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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A major obstacle to the successful application of suicide gene therapy strategies that rely on in situ transduction of tumor cells is the poor distribution of the vector throughout the tumor mass. To address this problem, we evaluated the use of Ad.TK(RC), an E1b Mr 55,000 deleted replicating adenoviral vector engineered to express the herpes simplex virus type 1 thymidine kinase gene (HSV-tk) in combination with ganciclovir (GCV) as a treatment for human colon cancer xenografts in nude mice. We compared the efficacy of this system with that of a standard replication-deficient adenovirus expressing HSV-tk (Ad.TK) in mice bearing LS180 tumors. In this system, Ad.TK(RC) alone was as effective as a traditional Ad.TK vector in combination with GCV. The addition of GCV significantly enhanced the antitumor effect of Ad.TK(RC). Furthermore, we demonstrated that the survival of HT-29 human colon cancer xenografted mice treated with Ad.TK(RC) and GCV was prolonged compared with Ad.TK(RC) alone or with administration of a single cycle of topotecan. These data demonstrate that the addition of direct viral oncolysis to the HSV-tk/GCV suicide gene system resulted in a striking improvement in treatment efficacy and that it may offer advantages over the use of chemotherapeutic agents for treatment of localized disease.
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PMID:Therapy of colon cancer with oncolytic adenovirus is enhanced by the addition of herpes simplex virus-thymidine kinase. 992 55

A rat colonic adenocarcinoma was implanted subcutaneously in female nude (C57BL/6JBom-nu) mice. After 7 days, the animals were divided into different groups. One group received triple therapy with octreotide, galanin, and serotonin, 10 microg/kg body weight of each, twice daily. The second group served as controls and received only saline solution. Three groups received 10 microg/kg body weight twice daily of octreotide, galanin, or serotonin. The last group consisted of controls that received only saline solution. The treatment lasted for 5 days. The tumour volume, wet weight, and relative volume density of blood vessels were significantly decreased after the triple treatment, as compared to controls. Apoptotic index was significantly increased, but the proliferation index was not affected in the group of mice that received triple therapy. There was no significant difference between controls and mice treated with octreotide, galanin, or serotonin regarding tumour volume or weight. The relative volume density of blood vessels was decreased in tumours treated with galanin, but not with octreotide or serotonin. There was no statistical difference in the proliferation index between controls and animals treated with octreotide, galanin, or serotonin, as compared with controls. Tumour necrosis and increased apoptosis may be responsible for the reduction in the volume and weight of the tumour after triple therapy. Tumour necrosis may be caused by the induction of tumour ischemia due to a reduction in tumour blood flow, which is caused by decreased incidence of tumour-feeding blood vessels, and by constriction of tumour-feeding arterioles. These results are promising and may offer treatment for colon cancer.
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PMID:Triple therapy with octreotide, galanin, and serotonin reduces the size and blood vessel density and increases apoptosis of a rat colon carcinoma. 1260 62

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-small-cell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9-8.7 days and a steady-state volume of distribution of approximately 60 ml kg(-1). Clearance was 3.6-5.7 ml(-1) day(-1) kg(-1). These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.
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PMID:HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. 1584 98

Viral vectors are under development for anticancer therapy. As they can infect tumours and activate the immune system, viral vectors may directly destroy cancers (oncolysis), deliver genes with antitumour activity directly to the cancer cells, or act as cancer vaccines. Better insights into the biology of the various vectors in use (e.g., poxvectors, adenovirus, adeno-associated virus, reovirus, Newcastle disease virus) are making it possible to engineer viruses that are more tumour-specific, efficient at tumour infection, and which have enhanced safety due to incorporation of safeguards should dissemination occur. As considerable research has focused on therapy of colon cancer with viral vectors, this review will illustrate the major concepts of viral therapy of cancers with examples from studies targeting colorectal carcinoma.
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PMID:Virus-based therapies for colon cancer. 1631 26

We evaluated whether the expression of measles virus fusogenic membrane glycoproteins H and F (MV-FMG), encoded by a herpes simplex virus type 1 (HSV-1) amplicon vector, can serve with or without viral oncolysis (G47Delta) and facultative irinotecan chemotherapy, alone or in combination with the monoclonal epidermal growth factor receptor (EGFR) inhibitory antibody cetuximab, as a platform for inducing tumor-specific immune responses against colon cancer. We demonstrated in vitro that MV-FMG expression in murine cells resulted in cell-cell fusion and synergistically enhanced the cytotoxicity of irinotecan alone or in combination with cetuximab. In a bilateral syngeneic subcutaneous MC38 and Colon26 tumor model in C57BL/6 and BALB/c mice we assessed both the effect on directly vector-treated tumors and the effect on contralateral, not directly vector-treated tumors. We demonstrated that the combination of three treatment components with or without cetuximab resulted in the best volume reduction of both directly vector-treated and not directly vector-treated tumors as well as pronounced infiltration of both tumor types with natural killer cells, macrophages, and T cells. T cells of these animals exhibited strong ex vivo cytotoxic activity against the tumor cells, indicating that the antineoplastic effect on untreated tumors was mediated by an antitumor immune response. Preexisting immunity against HSV-1 or measles virus had no detrimental effect on overall treatment efficacy. Our data indicate that MV-FMG expression in combination with viral oncolysis with or without clinically relevant chemotherapy for colon cancer treatment warrants further investigation.
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PMID:Local and distant immune-mediated control of colon cancer growth with fusogenic membrane glycoproteins in combination with viral oncolysis. 1751 12

Human intestinal intraepithelial lymphocytes (IELs), which are T-cell receptor alphabeta+ CD8+ T cells located between epithelial cells (ECs), are likely to participate in the innate immune response against colon cancer. IELs demonstrate spontaneous cytotoxic (SC) activity specifically directed against EC tumours but not against other solid tumour types. The aim of this study was to dissect out the mechanism of SC activity, focusing on the interaction of NKG2D on IELs with its ligands [major histocompatibility complex (MHC) class I chain-related protein (MIC) and UL16 binding protein (ULBP)] found mainly on EC tumours. A novel series of events occurred. The NKG2D-MIC/ULBP interaction induced Fas ligand (FasL) production and FasL-mediated SC activity against HT-29 cells and MIC-transfectants. Tumour necrosis factor-alpha and interferon-gamma, produced independently of this interaction, promoted SC activity. The immune synapse was strengthened by the interaction of CD103 on IELs with E-cadherin on HT-29 cells. Neither T-cell receptor nor MHC class I was involved. While the HT-29 cells were destroyed by soluble FasL, tumour necrosis factor-alpha and interferon-gamma, the IELs were resistant to the effects of these mediators and to FasL expressed by the HT-29 cells. This unidirectional FasL-mediated cytotoxicity of IELs against HT-29 cells, triggered through NKG2D, is unique and is likely to be a property of those CD8+ tumour-infiltrating lymphocytes that phenotypically resemble IELs.
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PMID:Dissection of spontaneous cytotoxicity by human intestinal intraepithelial lymphocytes: MIC on colon cancer triggers NKG2D-mediated lysis through Fas ligand. 1828 69

The efficacy of adenovirus vector-based cancer gene therapy is controversial. Its uptake by cells in many cases requires the major receptor for adenoviruses, the coxsackievirus and adenovirus receptor (CAR). Low transduction is believed to be one of the main barriers as the expression of CAR on tumor cells is frequently reduced. Increasing CAR expression on tumor cells thus offers a promising opportunity for more effective adenovirus based treatment. Expression of CAR in 62 cases of colon tumor specimens were examined with immunohistochemistry. To modify the CAR expression, the effects of proteasome inhibitor MG132 on CAR expression of colon cancer cell lines were determined by flow cytometry, RT-PCR, and western blot. To evaluate adenovirus transfer, we further used rAd.EGFP, rAd.p53, and oncolytic adenovirus to infect target cells. The CAR expression was significantly decreased in colon carcinomas, both in primary tumors and lymphonode metastasis. Though the deregulation of CAR occurred in early disease and showed no relationship with TNM stage, when primary tumors are more than 5 cm in diameter, this deregulation becomes more frequent. More importantly, proteasome inhibitor MG-132 could enhance CAR expression in colon carcinoma cell line lovo, accompanied with enhanced adenovirus transfer, target gene expression, and oncolysis. These data provide a rational basis for evaluation of CAR expression in tumors and pretreatment with CAR conditioner prior to adenovirus vector-based gene therapy.
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PMID:Proteasome inhibitor MG-132 modifies coxsackie and adenovirus receptor expression in colon cancer cell line lovo. 1841 65

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis on binding to its receptors, death receptor 4 and 5 (DR4, DR5). TRAIL can also activate c-Jun N-terminal kinase (JNK) through the adaptor molecules, TNF receptor-associated factor 2 (TRAF2) and receptor-interacting protein (RIP). The role of JNK in TRAIL-induced tumour cell apoptosis is unclear. In this study, we demonstrate that JNK is activated by TRAIL in colon cancer cells. Inhibition of JNK with L-JNKI reduced rhTRAIL-induced cell death but enhanced cell death induced by selective activation of DR4 or DR5. This difference was unrelated to receptor internalisation or differential activation of c-Jun, but activation of different JNK isoforms. Our data demonstrate that JNK1, but not JNK2 is activated by rhTRAIL in the examined colon cancer cell lines. Although rhTRAIL activated both the long and short isoforms of JNK1, selective activation of DR4 or DR5 led to predominant activation of the short JNK1 isoforms (JNK1alpha1 and/or JNK1beta1). Knockdown of JNK1alpha1 by shRNA enhanced apoptosis induced by TRAIL, agonistic DR4 or DR5 antibodies. On the other hand, knockdown of the long JNK1 isoforms (JNK1alpha2 and JNK1beta2) had the opposite effect; it reduced TRAIL-induced cell death. These data indicate that the short JNK1 isoforms transmit an antiapoptotic signal, whereas the long isoforms (JNK1alpha2 or JNK1beta2) act in a proapoptotic manner.
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PMID:Differential activation of JNK1 isoforms by TRAIL receptors modulate apoptosis of colon cancer cell lines. 1935 84

Reovirus functions as an oncolytic agent for many types of cancer including colon cancer. Although most studies have emphasized the role of activated Ras signaling in enhancing reoviral oncolysis in susceptible cells, we note that many colon cancers also display elevated beta-catenin. Thus, it is possible that enhanced beta-catenin may augment reoviral susceptibility in colon cancer cells. To explore this hypothesis, HEK293 cells were treated with the glycogen synthase kinase (GSK)-3beta inhibitor LiCl, thereby inducing beta-catenin, followed by reoviral infection. Co-administration with LiCl indeed enhanced cell death compared to reovirus infection alone, but this was not associated with elevated reoviral replication. Similarly, HEK293 cells expressing the Frizzled-1 receptor in Wnt3a-conditioned medium also showed reovirus replication equivalent to that in cells in control medium, further suggesting that up-regulation of beta-catenin does not enhance the replication of reovirus. Instead, we observed that inhibition of GSK-3beta with LiCl decreased reovirus-induced NF-kappaB activation, leading to accelerated apoptosis via caspase 8 activation. We further found that colon cancer HCT116 cells were sensitized to apoptosis by co-treatment with reovirus and a GSK-3beta inhibitor, AR-A014418. Finally, we identified that inhibition of NF-kappaB sensitized apoptosis of HEK293 or HCT 116 cells during reovirus infection. Taken together, we propose that inhibition of GSK-3beta sensitizes reovirus-induced apoptosis of colon cancer cells by down-regulation of NF-kappaB activity, offering a potentially improved therapeutic strategy for the treatment of colon cancer.
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PMID:Inhibition of GSK-3beta enhances reovirus-induced apoptosis in colon cancer cells. 1963 82

Replication-competent adenovirus type 5 (Ad5) vectors promise to be more efficient gene delivery vehicles than their replication-deficient counterparts, and chimeric Ad5 vectors that are capable of targeting CD46 are more effective than Ad5 vectors with native fibers. Although several strategies have been used to improve gene transduction and oncolysis, either by modifying their tropism or enhancing their replication capacity, some tumor cells are still relatively refractory to infection by chimeric Ad5. The oncolytic effects of the vectors are apparent in certain tumors but not in others. Here, we report the biological and oncolytic profiles of a replication-competent adenovirus 11p vector (RCAd11pGFP) in colon carcinoma cells. CD46 was abundantly expressed in all cells studied; however, the transduction efficiency of RCAd11pGFP varied. RCAd11pGFP efficiently transduced HT-29, HCT-8, and LS174T cells, but it transduced T84 cells, derived from a colon cancer metastasis in the lung, less efficiently. Interestingly, RCAd11p replicated more rapidly in the T84 cells than in HCT-8 and LS174T cells and as rapidly as in HT-29 cells. Cell toxicity and proliferation assays indicated that RCAd11pGFP had the highest cell-killing activities in HT29 and T84 cells, the latter of which also expressed the highest levels of glycoproteins of the carcinoma embryonic antigen (CEA) family. In vivo experiments showed significant growth inhibition of T84 and HT-29 tumors in xenograft mice treated with either RCAd11pGFP or Ad11pwt compared to untreated controls. Thus, RCAd11pGFP has a potent cytotoxic effect on colon carcinoma cells.
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PMID:Transduction and oncolytic profile of a potent replication-competent adenovirus 11p vector (RCAd11pGFP) in colon carcinoma cells. 2145 97


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