Adenoviruses, attenuated

Ad-G/iCasp 3 Chemically inducible caspase-3 adenoviruses Attenuates tumor growth in a prostate cancer mouse model Preclinical 91... 

Yu DC, Sakamoto GT, Henderson DR. Identification of the transcriptional regulatory sequences of human kallikrein 2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy. Cancer Res 1999 59 1498-1504. 

C. Heise, J. A. Sampson, A. Williams, F. McCormick, H. D. Von, and D. H. Kim, ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents [see comments], Nat. Med. 3 639 (1997). 

R. Rodriguez, E. R. Schuur, H. Y. Lim, G. A. Henderson, J. W. Simons, and D. R. Henderson, Prostate attenuated replication competent adenovirus (ARCA) CN706 a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells, Cancer Res. 57 2559 (1997). 

Bristol, J. A., Gallo-Penn, A., Andrews, J., Idamakanti, N., Kaleko, M. and Connelly, S. (2001). Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VHI-specific immunity in hemophilia A mice compared with factor VIII protein infusion. Hum. Gene Ther. 12, 1651-1661. 

The oncolytic viruses include adenovirus, measles, reovirus, vesicular stomatitis virus (VSV),HSV,poxvirus, and vaccinia. Specific examples include (1) ONYX-015, which is an adenoviral oncolytic virus, administered to patients with liver metastases of colorectal cancer and pancreatic cancer [29], (2) Reolysin, which is an oncolytic reovirus administered to patients with glioma [30], and (3) MV-CEA, which is an oncolytic measles virus expressing carcinoembryonic antigen, administered to patients with ovarian cancer [31]. Some oncolytic viruses are wild type and are apparently not pathogenic in humans, such as the Newcastle disease virus (NDV), which is an RNA avian paramyxovirus. PV701, a naturally attenuated, replication-competent strain of NDV, has been administered to patients with advanced solid tumors [32], The applicability of oncolytic viruses as a therapy for clinical oncology trials is due to their potential selectivity the ability to kill tumor cells but not normal cells. However, the level of attenuation of viral replication in normal cells is limited for most oncolytic vectors. 

Mostly attenuated organisms are being used as live virus vaccines however, in some instances, even virulent organisms could be used, provided they are not administered via the natural route of infection. For example, human adenovirus types 4 and 7 may cause acute respiratory infections in humans when administered via the oronasal route but provide protection when given orally in enteric-coated capsules. ... 

The DNA tumor virus adenovirus produces a 55-kDa protein from the ElB region of its genome, which binds and inactivates p53. It was hypothesized that an adenovirus lacking ElB would not be able to replicate in normal cells but would in cancer cells lacking p53 function. For this reason, ONYX-015, an ElB gene-attenuated adenovirus was compared with normal adenovirus in human and colonic cancer cell lines with and without p53 function. As expected, the ONYX-015 virus replicated as efficiently as the normal virus in the cell line lacking wild-type p53, but not in the line with normal p53 function. This vector is in early clinical trials. 

Hogaboam CM, Simpson KJ, Chensue SW, Steinhauser ML, Lukacs NW, Gauldie J, Strieter RM, Kunkel SL (1999) Macrophage inflammatory protein-2 gene therapy attenuates adenovirus-and acetaminophen-mediated hepatic injury. Gene Ther 6 573-584... 

Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an El B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther 2004 10 958-966. 

D Ovidio et al. delivered naked plasmid TGF- pi via endobronchial transfection. They demonstrated selective airway transfection, improved lung graft oxygenation, and reduced rejection scores (102). Suda et al. demonstrated that in vivo intramuscular gene transfer of adenovirus-mediated TGF-pi attenuated acute allograft rejection (96). 

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