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:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncolytic viruses are an innovative therapeutic strategy for cancer, wherein viral replication and cytotoxicity are selective for tumor cells. Here we show the efficacy of systemically administered oncolytic viruses for the treatment of spontaneously arising tumors, specifically the use of oncolytic herpes simplex viruses (HSV) administered i.v. to treat spontaneously developing primary and metastatic prostate cancer in the transgenic TRAMP mouse, which recapitulates human prostate cancer progression. Four administrations of systemically delivered NV1023 virus, an HSV-1/HSV-2 oncolytic recombinant, to TRAMP mice at 12 or 18 weeks of age (presence of prostate adenocarcinoma or metastatic disease, respectively) inhibited primary tumor growth and metastases to lymph nodes. Expression of interleukin 12 (IL-12) from NV1042 virus, a derivative of NV1023, was additionally effective, significantly reducing the frequency of development of prostate cancer and lung metastases, even when the mice were treated after the onset of metastasis at 18 weeks of age. NV1042-infected cells, as detected by 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining for Lac Z expressed by the virus, were present in prostate tumors 1 week after the final virus injection and viral DNA was detected at 2 weeks after final virus injection by real-time PCR in primary and metastatic tumors but not in liver or blood. No toxicity was observed in any of the treated mice. The efficacy of the IL-12-expressing NV1042 virus in this aggressive prostate cancer model using a clinically relevant treatment paradigm merits its consideration for clinical studies.
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PMID:Systemic therapy of spontaneous prostate cancer in transgenic mice with oncolytic herpes simplex viruses. 1790 46

Oncolytic Herpes simplex virus -1 (HSV-1) mutants based on deletion of the gamma134.5 gene are promising therapies for cancer. Deltagamma134.5 mutant replication and cytolysis is tumor cell type specific and severely attenuated in normal tissues. The basis for attenuation lies in the activation of the protein kinase R (PKR)-mediated host cellular defense pathway, which inhibits protein synthesis in infected cells. Tumor cells which overexpress MAPK kinase (MEK) activity support robust replication of Deltagamma134.5 mutants via MEK-mediated inhibition of PKR, resulting in tumor oncolysis. Systemic delivery of gamma(1)34.5 mutants may allow selective targeting and destruction of metastases from a broad range of solid human tumors that overexpress MEK. Barriers to systemic HSV-1 oncolytic therapy include innate immunity, adaptive immunity and hepatic adsorption. Immunomodulating agents may overcome innate immunity to HSV-1-based vectors. Preclinical data combined with the pervasiveness of HSV-1 despite widespread immunity suggest that preexisting immunity may not eliminate oncolytic efficacy. In the future, biopsy-determined tumor MEK status may select patients for Deltagamma134.5 oncolytic therapy.
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PMID:Tumor genotype determines susceptibility to oncolytic herpes simplex virus mutants: strategies for clinical application. 1792 20

Effective treatment for recurrent, disseminated prostate cancer is notably limited. We have developed adenoviral vectors with a prostate-specific two-step transcriptional amplification (TSTA) system that would express therapeutic genes at a robust level to target metastatic disease. The TSTA system employs the prostate-specific antigen (PSA) promoter/enhancer to drive a potent synthetic activator, which in turn activates the expression of the therapeutic gene. In this study, we explored different configurations of this bipartite system and discovered that physical separation of the two TSTA components into E1 and E3 regions of adenovirus was able to enhance androgen regulation and cell-discriminatory expression. The TSTA vectors that express imaging reporter genes were assessed by noninvasive imaging technologies in animal models. The improved selectivity of the E1E3 configured vector was reflected in silenced ectopic expression in the lung. Significantly, the enhanced specificity of the E1E3 vector enabled the detection of lung metastasis of prostate cancer. An E1E3 TSTA vector that expresses the herpes simplex virus thymidine kinase gene can effectively direct positron emission tomography (PET) imaging of the tumor. The prostate-targeted gene delivery vectors with robust and cell-specific expression capability will advance the development of safe and effective imaging guided therapy for recurrent metastatic stages of prostate cancer.
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PMID:Configurations of a two-tiered amplified gene expression system in adenoviral vectors designed to improve the specificity of in vivo prostate cancer imaging. 1830 74

Liver transplantation with a part of the liver from a healthy living donor can be life saving for selected patients with end-stage liver failure. The experiences with the first 3 adult patients in the Netherlands were as follows. The first patient was a 56-year-old man with primary sclerosing cholangitis, who received half of the liver from his 53-year-old sister. Postoperatively, the donor developed a urinary tract infection, which was treated with antibiotics. The recipient developed fever and paralytic ileus 6 days after transplantation. Relaparotomy revealed minimal bile leakage from the cut surface of the liver, which was corrected with a suture. Three years after donation, both donor and recipient were doing well. The second patient was a 63-year-old man with hepatic cirrhosis due to hepatitis B, recurrent bleeding from varices, and hepatocellular carcinoma. The carcinoma was treated percutaneously with radiofrequency ablation. He was given a liver transplant from his 28-year-old son. The donor later developed transient ileus and mild liver function disorders. The recipient developed a bacterial infection of the ascites, which was treated with antibiotics, and later Candida-oesophagitis and a herpes simplex infection, which were also treated successfully. More than 2 years after donation and transplantation, both donor and recipient were in good condition. The third patient was a 42-year-old man with a chronic hepatitis B virus infection and 2 hepatocellular carcinomas. The donor was his 34-year-old sister-in-law. The recipient developed prolonged jaundice due to stenosis at the site of the bile duct anastomosis, for which a stent was placed. He was discharged in good condition but died 11 months later of cerebral metastases. One year after the procedure, the donor was doing well. The Rotterdam liver transplantation programme with living donors demonstrates that excellent results can be accomplished with minimal risk for the donor.
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PMID:[Liver transplantation with a living donor: the first 3 cases in Rotterdam]. 1849 25

Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 microg ml(-1)), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.
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PMID:Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter. 1877 2

hrR3 is an oncolytic herpes simplex virus 1 (HSV-1) mutant that replicates preferentially in tumors compared with normal tissues. Portal venous administration of hrR3 in mice bearing diffuse colorectal carcinoma liver metastases significantly reduces tumor burden and prolongs animal survival. In this study, we compared survival benefit and biodistribution of hrR3 following intravenous (i.v.) administration versus intraperitoneal (i.p.) administration in immunocompetent mice bearing colon carcinoma peritoneal metastases. Mice bearing peritoneal metastases received 1 x 10(8) plaque-forming units hrR3 or mock-infected media every other day for three doses and were randomized to have the viruses administered by either an i.p. or i.v. route. Biodistribution was assessed by PCR amplification of HSV-1-specific sequences from tumor and normal tissues including the small bowel, liver, spleen, kidney, lung, heart and brain. LD(50) for i.p. administration was compared with the LD(50) for i.v. administration. In subsequent experiments, animals were monitored for survival. The frequency of HSV-1 detection in peritoneal tumors was similar in mice randomized to either i.p. or i.v. administration. However, i.p. administration resulted in a more restricted systemic biodistribution, with a reduced frequency of virus detected in the kidney, lung and heart. The LD(50) associated with i.p. administration was higher than that with i.v. administration. Tumor burden was more effectively reduced with i.p. compared with i.v. administration. Median survival following i.p. administration was approximately twice that observed with i.v. administration. I.p. administration of an HSV-1 oncolytic mutant is associated with a more restricted biodistribution, less toxicity and greater efficacy against peritoneal metastases compared with i.v. administration.
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PMID:Comparison of intravenous versus intraperitoneal administration of oncolytic herpes simplex virus 1 for peritoneal carcinomatosis in mice. 1898 55

Transcription-targeted gene delivery directed against angiogenic endothelial cells is a new approach against advanced cancer. Moreover, the herpes simplex virus-thymidine kinase (HSV-TK) gene coupled with low dose radiotherapy is an efficient and externally controlled cytotoxic system. We have previously demonstrated enhanced endothelial-specific cell expression and killing using the modified murine pre-proendothelin-1 promoter (PPE1-3x) to direct adenoviral expression of a pro-apoptotic gene. The purpose of this study was to create an externally potentiated systemic antiangiogenic gene delivery system based on an adenoviral vector expressing HSV-TK under the regulation of PPE1-3X promoter combined with radiotherapy for eradicating metastatic cancer. Ad-PPE1-3x-TK induced endothelial-specific cell killing in-vitro upon introduction of the prodrug ganciclovir (GCV). BALB/c mice bearing a primary CT-26 colon carcinoma tumor showed tumor growth suppression and diminished tumor angiogenesis when the vector was administered intravenously, activated with GCV and potentiated with a single sub-therapeutic and non-toxic radiation dose. Moreover, intravenous administration of the vector, activated with GCV and potentiated with chest aimed radiation, to C57BL/6 mice bearing Lewis lung carcinoma metastases resulted in prolongation of mice survival. PPE1-3x-regulated HSV-TK expression was detected only in lung metastases in contrast to CMV-regulated expression. This novel system may benefit patients with metastatic disease.
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PMID:Systemic administration of radiation-potentiated anti-angiogenic gene therapy against primary and metastatic cancer based on transcriptionally controlled HSV-TK. 1927 57

An infection with Bartonella henselae transmitted from domestic cats to humans by scratching normally leads to cat-scratch disease. When the human host has severe immunosuppression or HIV infection, the potentially life-threatening disease bacillary angiomatosis can develop. A 79-year-old man presented with livid-erythematous, angioma-like skin lesions. We considered a cutaneous infiltrate from his known chronic lymphocytic leukemia, Merkel cell carcinoma, cutaneous metastases of internal tumors, cutaneous sarcoidosis, mycobacterial infection and even atypical herpes simplex infection. The correct diagnosis was proven histologically and by PCR. Because of increasing numbers of immunosuppressed and HIV-positive patients, as well as an infection rate of 13% for B. henselae in domestic cats in Germany, one must be alert to the presence of bacillary angiomatosis.
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PMID:Bacillary angiomatosis. 1929 47

Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem-like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although ICP6 (UL39)-deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of gamma34.5 significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of alpha47. Infection with oHSV G47Delta (ICP6(-), gamma34.5(-), alpha47(-)) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47Delta significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis.
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PMID:Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. 1935 38

Cancer gene therapy by adenovirus vectors (Advs) for metastatic cancer is limited because systemic administration of Adv produces low therapeutic effect and severe side effects. In this study, we generated a dual cancer-specific targeting vector system by using PEGylation and the telomere reverse transcriptase (TERT) promoter and attempted to treat experimental metastases through systemic administration of the vectors. We first optimized the molecular size of PEG and modification ratios used to create PEG-Ads. Systemic administration of PEG-Ad with 20-kDa PEG at a 45% modification ratio (PEG[20K/45%]-Ad) resulted in higher tumor-selective transgene expression than unmodified Adv. Next, we examined the effectiveness against metastases and side effects of a TERT promoter-driven PEG[20K/45%]-Ad containing the herpes simplex virus thymidine kinase (HSVtk) gene (PEG-Ad-TERT/HSVtk). Systemic administration of PEG-Ad-TERT/HSVtk showed superior antitumor effects against metastases with negligible side effects. A cytomegalovirus (CMV) promoter-driven PEG[20K/45%]-Ad also produced antimetastatic effects, but these were accompanied by side effects. Combining PEG-Ad-TERT/HSVtk with etoposide or 5-fluorouracil enhanced the therapeutic effects with negligible side effects. These results suggest that modification with 20-kDa PEG at a 45% modification ratio is the optimal condition for PEGylation of Adv, and PEG-Ad-TERT/HSVtk is a prototype Adv for systemic cancer gene therapy against metastases.
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PMID:Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis. 1964 32


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