Bernard, you're always giving me homework..this one was fun..Dr. Juan Fueyo-Margareto and his wife, Dr. Calendaria Gomez-Manzano and Dr. Alemany[now in Birmingham, Alabama University] may have gone to college together..and I don't think they use the zeta-g-
They along with below authors are known as the 'delta team'..these folk are also the heaviest-hitter neuro-onc's at M.D.Anderson..
I see that delta-24 now has a name-g-.."ICOVIR-5"
Abstract Number: 4017
Presentation Title: New alliance against gliomas: Treatment with oncolytic adenovirus ICOVIR-5 in combination with TMZ or RAD001 significantly improves survival in glioma xenografts
Presentation Start/End Time: Tuesday, Apr 04, 2006, 10:25 AM -10:40 AM
Location: Room 152, Washington Convention Center
Author Block: Marta M. Alonso, Ramon Alemany, Candelaria Gomez-Manzao, Manel Cascallo, Frederick F. Lang, Jing Xu, Verlene Henry, Alfred W.K. Yung, Alfred W.K. Yung, Juan Fueyo. MD Anderson Cancer Center, Houston, TX, Instituto Catala d'Oncologia, Barcelona, Spain
Oncolytic adenoviruses are alternative promising therapies for the treatment of gliomas. Nevertheless, the effective treatment of gliomas with oncolytic adenovirus has been hampered by the relative low persistence of the vectors, difficulty in systemic delivery and side toxicity due to undesired targeting of normal cells and to the immune system response. One strategy to improve the efficacy of oncolytic adenoviruses is to combine them with chemotherapeutic drugs. We have generated an adenovirus, termed ICOVIR, that encompasses three elements: enhanced tropism trough integrin infection (RGD-4C modification of the fiber HI loop), tumor selectivity (Delta-24 mutation in the Rb-binding CR2 region of E1A), and decrease of E1A-mediated toxicity (insertion of two E2F1 promoter sequences preceded by an insulator upstream of the E1A coding sequence in substitution of the native E1A promoter) to provide the construct with both cell-specific gene expression and strong viral replication capability in cancer cells. In this regard, ICOVIR-5 probed to be a highly selective vector in gliomas at the same time that retained a robust cell killing potential and a negligible toxicity in vitro and which is more important in vivo. To test the hypothesis that ICOVIR-5 infection favors the effect of temozolomide (TMZ) and RAD001, we first examine in vitro the effect of ICOVIR-5 alone or in combination with TMZ or RAD001 in U87-MG and U251-MG glioma cell lines by MTT. Our data showed that both drugs were more efficient in combination with ICOVIR-5 that when administer alone. In addition, ICOVIR-5 replication properties were not affected by the addition either drug. Of interest, individually systemic administration of ICOVIR-5 resulted in improved survival and generation of long-term survivors (animal living more than 100 days after treatment). Importantly, the combination of the drugs with ICOVIR-5 resulted in a significant increased in the median survival (P<0.001) and in 40% of long time survivors. Examination of the brains by IHC showed E1A and hexon staining meaning the ability of the virus to infect and efficiently replicate in combination with the drugs. Of importance, all the regimens showed very low hepatotoxicity as probed by the low expression levels of E1A in liver and serum levels of AST and ALT similar to the physiological values. We believe that the combination of ICOVIR and chemotherapy allows for multi-compartmental treatment. The antiangiogenic, cytostatic and immunosuppressant effect of the drugs facilitates the local spread of the virus within the tumour and into the surrounding brain areas that may contain invading cells from the glioma at the same time that generate a wider window of time for the virus to elicit an oncolytic effect. In summary, ICOVIR-5 in combination with TMZ and RAD001 constitutes a promising strategy for the treatment of gliomas.
Genetically modified adenoviruses against gliomas
From bench to bedside
Candelaria Gomez-Manzano, MD, W.K. Alfred Yung, MD, Ramon Alemany, PhD and Juan Fueyo, MD
From the Department of Neuro-Oncology (Drs. Gomez-Manzano, Yung, and Fueyo), The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Institut Catala d’Oncologia (Dr. Alemany), Barcelona, Spain.
Address correspondence and reprint requests to Dr. Juan Fueyo, Department of Neuro-Oncology, Box 316, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX; e-mail: jfueyo@mdanderson.org
Oncolytic or tumor-selective adenoviruses are constructed as novel antiglioma therapies. After infection, the invading genetic adenoviral material is activated within the host cell. E1A and E1B adenoviral proteins are expressed immediately. E1A protein interacts with cell cycle regulatory proteins, such as retinoblastoma (Rb), driving the cell into the S phase and ensuing viral replication. The action of E1A stimulates the cellular p53 tumor suppressor system, which results in growth arrest or apoptosis, and halts adenovirus replication. However, adenoviral E1B interacts with p53 protein, preventing the DNA replication process from being abrogated by the induction of p53-mediated apoptosis. It was subsequently hypothesized that mutant adenoviruses that were unable to express wild-type E1A or E1B proteins could not replicate in normal cells with functional Rb or p53 pathways but instead would replicate and kill glioma cells that had defects in the regulation of these tumor suppressor pathways. Mutant E1B adenoviruses have already entered the clinical setting as an experimental treatment for patients with malignant gliomas. Mutant E1A adenoviruses are now in preclinical development as antiglioma therapy. In this review, the authors describe the mechanisms underlying the production of oncolytic adenoviruses, preclinical and clinical experiences with specific oncolytic adenoviruses, and the possibilities of combining mutant oncolytic adenoviruses with gene therapy or conventional therapies for managing malignant gliomas. |
