compounds yielding IC50 values in the microM range. Furthermore, inhibition of IMP dehydrogenase activity led to the selective depletion of dGTP pool levels by two of the compounds. The DNA molecule was not a target of the agents since no alkylation of the bases, cross-linking of the DNA strands or intercalation between base pairs occurred. Yet, the compounds did cause DNA fragmentation after incubating at 100 microuM for 24 h which was consistent with the observed decrease in ct-DNA viscosity.
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PMID:Analysis of the in vitro inhibition of murine and human tumor cell growth by pyrazole derivatives and a substituted azabicyclo [3.1.0] hexane-2,4-dione. 1172 88

The current standard of care for malignant gliomas is surgical resection and radiotherapy followed by extended adjuvant treatment with the alkylating agent temozolomide. Temozolomide causes DNA damage, which induces cell death. Through changes in the DNA-repair machinery, glioma cells develop resistance to temozolomide, compromising the therapeutic effect of the drug. Oncolytic viruses, such as herpes simplex viruses and adenoviruses, are being introduced into clinical trials as a new treatment for this malignancy. Biological studies have revealed that these viruses use mechanisms to either inactivate (adenovirus) or take advantage of (herpes simplex virus) the cellular DNA-repair machinery to achieve productive replication. Adenoviruses express proteins from the early genes to either downregulate the damage-repair enzyme, O(6)-methylguanine-DNA methyltransferase, or degrade poly (ADP-ribose) polymerase or the Mre11-Rad50-NBS1 complex, which detects DNA strand breaks. Temozolomide enhances herpes simplex virus oncolysis by upregulating the DNA repair-related genes growth arrest DNA damage 34 and ribonucleotide reductase. The interactions between viruses and the DNA-repair machinery suggest that a combined temozolomide and viral therapy will overcome the limitations of a single therapy by diminishing chemoresistance or enhancing oncolysis. This hypothesis has been supported by promising findings from preclinical and clinical studies.
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PMID:Oncolytic viruses and DNA-repair machinery: overcoming chemoresistance of gliomas. 1713 63

Although second-generation replication-conditional herpes simplex virus type 1 (HSV-1) vectors defective for both ribonucleotide reductase (RR) and the virulence factor gamma(1)34.5 have been proven safe through a number of animal experiments and clinical trials, their therapeutic efficacy was also markedly reduced. To overcome this situation, we concentrated on the use of a tumor-specific promoter in this study, to express ICP34.5 selectively in malignant glioma cells. As a molecular marker for malignant glioma, we focused on the neural RNA-binding protein, Musashi1. On the basis of the results of defective vector dvM345, as reported previously, we created, via homologous recombination, a novel HSV-1 vector termed KeM34.5, which expresses ICP34.5 under the transcriptional control of the musashi1 gene promoter (P/musashi1). Cytotoxicity mediated by KeM34.5 was significantly enhanced in human glioma cell lines (U87MG, U87MG-E6, U251, and T98G), resulting in an approximately 2-log increase in viral yield, compared with its parental vector G207. This virus also showed much higher therapeutic efficacy in the in vivo glioma model, while maintaining the desirable neuroattenuated phenotype. These results suggest that oncolytic HSV-1 expressing ICP34.5 under the transcriptional control of the musashi1 gene promoter could be a promising therapeutic agent for the treatment of malignant glioma.
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PMID:Augmented therapeutic efficacy of an oncolytic herpes simplex virus type 1 mutant expressing ICP34.5 under the transcriptional control of musashi1 promoter in the treatment of malignant glioma. 1723 3

Oncolytic herpes simplex viruses (HSVs), in clinical trials for the treatment of malignant gliomas, are assumed to be selective for tumor cells because their replication is strongly attenuated in quiescent cells, but not in cycling cells. Oncolytic selectivity is thought to occur because mutations in viral ICP6 (encoding a viral ribonucleotide reductase function) and/or gamma34.5 function are respectively complemented by mammalian ribonucleotide reductase and GADD34, whose genes are expressed in cycling cells. However, it is estimated that only 5-15% of malignant glioma cells are in mitosis at any one time. Therefore, effective replication of HSV oncolytic viruses might be limited to a subpopulation of tumor cells, since at any one time the majority of tumor cells would not be cycling. However, we report that an HSV with defective ICP6 function replicates in quiescent cultured murine embryonic fibroblasts obtained from mice with homozygous p16 deletions. Furthermore, intracranial inoculation of this virus into the brains of p16-/- mice provides evidence of viral replication that does not occur when the virus is injected into the brains of wild-type mice. These approaches provide in vitro and in vivo evidence that ICP6-negative HSVs are 'molecularly targeted,' because they replicate in quiescent tumor cells carrying specific oncogene deletions, independent of cell cycle status.
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PMID:Oncolytic herpes virus with defective ICP6 specifically replicates in quiescent cells with homozygous genetic mutations in p16. 1834 32


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