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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite aggressive therapy, many nervous system neoplasms, including malignant gliomas, medulloblastomas, malignant meningiomas, and neurofibrosarcomas, maintain high mortality rates. The authors recently utilized a thymidine kinase-negative herpes simplex-1 mutant virus, dlsptk, with reduced neurovirulence, for the effective treatment of malignant human gliomas in cell culture and in nude mouse in vivo models. The range of human nervous system tumors that might be responsive to viral therapy is now expanded. Three medulloblastoma, four malignant or atypical meningioma, and five neurofibrosarcoma cell lines or early-passage tumors were treated with the dlsptk virus in cell culture. A cell death rate of at least 99% was evident in every tumor tested for at least one multiplicity of infection within 14 days after treatment. Control tumor cell cultures remained viable. To test dlsptk therapy in vivo, the authors treated human medulloblastoma subcutaneous xenografts with two doses of dlsptk. Mean growth ratios were significantly inhibited in the treated group when compared to control tumors, and there was a significant number of tumor regressions in the treated animals. Similar results were seen with human malignant meningioma xenografts in a subrenal capsule study. These results encourage the further investigation of viral therapy in the treatment of a broad spectrum of nervous system tumors refractory to conventional treatment methods.
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PMID:Expanded spectrum of viral therapy in the treatment of nervous system tumors. 132 12

Tumor cells infected with a retrovirus vector (VIK) containing the herpes simplex virus thymidine kinase (HSV-TK) gene can be selectively killed by treatment with nucleoside analogues, such as ganciclovir. To mediate delivery of the HSV-TK gene to "recipient" tumor cells, "donor" C6 rat glioma cells infected with the VIK vector (C6VIK) were superinfected with wild type Moloney murine leukemia virus (WT Mo-MLV). These modified donor cells (C6VIKWT) produced both wild type retrovirus and the VIK vector. In culture, C6VIKWT cells were 300-fold more sensitive to the toxicity of ganciclovir than were C6VIK cells, suggesting that the presence of wild type retrovirus contributed to the toxicity. Co-culture of C6VIKWT cells with the C6 subline, C6BAG, sensitized the latter to ganciclovir treatment. Nude mice inoculated subcutaneously with a mixture of C6VIKWT and C6BAG cells showed regression of subsequent tumors when treated with ganciclovir. The observations show that tumor cells modified in culture by infection with a retrovirus bearing the HSV-TK gene and wild type retrovirus are not only sensitive to ganciclovir, but can transfer this sensitivity to neighboring "naive" tumor cells in culture and in vivo.
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PMID:Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells. 133 91

Recent experiments with genetically engineered tumors have generated renewed interest in active cellular immunotherapy as a cancer treatment modality. In order to consider the use of live tumor cells for immunotherapy in human cancer patients, it will be important to ensure that these cells do not themselves produce morbidity in the event the immune system fails to eliminate them. Toward this end, we have examined a strategy for eliminating genetically manipulated nonimmunogenic tumors in vivo. When B16F10 melanoma cells were transfected with the Herpes simplex virus 1 thymidine kinase (HSV-TK) gene, cells were rendered susceptible to killing by the nucleoside analogs acyclovir (ACV) and ganciclovir (GCV). B16-HSV-TK+ tumors established in C57BL6 mice were successfully "suicided" in vivo when GCV was administered by continuous infusion. However, late recurrences were observed even after 1 month of continuous GCV treatment. In vivo growth kinetics suggested that the recurrences resulted from a tiny number (< 20) of cells that had survived the GCV treatment. Interestingly, recurrent tumors were as sensitive to GCV as the parental B16-HSV-TK+ line. While these results demonstrate potential feasibility of the suicide gene strategy for active immunotherapy with live tumor cells, they also illustrate that approaches dependent on the intracellular generation of cell cycle-dependent toxins may fail to eliminate small numbers of cells that temporarily exit cell cycle or that are pharmacologically sequestered.
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PMID:Herpes simplex-1 virus thymidine kinase gene is unable to completely eliminate live, nonimmunogenic tumor cell vaccines. 133 54

We investigated whether the transduction of a suicide gene might induce the elimination of malignant solid tumours. BDIX male rats were given an intra-hepatic injection of a mixture containing DHDK12 tumor cells and xenogeneic fibroblasts. The latter were producing either the herpes simplex virus type 1 thymidine kinase HSV1-TK- or nls-lac Z(control)-expressing recombinant retroviral particles. 5 days later, a time at which the tumor is macroscopic, all the rats were treated with ganciclovir, a nucleoside analog that is metabolized by HSV1-TK into a toxic compound. After 5 days of treatment, a dramatic reduction in tumour volume was noted in the HSV1-TK group. These results delineate a new therapeutical strategy for the treatment of disseminated liver metastases or of a large variety of solid malignant tumours.
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PMID:[Treatment of experimental liver tumors by in vivo suicide gene transfer in rats]. 133 22

Deletion mutagenesis and transfection studies into hepatic (mouse hepatoma (Hepa-1) and human hepatoblastoma (Hep-G2)) and nonhepatic (HeLa) cells indicated that high levels of expression of the human NAD(P)H:quinone oxidoreductase gene in tumor cells and its induction by beta-naphthoflavone and 3-(2)-tert-butyl-4-hydroxyanisole are mediated by human antioxidant response element (hARE) located in the region between -470 and -445. The hARE, when attached to the thymidine kinase promoter and transfected into several mammalian cells, expressed high levels of the chloramphenicol acetyltransferase gene that was inducible by beta-naphthoflavone and 3-(2)-tert-butyl-4-hydroxyanisole. Nucleotide sequence analysis of the hARE revealed the presence of a recognition site for binding to the AP1 protein. Mutation of the AP1 binding site located within the hARE resulted in the loss of expression and induction upon transfection into various cell types. Band shift and competition assays with hARE and nuclear extracts from control and beta-naphthoflavone-treated Hepa-1, Hep-G2 and HeLa cells indicated specific interaction of regulatory protein(s) to the hARE. The supershift assays using antibodies against specific proteins of the AP1 family identified Jun-D and c-Fos as two members in the hARE-protein complex observed in band shift assays.
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PMID:Regulation of human NAD(P)H:quinone oxidoreductase gene. Role of AP1 binding site contained within human antioxidant response element. 840 91

Mutation of the p53 tumor suppressor gene is a recurring event in a variety of human cancers. Wild-type p53 may regulate cell proliferation and has recently been shown to repress transcription from several cellular promoters. We studied the effects of wild-type and mutant human p53 on the human proliferating-cell nuclear antigen promoter and on several viral promoters including the simian virus 40 early promoter-enhancer, the herpes simplex virus type 1 thymidine kinase and UL9 promoters, the human cytomegalovirus major immediate-early promoter-enhancer, and the long terminal repeat promoters of Rous sarcoma virus, human immunodeficiency virus type 1, and human T-cell lymphotropic virus type I. HeLa cells were cotransfected with a wild-type or mutant p53 expression vector and plasmids containing a chloramphenicol acetyltransferase reporter gene under viral (or cellular) promoter control. Expression of wild-type p53 correlated with a consistent and significant (6- to 76-fold) reduction of reporter enzyme activity. A mutation at amino acid 143 of p53 releases this inhibition significantly with all the promoters studied. Expression of a p53 mutated at any one of the five amino acid positions 143, 175, 248, 273, and 281 also correlated with a much smaller (one- to sixfold) reduction of reporter enzyme activity from the herpes simplex virus type 1 thymidine kinase promoter. These mutant forms of p53 are found in various cancer cells. Thus, failure of tumor suppression correlates with loss of the promoter inhibitory effect of p53.
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PMID:Inhibition of viral and cellular promoters by human wild-type p53. 135 31

The activity of nuclear DNA polymerases alpha, beta and delta/epsilon, uracil-DNA glycosylase, thymidine kinase and the presence of Proliferating Cell Nuclear Antigen (PCNA) have been examined in developing rat glial cells, in rat and human glioma, in human neuroblastoma and in differentiated neuroblastoma cell lines in vitro. During glial development the activity of all enzymes tested, except DNA polymerase beta, markedly decreased, suggesting their coordinate regulation in respect to the proliferative state of the cells. Glioma and neuroblastoma cell lines restore the enzymatic activities that were no longer expressed in normal adult cells. Neuroblastoma cell lines induced to differentiate in vitro by retinoic acid showed a decline of the activities of DNA polymerase alpha, DNA polymerase delta/epsilon, uracil-DNA glycosylase and thymidine kinase similar to that observed during in vivo differentiation. We also demonstrate that PCNA is not detectable in glial and neuronal cells at all developmental stages, but can be found in tumor nerve cells. A possible use of enzymatic assays or anti-PCNA antibodies to detect brain tumors is discussed.
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PMID:DNA synthesis enzymes and proliferating cell nuclear antigen in normal and neoplastic nerve cells. 135 31

This report describes a highly active chemotherapeutic drug combination, consisting of N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide plus 5-fluorouracil, in CD8F1 mice bearing spontaneous, autochthonous, breast tumors or first-passage advanced transplants of these spontaneous tumors. The combination and sequence of administration of these drugs were selected on the basis of known potentiating biochemical interactions. High performance liquid chromatography and nuclear magnetic resonance spectroscopy measurements of biochemical changes resulting from treatment with N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide indicated a severe depletion of cellular energy levels in the treated tumors. 6-Aminonicotinamide produced a severe block of the pentose shunt, and 5-fluorouracil severely inhibited both thymidylate synthase and thymidine kinase in the treated tumors. This quadruple drug combination, administered on a 10-11-day schedule, produced an impressive partial tumor regression rate of 67% of large, spontaneous, autochthonous, murine breast tumors and a tumor regression rate of 74% of first-passage transplants of the spontaneous breast tumors.
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PMID:Biochemical modulation of tumor cell energy: regression of advanced spontaneous murine breast tumors with a 5-fluorouracil-containing drug combination. 137 19

In HeLa cells transcription of the c-jun gene is activated strongly and rapidly by ultraviolet (UV) irradiation and, to a somewhat lesser extent, by treatment with phorbol ester tumor promoters. In the same cells UV and phorbol esters only marginally enhance the abundance of RNA transcribed from the jun D gene and from the gene coding for the serum response factor (which in turn acts on the UV and phorbol ester response element of the c-fos gene). In contrast to c-jun, jun B transcription is induced more efficiently by phorbol ester than by UV irradiation, suggesting that the members of the jun family are differently regulated. The promoter of c-jun carries two enhancer elements resembling AP-1 binding sites: the jun1 UV response element (URE-71 TGACATCA -64) and the jun2 URE (-190 TTACCTCA-183). These elements act independently in the UV induced expression of c-jun. In the context of the complete c-jun promoter they seem not to be required for c-jun induction by phorbol esters. When fused to the Herpes simplex thymidine kinase promoter, however, the isolated elements mediate induction by both UV and phorbol esters. UV and phorbol ester treatment of cells increases the binding of transcription factors to both elements. Both elements bind factors different in modification or/and constitution from AP-1, the heterodimeric transcription factor composed of c-Fos and c-Jun that controls the activity of the UV and phorbol ester response element (-72 TGAGTCA-66) of the human collagenase gene.
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PMID:Ultraviolet-radiation induced c-jun gene transcription: two AP-1 like binding sites mediate the response. 156 Dec 39

An important question in the management of patients with cancer is early identification of the individual who following 'curative' primary therapy will develop recurrence. Another question is which of several alternative treatments is most appropriate. If the patient at risk can be identified early more aggressive and appropriate adjuvant chemotherapy can be initiated to insure remission or longer periods of disease free survival. In this review the role of tissue and/or serum enzyme activities in this regard is considered. Enzymes alone or in combination with tumor markers or other factors may be used. Lactic dehydrogenase (LDH) is perhaps the most common clinical enzyme used in cancer patients for prognostic purposes. It has an important role in germ cell tumors and in association with chorionic gonadotropin and can predict response to therapy and the prospects of remission. LDH is a valuable prognostic marker in lymphoma, leukemia and in colon cancer. Patients can be stratified into treatment protocols based on LDH activity. The stage of cellular proliferation can be evaluated by assay of thymidine kinase in the serum of patients with Hodgkins Disease and in Lymphoma. An important new marker, Cathepsin D in breast tissue may be useful in predicting women with breast cancer who are at risk for early recurrence.
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PMID:Enzymes as prognostic markers and therapeutic indicators in patients with cancer. 157 80


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