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

Ten years ago Frank McCormick proposed dl1520 as an oncolytic adenovirus. Although great as an inspiration for better oncolytic viruses it was far from a good product. As Onyx-015, it underwent a wish-fulfilling clinical development program seizing the opportunity left by its p53-targeted non-replicative counterpart Ad-p53. Now, facing a skeptical environment, more selective and potent oncolytic adenoviruses await their clinical opportunity. However, advance in key issues remains elusive, such as, selectivity or retargeting at the level of cell receptors to improve pharmacokinetics. Preclinical models and a few clinical data on biodistribution show that only a minimal proportion of the injected dose reaches the tumors after systemic administration. Once in the tumor, the virus must overcome barriers to efficient spread imposed by stroma and immune responses. Arming the oncolytic virus with transgenes is a natural combination of virotherapy and gene therapy strategies. Transgenes that increase virus production or cellular spread may help to overcome these barriers. Cytotoxic transgenes can help to eliminate tumor cells but need to be compatible with efficient virus replication. These challenges require a careful approach to clinical development and a great deal of collaboration to launch clinical tests with a virus backbone that contains intellectual property from multiple sources.
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PMID:Cancer selective adenoviruses. 1730 Aug 34

The current field of oncolytic virus development has evolved from, and been educated by, the route adenoviruses have taken to Phase III development in the United States (Onyx-015) and commercial approval in China (H101). Clinical development of these E1B-deleted viruses showed that a staged approach, from single-agent intratumoral injections to trials testing intravenous delivery and trials in combination with approved therapies is judicious and can be successful. Additional oncolytic products are in development, including andenovirus plus other promising platforms such as herpes simplex virus, Newcastle disease virus, reovirus and vaccinia virus. These second-generation products seek to expand clinical utility beyond the modest local efficacy of Onyx-015/H101 to potent systemic delivery and efficacy. Improvement of efficacy in metastatic cancer will depend not only on enhanced killing of tumor cells, but also on achieving intravenous delivery and better intratumoral dissemination. Many viruses inherently replicate preferentially in tumors, and engineering can increase this therapeutic index by targeting genetic features of cancers. However, both viruses and cancer cells have complex biologies. Therefore, research may reveal that there is not a single predictive factor for tumor specificity. For example, the Onyx-015 mechanism-of-selectivity has proved to be complex. Further research regarding pathway dependence for other oncolytic viruses may also reveal multiple influences on their tumor tropism.
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PMID:From ONYX-015 to armed vaccinia viruses: the education and evolution of oncolytic virus development. 1734 4

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors and shows morphological features of a highly malignant, undifferentiated neoplasm. Patients with ATC have a poor prognosis with a mean survival time of 2-6 months; surgery, radiotherapy, and chemotherapy do not improve survival. Gene therapy approaches and oncolytic viruses have been tested for the treatment of ATC. To enhance the antineoplastic effects of the oncolytic adenovirus dl1520 (Onyx-015), we treated ATC cells with lovastatin (3-hydroxy-methylglutaryl-CoA reductase inhibitor), a drug used for the treatment of hypercholesterolemia, which has previously been reported to exert growth-inhibitory and apoptotic activity on ATC cells. Lovastatin treatment significantly increased the effects of dl1520 against ATC cells. The replication of dl1520 in ATC cells was enhanced by lovastatin treatment, and a significant increase of the expression of the early gene E1A 13 S and the late gene Penton was observed in lovastatin-treated cells. Furthermore, lovastatin treatment significantly enhanced the effects of dl1520 against ATC tumor xenografts. Lovastatin treatment could be exploited to increase the efficacy of oncolytic adenoviruses, and further studies are warranted to confirm the feasibility of the approach in ATC patients.
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PMID:Lovastatin enhances the replication of the oncolytic adenovirus dl1520 and its antineoplastic activity against anaplastic thyroid carcinoma cells. 1769 Jan 62

Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.
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PMID:Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. 1796 76

Paragangliomas, or glomus tumors, are highly vascular benign tumors of the head and neck. Clinical symptoms are essentially progressive and neurological, involving infiltration of the regional cranial nerves. The usual treatment is surgery, which itself is a challenge because of the close proximity of vital structures and the considerable blood loss. Preoperative embolization can reduce morbidity, and several techniques have been described using arterial injection of particles or of cyanoacrylate directly into the tumor. This case report is of a patient treated by surgery using a new technique-preoperative embolization involving both the arteries and veins, and injection of Onyx, resulting in complete devascularization of the tumor's arteriovenous network.
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PMID:[Preoperative mixed embolization of a paraganglioma using Onyx]. 1798 40

We report the first use of Onyx in the embolization of spinal tumors in 2 cases of aggressive vertebral hemangioma. In both cases, Onyx embolization provided effective preoperative tumor devascularization after the initial prolonged particulate embolization with Embospheres made little overall impact. Onyx enables a more rapid and visible embolization than particles and is less technically demanding than traditional liquid embolic agents, such as n-butyl cyanoacrylate.
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PMID:Preoperative Onyx embolization of aggressive vertebral hemangiomas. 1837 19

Cutaneous melanoma is the most serious form of skin cancer and is curable only if it is detected early. The most effective treatment for the melanoma is surgical excision of the lesion. Traditionally, wide margins of excision have been used for effective treatment, but are not always desirable due to increased risk of infection and esthetic reasons. Besides, safe surgical margins of the lesion are not always correlated well with the size of the lesions. We have previously developed a system using elastic light single-scattering spectroscopy to differentiate cancerous tissue from non-cancerous tissue and tested it in vitro. The goal of this study was, therefore, to determine the effectiveness of this system ex vivo by using a mouse model of melanoma. First, a melanoma cell line; B16F10 were injected subcutaneously at right mid flank region of C57BL6 mice (n=5) and allowed to develop for two weeks. Tumors were dissected and spectra were taken on tumor tissue and on normal looking skin tissue that was 10 mm distant from the incision. Since these tumors become markedly necrotic in the middle, spectra of necrotic area was also taken. Slopes of the spectra were positive taken on non-cancerous skin tissues that were later verified by histological examination. On the other hand, it gave negative slopes on melanomas. Increased sizes of the nuclei correlated with the negative slope while smaller nuclei found in non-cancerous tissue gave positive slope. Spectrum taken from necrotic area differed from both cancerous and non-cancerous tissue such that it gave a U-shaped spectrum. These results demonstrate that elastic light single-scattering spectroscopy system can differentiate cancerous tissue from non-cancerous and has potential to be used intraoperatively to determine the surgical margins.
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PMID:Differentiation of melanoma from non-cancerous tissue in an animal model using elastic light single-scattering spectroscopy. 1847 95

Oncolytic viruses are regulated by the tumor phenotype to replicate and lyse cancer cells selectively. To identify optimal strategies for breast cancer we compared five adenoviruses with distinct regulatory mechanisms: Ad-dl922-947 (targets G1-S checkpoint); Ad-Onyx-015 and Ad-Onyx-017 (target p53/mRNA export); Ad-vKH1 (targets Wnt pathway), and AdEHE2F (targets estrogen receptor/G1-S checkpoint/hypoxic signaling). The quantity of virus required to kill 50% of breast cancer cells after 6 days (EC(50), plaque-forming units per cell) was measured. The most potent virus was Ad-dl922-947 (EC(50), 0.01-5.4 in SkBr3, MDA-231, MDA-468, MCF7, and ZR75.1 cells), followed by wild-type (Ad-WT; EC(50), 0.3-5.5) and AdEHE2F (EC(50), 1.4-3.9). Ad-vKH1 (EC(50), 7.2-72.1), Ad-Onyx-017 (EC(50), 8.4-167), and Ad-Onyx-015 (EC(50), 17.7-377) showed less activity. Most viruses showed limited cytotoxicity in normal human cells, including breast epithelium MCF10A (EC(50), >722) and fibroblasts (EC(50), >192) and only moderate cytotoxicity in normal microvascular endothelial cells (HMVECs; EC(50), 42.8-149), except Ad-dl922-947, which was active in HMVECs (EC(50), 1.6). After injection into MDA-231 xenografts, Ad-WT, AdEHE2F, and Ad-dl922-947 showed replication, assessed by hexon staining and quantitative polymerase chain reaction measurement of viral DNA, and significantly inhibited tumor growth, leading to extended survival. After intravenous injection Ad-dl922-947 showed DNA replication (233% of the injected dose was measured in liver after 3 days) whereas AdEHE2F did not. Overall, AdEHE2F showed the best combination of low toxicity in normal cells and high activity in breast cancer in vitro and in vivo, suggesting that molecular targeting using estrogen response elements, hypoxia response elements, and a dysregulated G1-S checkpoint is a promising strategy for virotherapy of breast cancer.
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PMID:Comparison of molecular strategies for breast cancer virotherapy using oncolytic adenovirus. 1871 Mar 28

Carotid body tumors (CBTs) are rare highly vascular lesions that frequently require preoperative embolization to minimize surgical morbidity secondary to blood loss. Embolization has typically been performed via a transarterial route. However, this frequently results in incomplete devascularization of the tumor due to the complex angioarchitecture of the feeding arteries. Direct intralesional embolization has been used to gain easier accesses to the tumor vasculature and thus increase the likelihood of complete embolization. Cyanoacrylate glue has been the most commonly used embolic agent. The authors present a case of CBT that underwent direct intralesional embolization using Onyx (ev3; ethylene vinyl alcohol copolymer). To their knowledge, there have been no previous reports of direct percutaneous embolization of a CBT with this agent.
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PMID:Direct percutaneous embolization of a carotid body tumor with Onyx. 1884 39

Preclinical and clinical studies of CYP gene-directed enzyme prodrug therapy have been focused on anticancer prodrugs activated by CYP2B enzymes, which have low endogenous expression in human liver; however, the gene therapeutic potential of CYP3A enzymes, which are highly expressed in human liver, remains unknown. This study investigated methoxymorpholinyl doxorubicin (MMDX; nemorubicin), a novel CYP3A-activated anticancer prodrug. Retroviral transfer of CYP3A4 increased 9L gliosarcoma cell chemosensitivity to MMDX 120-fold (IC(50)=0.2 nM in 9L/3A4 cells). In CHO cells, overexpression of P450 reductase in combination with CYP3A4 enhanced chemosensitivity to MMDX, and to ifosfamide, another CYP3A4 prodrug, 11- to 23-fold compared with CYP3A4 expression alone. CYP3A4 expression and MMDX chemosensitivity were increased in human lung (A549) and brain (U251) tumor cells infected with replication-defective adenovirus encoding CYP3A4. Coinfection with Onyx-017, a replication-conditional adenovirus that coamplifies and coreplicates the Adeno-3A4 virus, led to large increases in CYP3A4 RNA but only modest increases in CYP3A4 protein and activity. MMDX induced remarkable growth delay of 9L/3A4 tumors, but not the P450-deficient parental 9L tumors, in immunodeficient mice administered low-dose MMDX either intravenous or by direct intratumoral (i.t.) injection (60 microg kg(-1), every 7 days x 3). Notably, the i.t. route was substantially less toxic to the mouse host. No antitumor activity was observed with intraperitoneal MMDX treatment, suggesting a substantial hepatic first pass effect, with activated MMDX metabolites formed in the liver having poor access to the tumor site. These studies demonstrate that human CYP3A4 has strong potential for MMDX prodrug-activation therapy and suggest that endogenous tumor cell expression of CYP3A4, and not hepatic CYP3A4 activity, is a key determinant of responsiveness to MMDX therapy in cancer patients in vivo.
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PMID:Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. 1901 99


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