Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current treatment of osteosarcoma produces disappointing outcomes, and innovative therapies must be investigated. We have used retroviral vectors to transfer the herpes simplex virus thymidine kinase (HSVtk) and interleukin-2 genes to human osteosarcoma cells. Each gene was stably transduced and expressed; the HSVtk gene effectively conferred ganciclovir (GCV) susceptibility to transduced cells. A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to GCV killing. Human osteosarcoma cells were used to develop a series of experiments in athymic nude mice to treat experimental osteosarcoma. Subcutaneously implanted mixtures of tumor cells and HSVtk vector producer cells developed into tumors that completely regressed upon administration of GCV. Subcutaneously implanted mixtures of transduced and wild-type cells showed a potent bystander effect upon administration of GCV, with complete tumor ablation when as little as 10% of the cells were HSVtk+. A significant (P < .05) antitumoral response was seen against primary tumors composed of unmodified cells when a secondary tumor of transduced cells was implanted at a distance of 1 cm, suggesting a diffusible bystander factor. The presence of interleukin-2-transduced cells improved the efficacy of treatment. A significant (P < .03) antitumoral response was seen in the treatment of established osteosarcomas by the injection of HSVtk vector producer cells.
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PMID:Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes. 1077 Jun 26

Herpes simplex viruses (HSV) type 1 are the basis of a number of anticancer strategies that have proven efficacious in animal models. They are natural human pathogens and the majority of adults have anti-HSV immunity. The current study examined the effect of preexisting immunity on the response to herpes-based oncolytic viral treatment of hepatic metastatic cancer in a murine model designed to simulate a clinical approach likely to be utilized for nonneurological tumors. Specifically, the anticancer effects of NV1020 or G207, two multimutated HSV-1 oncolytic viruses, were tested in immunocompetent mice previously immunized with a wild-type herpes simplex type 1 virus. Mice were documented to have humoral as well as cell-mediated immunity to HSV-1. Tumor response to oncolytic therapy was not measurably abrogated by immunity to HSV at the doses tested. The influence of route of viral administration was also tested in models of regional hepatic arterial and intravenous therapy. Route of viral administration influenced efficacy, as virus delivered intravenously produced some detectable attenuation while hepatic arterial therapy remained unaffected. These results demonstrate that when given at appropriate doses and in reasonable proximity to tumor targets, HSV-based oncolytic therapy can still be expected to be effective treatment for patients with hepatic malignancies.
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PMID:Effects of preexisting immunity on the response to herpes simplex-based oncolytic viral therapy. 1111 18

Gallbladder cancer is an extremely difficult disease to cure once metastases occur. In this paper, we explored the potential of G207, an oncolytic, replication-competent herpes simplex virus type 1 mutant, as a new therapeutic means for gallbladder cancer. Gallbladder carcinoma cell lines (four human and one hamster) showed nearly total cell killing within 72 h of G207 infection at a m.o.i. of 0.25 to 2.5 in vitro. The susceptibility to G207 cytopathic activity correlated with the infection efficiency demonstrated by lacZ expression. Intraneoplastic inoculation of G207 (1 x 10(7) pfu) in immunocompetent hamsters bearing established subcutaneous KIGB-5 tumors caused a significant inhibition of tumor growth and prolongation of survival. Repeated inoculations (three times with 4-day intervals) were significantly more efficacious than a single inoculation. In hamsters with bilateral subcutaneous KIGB-5 tumors, inoculation of one tumor alone with G207 caused regression or growth reduction of uninoculated tumors as well as inoculated tumors. In athymic mice, however, the anti-tumor effect was largely reduced in inoculated tumors and completely abolished in remote tumors, suggesting large contribution of T-cell-mediated immune responses to both local and systemic anti-tumor effect of G207. These results indicate that G207 may be useful as a new strategy for gallbladder cancer treatment.
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PMID:Therapeutic efficacy of G207, a conditionally replicating herpes simplex virus type 1 mutant, for gallbladder carcinoma in immunocompetent hamsters. 1131 3

Adenoviral-mediated gene therapy delivery, combining the herpes simplex virus thymidine kinase gene (Ad-tk) with gancyclovir, has been evaluated as a treatment modality for numerous tumors in the laboratory and in the clinics. As a single modality, gene therapy has shown some promising local and systemic results but no curative success. Surgery is the standard of care for many solid tumors. However, minor residual tumor following surgical resection can lead to local recurrence, and surgery is neither efficient nor plausible for metastatic disease. In this study, two tumor models were used to evaluate the effects of Ad-tk gene therapy as an adjuvant to surgery. Subcutaneous mammary- and prostate-derived tumors were produced in syngeneic mice. To evaluate systemic effects, tumor cells were injected intravenously, with subsequent formation of lung nodules. The subcutaneous tumors were surgically resected and the tumor bed was bathed with saline or Ad-tk. The animals were evaluated for toxicity, local tumor recurrence, survival, and lung nodule formation. No evidence of additional toxicity was observed. In the less aggressive mammary model, the time to recurrence was increased from 11.7 (+/-1.0) days to 22.7 (+/-5.5) days. In the prostate model, recurrence went from a mean of 17.3 (+/-5.6) to 22.6 (+/-6.8) days. Survival was also improved from a mean of 19.7 (+/-1.1) to 32.3 (+/-4.8) and 26.1 (+/-5.0) to 34.1 (+/-6.1) days in the mammary and prostate models, respectively. Evidence of systemic benefits from the use of adjuvant Ad-tk therapy was demonstrated by a significant reduction in lung nodules from a mean of 17 to 3.5. These results suggest that Ad-tk gene therapy may be a useful adjuvant for patients undergoing surgery for treatment of cancer.
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PMID:In vivo surgical resection plus adjuvant gene therapy in the treatment of mammary and prostate cancer. 1131 10

High grade gliomas in adults are devastating diseases, with very poor survival despite their lack of distant metastases. Local treatments, such as surgical resection and stereotactic radiosurgery, have been most successful, whereas systemic therapy (for example, chemotherapy and immunotherapy) have been rather disappointing. Several gene therapy systems have been successful in controlling or eradicating these tumours in animal models and are now being tested as a logical addition to current clinical management. This review describes the gene therapy clinical protocols that have been completed or that are ongoing for human gliomas. These include the prodrug activating system, herpes simplex thymidine kinase (HSVtk)/ganciclovir (GCV), utilising either retrovirus vector producer cells or adenovirus vectors; adenovirus mediated p53 gene transfer; adenovirus mediated IFN-beta gene transfer and oncolytic herpes virus and adenovirus vectors. To date, all of the clinical studies have used direct injection of the vector into the glioma. The Phase I clinical studies have demonstrated low to moderate toxicity and variable levels of gene transfer and in some cases anti-tumour effect. Future directions will rely upon improvements in gene delivery as well as gene therapies and combinations of gene therapy with other treatment modalities.
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PMID:Gene therapy for high grade gliomas. 1172 33

We evaluated the effect of gene therapy in the murine osteosarcoma cell line, LM8, which preferentially metastasizes to the lungs. LM8 cells were transduced with the gene for a herpes simplex virus thymidine kinase (HSV-tk) or Escherichia coli beta-galactosidase (lacZ). We investigated the cytotoxicity of LM8 cells bearing an HSV-tk gene after treatment with ganciclovir (GCV). LM8 cells bearing an HSV-tk gene were more sensitive than non-transduced cells. The remarkable inhibition of tumor growth and pulmonary metastases was confirmed in vivo. Our findings indicated that GCV kills tumor cells transduced with HSV-tk in vitro and in vivo.
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PMID:Suppression of tumor growth and pulmonary metastasis in murine osteosarcoma using gene therapy. 1183 3

The effectiveness of electroporation as a means of gene transfection, both in vitro and in vivo, was tested using the herpes simplex virus 1 thymidine kinase (HSVtk) gene in combination with ganciclovir (GCV) administration as therapy against murine mammary cancer. Approximately 80% of BJMC3879 metastatic mammary carcinoma cells, derived from MMTV-infected BALB/c mice, died as a result of HSVtk/GCV treatment 72 hours after the transfection; decreased DNA synthesis was also seen. Mammary tumors induced by inoculation of syngeneic mice with BJMC3879 cells were subsequently treated by direct injection of vector containing HSVtk (pHSVtk) alone, empty vector or saline alone twice a week. After each injection, the tumors were subjected to in vivo electroporation. Mice treated with pHSVtk or saline were intraperitoneally injected with GCV at 40 mg/kg five times a week. Significantly reduced tumor volumes were observed for the pHSVtk+GCV group in experimental week 2 and thereafter throughout the 2-month study. DNA synthesis was significantly decreased as well in the pHSVtk+GCV group compared with all other groups. Furthermore, metastasis to lymph nodes and lungs was significantly suppressed by HSVtk/GCV treatment. Expression of HSVtk in the tumors was confirmed by RT-PCR. Macrophage accumulations were frequently observed in the peripheries of necrotic regions in HSVtk/GCV-treated tumors, where levels of apoptosis were significantly higher than those observed in other groups. We therefore conclude that in vivo electroporation can result in efficient gene transfer and that the HSVtk/GCV prodrug system strongly suppresses tumor growth and metastases in this model.
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PMID:Suppression of murine mammary carcinoma growth and metastasis by HSVtk/GCV gene therapy using in vivo electroporation. 1191 41

The herpes simplex virus (HSV) thymidine kinase gene (tk) forms the basis of a widely used strategy for suicide gene therapy. A library of HSV thymidine kinase enzyme (TK) active site mutants having different affinities for guanosine analog prodrugs was developed. We sought to determine the optimal combination of tk variant and prodrug specifically for prostate cancer gene therapy, using in vitro and in vivo studies of adenovirally infected CL1, DU-145, and LNCaP tumor lines carrying wild-type tk, tk30, tk75, and sr39tk mutants expressed by a strong, constitutive cytomegalovirus promoter and treated with ganciclovir and acyclovir. In vitro experiments involving prostate cancer (CaP) cell line infection were carried out with a broad range of prodrug concentrations, and cell killing was determined by limiting dilution (colony-forming), MTT, and propidium iodide assays. In vivo studies based on CL1-GFP xenograft experiments were carried out to examine the ability of each TK variant to prevent tumor formation and to inhibit tumor growth and development of metastases in established orthotopic and subcutaneous tumors in SCID mice. Both in vitro and in vivo studies suggest improved killing with the sr39tk variant. Thus, the results suggest that the use of sr39tk in future trials of prostate cancer tk suicide gene therapy may be beneficial.
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PMID:Optimizing prostate cancer suicide gene therapy using herpes simplex virus thymidine kinase active site variants. 1197 45

Suicide gene therapy in combination with pro-drugs represents an attractive approach to the treatment of cancer. Unfortunately this approach is limited by difficulty in targeting all tumor cells, especially those at the distant metastases associated with the most complex tumors. For this reason, attempts to stimulate global anti-tumor immune responses at the sites of effective suicide gene/pro-drug-mediated tumor cell destruction are appealing. Here we show that, by including a gene coding for secreted secondary lymphoid tissue chemokine (SLC) along with the herpes simplex virus thymide kinase (HSV-TK) gene in a bicistronic vector for anti-tumor gene therapy in conjunction with the pro-drug ganciclovir (GCV), we are able to mediate a greatly enhanced anti-tumor effect in the murine B16 melanoma tumor model. The data presented suggests that this enhanced antitumor effect is the result of a strong induced CTL immune response resulting from the recruitment of immune cells to the site of HSV-TK/GCV-induced tumor destruction by the potent chemokine SLC.
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PMID:Combined HSV-TK/GCV and secondary lymphoid tissue chemokine gene therapy inhibits tumor growth and elicits potent antitumor CTL response in tumor-bearing mice. 1201 27

Drug resistance is often a limiting factor in successful chemotherapy. Our laboratory has been interested in studying mechanisms of resistance to drugs that are targeted to the thymidylate biosynthesis pathway especially those that target thymidylate synthase (TS) and dihydrofolate reductase (DHFR). We have used leukemia as a model system to study resistance to methotrexate (MTX) and colorectal cancer as the model system to study 5-fluorouracil (5-FU) resistance. In leukemias, we and others have shown that transport, efflux, polyglutamylation and hydrolase activities are major determinants of MTX resistance. We have further reported that some leukemic cells have an increase in DHFR gene copy number possibly contributing to the resistant phenotype. Recently, we have begun to study in detail the molecular mechanisms that govern translational regulation of DHFR in response to MTX as an additional resistance mechanism. Studies thus far involving colorectal tumors obtained from patients have focused predominantly on the predictive value of levels of TS expression and p53 mutations in determining response to 5-FU. Although the predictive value of these two measures appears to be significant, given the variety of resistance to 5-FU observed in cell lines, it is not likely that these are the only measures predictive of response or responsible for acquired resistance to this drug. The enzyme uridine-cytidine monophosphate kinase (UMPK) is an essential and rate-limiting enzyme in 5-FU activation while dihydropyrimidine dehydrogenase (DPD) is a catabolic enzyme that inactivates 5-FU. Alterations in UMPK and DPD may therefore explain failure of 5-FU response in the absence of alterations in TS or p53. Transcription factors that regulate TS may also influence drug sensitivity. We have found that mRNA levels of the E2F family of transcription factors correlates with TS message levels and are higher in lung metastases than in liver metastases of colorectal cancers. Moreover, gene copy number of the E2F-1 gene appears to be increased in a significant number of samples obtained from metastases of colorectal cancer. We have also generated mutants of both DHFR and TS that confer resistance to MTX as well as 5-FU by random as well as site-directed mutagenesis. These mutants used alone or as fusion cDNAs of the mutants have proven to be useful in transplant studies where transfer of these mutant cDNAs to bone marrow cells have been shown to confer drug resistance to recipients. The fusion cDNAs of DHFR such as the DHFR-herpes simplex virus type 1 thymidine kinase (HSVTK) are also useful for regulation of gene expression in vivo using MTX as the small molecule regulator that can be monitored by positron emission tomography (PET) scanning or by optical imaging using a fusion construct such as DHFR-EGFP.
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PMID:Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. 1208 58


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