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

Authors present an additional case report of pleomorphic hyalinizing angiectatic tumor (PHAT), only recently recognized entity amongst the soft tissue tumors. 63-year-old man underwent surgery for subcutaneous tumor growing on the forearm. Grossly, ovoid well demarcated tumor 4.0 x 3.5 x 2.5 cm was removed. Histologically, hypovascular areas of spindle-cells arranged in sheets and fascicles resembling spindle-cell sarcoma and areas rich on ectatic vessels with fibrin deposits or thickened hyalinized walls were present. Some cells contained intranuclear cytoplasmatic inclusions, lobulated nuclei with or without prominent nucleoli or multiple nuclei. Mitoses were less than 1 per 30 HPF, Ki-67 nuclear positivity was observed in 2.6% of tumor cells. Immunohistochemically, cells were positive with vimentin, but negative for CD34, S100, desmin, smooth-muscle actin, EMA, VWF, CD99, bcl-2 and cytokeratins. The patient did well, without recurrent tumor after 13 months follow-up. Spectrum of tumors including solitary fibrous tumor, giant-cell angiofibroma, neurilemmoma, malignant fibrous histiocytoma and acral myxoinflammatory tumor with atypical bizarre giant cells is discussed in differential diagnosis.
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PMID:Pleomorphic hyalinizing angiectatic tumor. 1181 37

Adenoviruses can be engineered to replicate selectively in tumor cells but inefficiently in normal cells. ONYX-015 (CI-1042, dl1520; Onyx Pharmaceuticals Inc), which replicates selectively in cells deficient in the p53 pathway, was the first such adenovirus to reach clinical testing. Multiple trials of ONYX-015 in over 300 cancer patients, and trials with other selectively replicating adenoviruses, have established the safety of this approach. Evidence of anticancer activity in patients is encouraging. Recently, the first clinical trial of a selectively replicating adenovirus carrying an inserted transgene was reported. Adenoviruses with improved efficiency of replication, technologies for use of the viruses as vectors for anticancer gene therapy, and various other approaches, provide promising directions to develop selectively replicating adenoviruses into systemic therapy for metastatic cancer.
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PMID:Selectively replicating adenoviruses for cancer therapy: an update on clinical development. 1252 15

The purpose of this study was to address the question whether patients with bilateral breast cancer (BBC) have a worse prognosis in terms of recurrence and survival than patients with primarily unilateral breast cancer (UBC) following breast-conserving treatment (BCT). From 1983 to 2000, a total of 1760 BCT were registered in the Radiotherapy Department of the Medisch Spectrum Twente. We defined synchronous a BBC as cancer diagnosed in both breasts at the same time or within a period of 3 months of diagnosis of the first tumor. One thousand seven hundred and sixty BCT were performed on 1705 patients, 26 of whom presented with BBC. Of these 26 patients, 18 had BCT for both breasts. A higher proportion of patients with BBC showed more tubular carcinoma (P=0.029) and medially located tumors (P=0.076) than those with UBC did. The 5- and 10-year local recurrence rates (LRRs) were 4.5% and 9.1%, respectively, in BBC patients, as against 3.3% and 7.6% for UBC after BCT. The 5- and 10-year distant metastasis rates were 26.9% and 50.7%, respectively, for BBC as against 13.4% and 21.1% for UBC after BCT (P=0.065 and P=0.014, respectively). The 5- and 10-year disease-specific survival (DSS) rates for the 1705 patients were 82.1% and 41%, respectively, after BBC, and 91.4% and 84% after UBC (P=0.086 and P=0.0045, respectively). Patients with BBC have a higher rate of distant metastasis and a worse DSS than those with UBC. As the LRR is similar for BBC and UBC, BCT is not contraindicated in BBC. The incidence of BBC is low, at 1.5% which makes it difficult to reach any more definitive conclusions on outcome and treatment.
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PMID:Synchronous, bilateral breast cancer: prognostic value and incidence. 1517 34

Cytochrome P450 (CYP) gene transfer sensitizes tumor xenografts to anticancer prodrugs such as cyclophosphamide (CPA) without a detectable increase in host toxicity. Optimal prodrug activation is achieved when a suitable P450 gene (e.g., human CYP2B6) is delivered in combination with NADPH-cytochrome P450 reductase (P450R), which encodes the flavoenzyme P450 reductase. We sought to improve this gene therapy by coordinated delivery and expression of P450 and P450R on a single bicistronic vector using an internal ribosomal entry site (IRES) sequence. Retrovirus encoding a CYP2B6-IRES-P450R expression cassette was shown to induce strong P450-dependent CPA cytotoxicity in a population of infected 9L gliosarcoma cells. Adeno-P450, a replication-defective, E1/E3 region-deleted adenovirus engineered to express CYP2B6-IRES-P450R, induced intracellular CPA 4-hydroxylation, and CPA cytotoxicity, in a broad range of human cancer cell lines. However, limited Adeno-P450 gene transfer and CPA chemosensitization was seen with certain human tumor cells, notably PC-3 prostate and HT-29 colon cancer cells. Remarkable improvements could be obtained by coinfecting the tumor cells with Adeno-P450 in combination with Onyx-017, an E1b-55k gene-deleted adenovirus that selectively replicates in p53 pathway-deficient cells. Substantial increases in gene expression were observed during the early stages of viral infection, reflecting an apparent coamplification of the Adeno-P450 genome, followed by enhanced viral spread at later stages, as demonstrated in cultured tumor cells, and in A549 and PC-3 solid tumor xenografts grown in scid mice. This combination of the replication-defective Adeno-P450 with a replication-conditional and tumor cell-targeted helper adenovirus dramatically improved the low gene transfer observed with some human tumor cell lines and correspondingly increased tumor cell-catalyzed CPA 4-hydroxylation, CPA cytotoxicity, and in vivo antitumor activity in a PC-3 tumor xenograft model. The use of tumor-selective, replicating adenovirus to promote the spread of replication-defective gene therapy vectors, such as Adeno-P450, substantially increases the therapeutic potential of adenoviral delivery systems, and should lead to increased activity and enhanced tumor selectivity of cytochrome P450 and other gene-directed enzyme prodrug therapies.
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PMID:Use of replication-conditional adenovirus as a helper system to enhance delivery of P450 prodrug-activation genes for cancer therapy. 1472 37

Despite recent improvements in the treatment of metastatic colorectal cancer, few patients are cured and the response rates to second-line treatments are poor. Onyx-015, an oncolytic virus, was administered to patients with metastatic colorectal cancer by hepatic artery infusion. No dose-limiting toxicities were observed in the phase I/II studies. Onyx-015 can kill tumor cells by mechanisms that are distinct from chemotherapeutic agents and may therefore have activity among patients who have failed first-line chemotherapy. The 24 patients included in this analysis had failed first-line therapy with 5-FU/leucovorin, 79% of the patients failed two or more regimens and 58% had failed treatment with Irinotecan. Despite the extensive prior therapy, the median survival of these patients was 10.7 months, 46% were alive at 1 year and two patients (8%) had partial responses. In all, 11 patients (46%) had stable disease at the completion of the four planned viral treatments (3 months). The median survival of this group of patients was 19 months, suggesting that stable disease may be an important predictor of benefit with oncolytic viruses. Eight of the 11 patients with stable disease at 3 months demonstrated a unique radiographic pattern of transient enlargement of tumor masses (10-48%) after the initial infusions of Onyx-015, followed by radiographic evidence of extensive tumor necrosis and regression. The initial enlargement and subsequent tumor necrosis resulted in a prolonged time to achieve objective tumor regression. In addition, the transient enlargement of the tumor masses may have resulted in premature removal of responding patients. Treatment of eight patients was stopped prior to completion of the planned four treatments due to presumed progression as defined by standard radiographic criteria (>25% increase in tumor size). Functional imaging, such as positron emission tomography (PET) scans, may help distinguish clinical responses from progressive disease following treatment with oncolytic viruses. Onyx-015 may benefit patients with refractory colorectal cancer and additional studies that include PET scans to assess clinical response are warranted.
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PMID:Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin. 1580 47

Replication-selective oncolytic adenoviruses hold promise, but novel mechanisms must be identified to maximize intratumoral virus persistence, spread and therapeutic transgene-carrying capacity while maintaining safety. One of the main approaches to engineering cancer-selectivity has been to delete a viral gene that is theoretically expendable in cancer cells. Results with this approach have been mixed, however, as evidenced by controversy over Onyx-015 (E1B-55kD(-)) selectivity. We hypothesized that the functional redundancy between viral gene products might limit selectivity and/or potency with this approach. Antiviral immune inducers of apoptosis (eg TNF-alpha) have not been thoroughly investigated in previous studies. We therefore explored whether deletion of functionally redundant viral genes, E1B-19kD and E3B, both independently antagonize TNF-alpha, could lead to enhanced oncolytic potency while maintaining selectivity. Since tumors have numerous blocks in apoptotic pathways, we hypothesized that deletion of one or both gene regions would result in cancer-selectivity in the presence of TNF-alpha. We have previously shown that the E1B-19kD deletion resulted in enhanced viral spread in vitro and in immunocompetent tumor models in vivo. In contrast, the impact of E3B deletion, especially its in vitro selectivity and potency, was not thoroughly characterized, although it resulted in rapid immune-mediated viral clearance in vivo. Furthermore, previous publications indicated that double-deleted mutants have selectivity but unsatisfactory efficacy. We compared the selectivity and potency of E1B-19kD(-), E3B(-) and E1B-19kD(-)/E3B(-) mutants to wild-type adenovirus. In cancer cells, the E1B-19kD(-) mutant had superior replication, spread and cytolysis (+) or (-) TNF-alpha; deletion of both E1B-19kD and E3B was relatively deleterious. In normal cells without TNF-alpha, similar results were obtained. In contrast, all three mutants were significantly inhibited in the presence of TNF-alpha. In immunocompetent mice, all three mutants were significantly inhibited in normal tissue. In tumors, only the E1B-19kD(-) mutant demonstrated enhanced replication, spread and antitumoral efficacy. Therefore, E1B-19kD deletion and E3B retention should be incorporated in oncolytic adenoviruses for enhanced safety and efficacy. In addition, functional redundant viral genes and their biological mediators/targets need to be carefully examined for the next generation of gene-deleted oncolytic viruses.
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PMID:Functional interactions of antiapoptotic proteins and tumor necrosis factor in the context of a replication-competent adenovirus. 1592 Apr 62

Gene therapy using the prodrug-activating enzyme P450 2B6 has shown substantial promise in preclinical and initial clinical studies with the P450 prodrugs cyclophosphamide and ifosfamide. We sought to optimize this therapy using the canine P450 enzyme 2B11, which activates cyclophosphamide and ifosfamide with Km of 80 to 160 micromol/L, approximately 10- to 20-fold lower than the Km of P450 2B6. Retrovirus encoding a P450 2B11-internal ribosome entry signal-P450 reductase expression cassette induced marked cyclophosphamide and ifosfamide cytotoxicity toward 9L gliosarcoma cells and exhibited an impressive bystander killing effect at micromolar prodrug concentrations, where P450 2B6 displayed low activity. Adeno-2B11, a replication-defective, E1/E3 region-deleted adenovirus engineered to coexpress P450 2B11 and P450 reductase, dramatically increased tumor cell-catalyzed cyclophosphamide 4-hydroxylation and cytotoxicity compared with Adeno-2B6 and effected strong bystander killing at low (20 micromol/L) cyclophosphamide concentrations. Further increases in cyclophosphamide cytotoxicity were obtained in several human cancer cell lines, including a 4-hydroperoxycyclophosphamide-resistant MCF-7 breast cancer cell line, when Adeno-2B11 was combined with Onyx-017, an E1b-55-kDa gene-deleted, tumor cell-replicating adenovirus that coamplifies and facilitates tumor cell spread of Adeno-2B11. To evaluate the therapeutic effect of P450 2B11 expression in vivo, 9L gliosarcoma cells transduced with P450-expressing retrovirus were grown as solid s.c. tumors in immunodeficient mice. Cyclophosphamide treatment on a metronomic, 6-day repeating schedule led to full regression of 9L/2B11 tumors but not P450-deficient control tumors, resulting in a tumor-free period lasting up to approximately 100 days. 9L/2B6 tumors regressed more slowly and exhibited a tumor-free period of only 21 to 39 days. Thus, P450 gene-directed enzyme prodrug therapy can be greatly improved by using the low Km P450 enzyme 2B11, which catalyzes intratumoral activation of cyclophosphamide and ifosfamide at pharmacologically relevant drug concentrations.
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PMID:Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11. 1654 68

The Informational Spectrum Method (ISM) is the tool for the in silico analysis of proteins which interprets protein sequence linear information using signal analyses methods. In this paper the ISM was employed to characterize the products of genetic variants of tumor suppressor gene p53 and its natural binding regulator protein Mdm2. Based on this we propose the criterion for identification of missense mutations that have impact on the p53-Mdm2 feedback loop. The efficiency of the proposed criterion was confirmed by the ISM analyses of p53 mutants reported in: (i) healthy individuals, (ii) germline mutations database and (iii) somatic mutations database.
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PMID:In silico criterion for prediction of effects of p53 gene missense mutations on p53-Mdm2 feedback loop. 1707 27

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015.
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PMID:Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver. 1713 21


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