Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Liver metastasis is the most serious event for physicians and surgeons treating patients with colorectal cancer. Gene therapy is expected to become a novel strategy to prevent liver metastasis. Four types of clinical studies are currently underway: 1) suicide-gene therapy with the cytosine deaminase gene; 2) immune gene therapy with cytokine (inter leukin-2) or major histocompatibility complex class I gene HLA-B7; 3) tumor suppressor gene p53 therapy; and 4) lysis of p53 mutant cancer cells with E1B55k-deleted adenovirus (Onyx-015). Basic research provided several candidates for the liver metastasis-associated genes, including MMP7, DCC, CDC25B, E-cadherin, CD44, vascular endothelial growth factor, etc. There is an alternative approach to liver metastasis, which attempts to introduce a specific gene such as cytosine deaminase and TIMP-2 into the hepatocytes but not into the tumor itself. This concept is based on results showing that hepatocytes can incorporate genes more readily than cancer cells can. Recently, mutant virus therapy has been developed, which includes Onyx-015, adenovirus dl922-947, and mutant-type herpes simplex virus. These mutant types of virus specifically proliferate in the cancer cells and result in their lysis. In the future, development of gene delivery systems that are powerful and specific to cancer type is essential.
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PMID:[Future scope for gene therapy for liver metastasis of colon cancer]. 1139 6

Infection of tumor cells by herpes simplex virus 1 (HSV-1) results in cell destruction and production of progeny virion in a process referred to as viral oncolysis. In this study, an HSV-1 mutant (HSV1yCD) was engineered such that the viral ribonucleotide reductase gene is disrupted by sequences encoding yeast cytosine deaminase, which efficiently metabolizes the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). HSV1yCD-infected cells convert 5-FC to 5-FU, which enhances cytotoxicity without significantly reducing viral replication and oncolysis. Oncolysis by a replicating HSV-1 mutant combined with therapeutic transgene delivery represents a new paradigm; HSV1yCD-infected cells are destroyed by viral replication, and uninfected cells are subjected to bystander killing from both progeny virion and extracellular diffusion of 5-FU. In contrast, HSV1yCD-mediated bioactivation of another prodrug, ganciclovir, impairs viral replication. HSV1yCD administered into the portal venous system replicates preferentially in liver metastases rather than normal liver. The anti-neoplastic activity of HSV1yCD combined with systemic 5-FC administration is greater than that achieved with HSV-1 replication alone. Combination oncolysis and prodrug bioactivation leads to significant prolongation of survival in mice with diffuse liver metastases.
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PMID:Multimodality therapy with a replication-conditional herpes simplex virus 1 mutant that expresses yeast cytosine deaminase for intratumoral conversion of 5-fluorocytosine to 5-fluorouracil. 1145 90

Fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopy provides a highly specific tool for identifying fluorine-containing drugs and their metabolites in biological media. This article focuses on the application of 19F NMR to the metabolic studies of fluoropyrimidine drugs in clinical use. The value and difficulties encountered in investigations on drug metabolism are first discussed. The metabolism and disposition studies of the anticancer drug 5-fluorouracil, the mainstay of antimetabolite treatment for solid tumors, and its prodrugs, doxifluridine and capecitabine, are then extensively reviewed. The studies dealing with the antimycotic agent, 5-fluorocytosine, as well as the novel anticancer drug, gemcitabine, are also considered. From in vitro (biofluids or tissue extracts) 19F NMR analysis, seven new metabolites of 5-fluorouracil, doxifluridine, capecitabine and 5-fluorocytosine were identified. Except two, they were only detected using this technique. This emphasizes the high analytical potential of in vitro 19F NMR. In vivo 19F NMR is non-invasive and thus allows the quantitative monitoring of the metabolism of 5-fluorouracil in the target tissue, e.g. the tumor, as well as its biodistribution. Another promising application is its ability to estimate the level of yeast cytosine deaminase gene expression in human tumors from the quantitative monitoring of 5-fluorouracil formation from the non-cytotoxic drug 5-fluorocytosine. Notwithstanding these successes, the limited sensitivity and spectral resolution of 19F NMR precludes its extensive applicability to all the fluorinated drugs.
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PMID:Fluorine nuclear magnetic resonance, a privileged tool for metabolic studies of fluoropyrimidine drugs. 1146 49

Tumor cells that express a fusion gene of Escherichia coli cytosine deaminase (CD) and herpes simplex virus type 1 thymidine kinase (TK) sequences activate and are subsequently killed by the nontoxic prodrugs 5-fluorocytosine and ganciclovir. We have previously developed a recombinant adenovirus containing the CD-TK fusion gene controlled by the human inducible heat shock protein 70 promoter so that heat at 41 degrees C for 1 hour induces therapeutic gene expression. This adenovirus effectively transduces heat-inducible expression of the CD-TK gene into human prostate carcinoma cells. However, because a limited number of cells in a tumor can actually be infected, we created a replicating adenoviral vector to increase CD-TK gene expression. This vector is a replication-competent, E1B-attenuated adenoviral vector containing the hsp70 promoter-driven CD-TK gene (Ad.E1A(+)HS-CDTK). When human prostate adenocarcinoma DU-145 cells (mutant p53) were infected with the virus at a multiplicity of infection (MOI) of 1 or 10, the viral replication was detected within 2 days at both MOIs. Similar results were observed in human colorectal carcinoma CX-1 cells. When DU-145 cells were infected with the virus at an MOI of 10, incubated for 24 hours, heated at 41 degrees C for 4 hours, and then harvested 20 hours later, Western blot analysis demonstrated that this virus successfully produced viral E1A proteins and heat shock stimulated the CD-TK gene expression by 12.3-fold. In addition, Ad.E1A(+)HS-CDTK effectively suppressed cell proliferation by viral cytopathic effect). Unlike with a replication-incompetent virus (Ad.HS-CDTK), the cytopathic effect of the virus and cytotoxicity in the presence of the prodrugs were still observed even at low MOI (MOI=1.0).
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PMID:Replicating adenoviral vector-mediated transfer of a heat-inducible double suicide gene for gene therapy. 1149 59

Tumor-specific gene delivery is crucial to achieving successful effects in suicide gene therapy. Carcinoembryonic antigen (CEA) promoter has been widely used for this purpose, but the expression level of tumor-specific promoters such as CEA promoter is generally low. In the previous study, we used the Cre/loxP system and showed that LacZ expression by the CEA promoter was remarkably enhanced and maintained its specificity using the Cre/loxP regulation system. In this study, the Cre/loxP system was first applied to augmentation of selective expression of the cytosine deaminase (CD) gene as a suicide gene therapy in CEA-producing cells. The double infection with AxCEANCre expressing Cre recombinase under the control of the CEA promoter and AxCALNLCD expressing the CD gene under the control of the CAG promoter by the Cre switching system rendered CEA-producing tumor cells 13-fold more sensitive to 5-fluorocytosine (5-FC) compared with the single infection with AxCEACD expressing CD gene driven by the CEA promoter. The therapeutic efficacy of the enhanced CD/5-FC suicide gene therapy was evaluated in orthotopic implantation models of human gastric carcinoma. Adenovirus vectors (1 x 10(9) plaque-forming units) were administered i.p. into mice three times, and then 5-FC was administered i.p. for the next 10 days. Tumor volume and weight in mice treated with AxCEANCre and AxCALNLCD/5-FC were significantly reduced as compared with those in mice treated not only with Mock (AxCALacZ) but also with AxCEACD/5-FC (P < 0.0001). This beneficial effect on tumor burden was also reflected in the overall survival. The survival periods of the mice treated with AxCEANCre and AxCALNLCD/5-FC were longer than those of mice treated with Mock or AxCEACD/5-FC (P < 0.01). These results suggested that application of the Cre/loxP system could provide a new approach for enhanced selective suicide gene therapy of CD/5-FC for the treatment of advanced gastric carcinoma.
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PMID:Carcinoembryonic antigen-specific suicide gene therapy of cytosine deaminase/5-fluorocytosine enhanced by the cre/loxP system in the orthotopic gastric carcinoma model. 1150 67

An attenuated strain of Salmonella typhimurium, designated VNP20009, was generated by deletion of the msbB and purl genes. When VNP20009 was administered intravenously (IV) to mice bearing spontaneous, syngeneic, or human xenograft tumors, the bacteria accumulated preferentially within the extracellular components of tumors, forming tumor-to-normal tissue ratios exceeding 300-1000 to 1. NVP20009 was administered safely at doses up to 2.5 x 10(9) cfu/kg in monkey toxicology studies. Based on the preclinical data, VNP20009 entered Phase I human clinical trials in November 1999, and has now been administered to >45 patients by IV or direct intratumoral injection. By the intratumoral route, a maximum tolerated dose has not been reached, and dose escalation continues past the current dose level of 4 x 10(7)/m2. Furthermore, VNP20009 persisted in injected tumors for at least 2 weeks in 8/11 patients treated to date. By 30-min IV administration, a maximum tolerated dose (MTD) of 3 X 10(8) cfu/m2 has been established. In all patients treated to date, VNP20009 was not shed in urine or stool. VNP20009 has been further modified by chromosomal insertion of an E. coli cytosine deaminase (CD) gene at the deltamsbB locus which, when expressed, converts 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The CD containing VNP20009 was designated TAPET-CD or VNP20029. TAPET-CD had similar efficacy and safety in murine tumor models and similar safety profiles in animal toxicology studies, compared to its parent VNP20009. Specifically, TAPET-CD had a reduced virulence of >10,000 fold, when compared to the wild-type Salmonella strain. It was well-tolerated at doses up to 2 x 10(6) cfu/mouse and 1 X 10(10) cfu/monkey. After an IV or direct tumor injection to tumor-bearing mice, TAPET-CD reached tumor levels as high as 10(8)-10(9) cfu/gm. When compared to the accumulation in liver or spleen, the normal tissues with the greatest colonization of TAPET-CD, tumor-to-normal tissue ratios of TAPET-CD were 300-1000 to 1. TAPET-CD also caused tumor growth inhibition of >90% in several murine tumor models. When 5-FC was administered by intraperitoneal (IP) injection once or 3 times daily to tumor-bearing mice that had been pre-treated with TAPET-CD, high levels of 5-FU (reaching 20-40 microM/g) were detected in the tumor, with low or undetectable 5-FU levels in normal tissues (e.g., spleen, liver, etc.). Furthermore, co-administration of 5-FC and TAPET-CD in 4 different murine tumor models enhanced anti-tumor activity compared to the significant anti-tumor activity of TAPET-CD alone, further confirming the benefit of the inserted CD gene. On the basis of the preclinical data, a Phase I clinical protocol is proposed in which advanced cancer patients will receive TAPET-CD by direct intratumoral injection and 5-FC. TAPET-CD will be administered on day 1. 5-FC will be given orally q8h daily beginning day 4 or when all toxicities of TAPET-CD have resolved to < or = grade 1, and continued for 14 days. Tumor tissues will be sampled to verify TAPET-CD colonization and to measure intratumoral 5-FC and 5-FU concentrations on day 8. A second sample of tumor tissue will be obtained between day 15-17 in selected patients to confirm the persistence of high levels of bacteria in tumor and to obtain a second measurement of 5-FC and 5-FU intra-tumoral concentrations. The TAPET-CD/5-FC treatment cycle will be repeated in appropriate patients on day 29.
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PMID:A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Version: April 9, 2001. 1152 49

Adenovirus (Ad) gene transfer vectors traffic to regional lymph nodes (RLNs) after footpad injections in mice, resulting in localized production of interferon gamma (IFN-gamma). With this background, we evaluated the hypothesis that Ad vector administration may inhibit RLN tumor metastasis independent of the transgene in the expression cassette. Tumors of MM48, a cell line with a propensity toward lymphogenous metastasis, were established in the footpads of syngeneic C3H mice, and E1(-)E3(-) Ad vectors encoding no transgene (AdNull) or encoding an irrelevant transgene (AdCD; Escherichia coli cytosine deaminase with no 5-fluorocytosine administration) were administered (10(10) particles) in a peritumoral location. Both vectors suppressed the growth of tumor in the regional (popliteal) lymph node. This effect was localized to the regional, but not distant, lymph nodes (p < 0.05). Heat inactivation of the vector or decreasing the dose of the vector to 10(9) particles did not suppress RLN growth of the tumor when compared with 10(10) particles of active AdNull (p < 0.05 and p < 0.01, respectively). The ability of an E1(-)E4(-) vector expressing beta-galactosidase (AdRSVbetagal.11) to suppress RLN tumor growth showed that the E4 region of the Ad vector was not responsible for the effect. Blocking either IFN-gamma or natural killer (NK) cells with systemic antibody treatment in immunocompetent mice allowed rapid growth of RLN metastases despite Ad vector administration, and Ad vector injection into the footpads of tumor-free mice induced the accumulation of NK cells in the RLN. These data demonstrate that, in a metastatic murine tumor model, a low dose (10(10) particles) of replication-deficient Ad vectors inhibits RLN metastases independent of a therapeutic transgene, an effect that is mediated, at least in part, by IFN-gamma and NK cells.
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PMID:Adenovirus gene transfer vectors inhibit growth of lymphatic tumor metastases independent of a therapeutic transgene. 1153 67

The in vivo gene delivery of E. coli cytosine deaminase (cd) cDNA and systemic 5-fluorocytosine (5-FC) administration have been studied extensively because of their clinical relevance to cancer gene therapy. This approach has the potent advantage of a stronger bystander effect compared to the previous thymidine kinase suicide gene system of the herpes simplex virus. However, 5-fluorouracil (5-FU), an active metabolite in cd with 5-FC therapy, is not always effective for every type of tumor since the enzymes responsible for further drug metabolism vary significantly in each tissue. In this study, we aimed to increase the sensitivity of 5-FU by transduction of thymidine phosphorylase (dThdPase) cDNA into brain tumor cells. After retroviral transfer of the cDNA, we obtained 9L murine gliosarcoma cells showing stable expression of the target enzyme (9L-dThdPase). The growth of the cells was identical to wild type (9L-WT) or control-vector transfected (9L-Neo) cells in vitro. Sensitivity to 5-FU was increased in 9L-dThdPase cells. After the adenoviral delivery of cytosine deaminase gene into these cells, 9L-dThdPase cells also demonstrated an increased sensitivity to 5-FC. Moreover, we showed that transduction of dThdPase cDNA prolongs the survival of animals bearing intracerebral tumors after experimental in vivo cytosine deaminase gene therapy. These results suggest that transduction of thymidine phosphorylase may be a beneficial approach to increasing the efficacy of cd/5-FC suicide gene therapy in certain types of tumor.
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PMID:Transduction of thymidine phosphorylase cDNA facilitates efficacy of cytosine deaminase/5-FC gene therapy for malignant brain tumor. 1172 81

We studied the effect of suicide gene therapy using an adenovirus vector expressing the cytosine deaminase (CD) gene combined with irradiation therapy (chemo-radio-gene therapy) for human colorectal cancer cells. Since serum CEA levels are elevated in patients with some malignant tumors including colorectal cancer, we applied the CEA promoter to chemo-radio-gene therapy, expecting tumor-specific expression of the CD gene. In in vitro study, we succeeded in selective expression of the target CD gene and growth inhibition in only CEA-producing tumor cells; Further the inhibitory effect was enhanced by combination with radiation therapy in an irradiation dose-dependent manner. In addition, in in vivo study, a significant growth inhibition was observed in chemo-radio-gene therapy in comparison with radiation therapy alone or suicide gene therapy alone. Thus, we suggest that tumor-specific chemo-radio-gene therapy may be a useful strategy for human colorectal cancer.
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PMID:Tumor-specific chemo-radio-gene therapy for colorectal cancer cells using adenovirus vector expressing the cytosine deaminase gene. 1172 28

5-Fluorouracil (5-FU) is a potent antimetabolite used for chemotherapy of gastrointestinal (GI), breast, and head and neck malignancies. Although clinical trials have been conducted, the poor therapeutic index of 5-FU has precluded its clinical use for a number of other tumor types. It is unclear whether this lack of utility is due to problems with drug delivery or inherent insensitivity. Adenovirus (Ad) vector-mediated cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy has the potential to overcome pharmacokinetic issues associated with systemic 5-FU and is particularly well suited to use with tumors in which local control is paramount, such as recurrent, localized prostate cancer and malignant gliomas. In this study, the in vitro response by a panel of human tumor cell lines derived from both GI (colon, pancreas) and non-GI (prostate, glioma) tumors to 5-FU and to AdCMVCD (an Ad encoding Escherichia coli CD)/5-FC was examined. Whereas the sensitivity (IC(50)) of individual cell lines to these agents varied, no significant difference in median IC(50) for either 5-FU or AdCMVCD/5-FC was evident for the four tumor types tested (P > 0.1). The relevant contributions of Ad gene transfer efficiency and inherent 5-FU sensitivity in determining response to AdCMVCD/5-FC were then assessed. Multiple linear regression analysis revealed that whereas both factors significantly contribute to the response, inherent 5-FU sensitivity was substantially more important (beta= 0.78 versus 0.48; P < 0.001). Finally, the therapeutic efficacy of a single intratumoral injection of AdCMVCD followed by systemic 5-FC was assessed in three intracranial C.B17 severe combined immunodeficient mouse models of human glioma. AdCMVCD/5-FC efficacy was specific, virus dose-dependent, and closely paralleled in vitro 5-FU and CD/5-FC sensitivity in two of three models tested. These results reveal that glioma cells are as sensitive as GI tumor cells to the antineoplastic effects of 5-FU, identify inherent 5-FU sensitivity as an important factor in determining CD/5-FC efficacy, and confirm previous findings in rat models that demonstrate the potential clinical utility of AdCMVCD/5-FC gene therapy for gliomas.
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PMID:Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas. 1183 May 32


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