Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.1 (cytosine deaminase)
 747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adaptation of gene therapy strategies to treat tumors has broadened the potential armamentarium of anticancer strategies to include approaches for local control of tumor growth as well as to enhance systemic antitumor immunity to treat metastases. A major focus of the author and colleagues has been to use replication-deficient adenovirus vectors, both in vivo and ex vivo, to enhance local control of and systemic immunity against cancer. Several examples will be used to demonstrate these strategies. Using prodrugs, systemically administered drugs converted to toxic metabolites in the local tumor milieu, has proven to be a useful strategy for achieving high local concentrations of the toxic product while avoiding the systemic toxicity that limits the use of chemotherapy agents. Transfer of genes encoding cytosine deaminase (with 5-fluorocytosine) and carboxylesterase (CE) (with irinotecan) are two paradigms that have been used in our laboratory. The data demonstrate that using adenoviruses to deliver these genes to the tumor site leads to production of the active chemotherapeutic agent, which diffuses from the cell in which it was produced to suppress tumor growth and attain regional control in a single organ. Extensive experimental and clinical data now exist to support the concept that tumor growth is critically dependent on angiogenesis and that vascular endothelial growth factor (VEGF) appears to play a central role in the process of tumor neovascularization. Data generated in our laboratory have shown that adenovirus-mediated regional anti-VEGF therapy using a gene encoding a soluble form of flt-1 (one of the VEGF receptors) can be used for regional control of tumor growth. The critical dependence of many tumors on VEGF for neovascularization and dissemination predicts the general applicability of this strategy for treatment of many solid tumors. Another paradigm involves dendritic cells, potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. Immunization of mice with dendritic cells genetically modified using an adenovirus vector transferring a gene encoding a tumor antigen confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. One clinical scenario to which this approach is relevant is treating micrometastases present at the time of primary detection of many malignancies. A possible clinical strategy would be to modify dendritic cells from such patients using an adenovirus vector encoding the relevant tumor antigen, and then administering the genetically modified dendritic cells as adjuvant treatment following primary therapy.
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PMID:In vivo and ex vivo gene therapy strategies to treat tumors using adenovirus gene transfer vectors. 1035 66

Gene-directed enzyme prodrug therapy (GDEPT) involves the treatment concept of having maximal efficacy and minimal adverse effects. Several GDEPT strategies have been developed combining cytosine deaminase and 5-fluorocytosine, cytochrome P450 2B1 and cyclophosphamide, and carboxylesterase (CES) and irinotecan in experimental models. The active forms of these prodrugs, however, are not a frontline therapy for the treatment of ovarian cancer. It would be beneficial to develop a more effective prodrug-enzyme combination for the treatment of this disease. Paclitaxel (Taxol; TAX) is currently one of the most important anti-cancer drugs in chemotherapy of ovarian cancer. One of TAX prodrugs, 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et), was generated and examined regarding its pharmacological aspects. The prodrug of TAX-2'-Et converts into active form TAX by carboxylesterase (CES). TAX-2'-Et did not exhibit polarized transport in the Caco-2 cells expressing P-glycoprotein (P-gp) in the absence or presence of verapamil which is a inhibitor of P-gp, suggesting that TAX-2'-Et is not a target of P-gp like TAX and rhodamine123. Moreover, SKOV3/TAX60 cells which are overexpressing P-gp did not also exhibit any change in cellular uptake of TAX-2'-Et regardless of the absence or presence of verapamil. Consequently, the uptake of TAX-2'-Et into the TAX-resistant cells was quantitatively similar to that internalized in the parental SKOV3 cells which are P-gp-negative. In the CES-transfected SKOV3 cells, the EC50 value of TAX (10.6 nM) was approximately 4-fold higher than that of TAX-2'-Et (2.5 nM). We herein provide evidence that TAX-2'-Et could circumvent P-gp-associated cellular efflux of TAX, suggesting that this combination therapy is a potential GDEPT strategy for ovarian cancer in the future. Finally, this review focuses on the development, application and potential of various GDEPTs for treating ovarian cancer, and the scope and progress of new GDEPTs are discussed.
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PMID:Gene directed enzyme prodrug therapy for ovarian cancer: could GDEPT become a promising treatment against ovarian cancer? 1828 24

The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-beta, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX). We and others have demonstrated that neural and mesenchymal stem cells can deliver therapeutic genes to elicit a significant antitumor response in animal models of intracranial glioma, medulloblastoma, melanoma brain metastasis, disseminated neuroblastoma and breast cancer lung metastasis. Most studies reported reduction in tumor volume (up to 90%) and increased survival of tumor-bearing animals. Complete cures have also been achieved (90% disease-free survival for >1 year of mice bearing disseminated neuroblastoma tumors). As we learn more about the biology of stem cells and the molecular mechanisms that mediate their tumor-tropism and we identify efficacious gene products for specific tumor types, the clinical utility of cell-based delivery strategies becomes increasingly evident.
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PMID:Stem and progenitor cell-mediated tumor selective gene therapy. 1836 24

Gene-directed enzyme prodrug therapy (GDEPT) consists of targeted delivery to tumor cells of a suicide gene responsible for the in situ conversion of a prodrug into cytotoxic metabolites. One of the major impediments of GDEPT is to target specifically the tumor cells with the suicide gene. Among gene delivery methods, mesenchymal stem cells (MSCs) have emerged recently as potential cellular vehicles for gene delivery. MSCs are particularly suited for gene transduction. They exhibit remarkable migratory property towards tumors and their metastases and they are weakly immunogenic. This review will summarize the current knowledge about MSCs engineered to express different suicide genes (cytosine deaminase, thymidine kinase, carboxylesterase, cytochrome P450) to elicit a significant antitumor response against brain tumors, ovarian, hepatocellular, pancreatic, renal or medullary thyroid carcinomas, breast or prostate cancer and pulmonary metastases. The potential side effects of these MSC-based tumor therapies will also be considered to highlight certain aspects that need to be improved prior to clinical use.
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PMID:Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors. 2497 33