PURPOSE: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma. EXPERIMENTAL DESIGN: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects. RESULTS: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD +/- GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time. CONCLUSIONS: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.
PURPOSE: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma. EXPERIMENTAL DESIGN: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects. RESULTS: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD +/- GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time. CONCLUSIONS: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.
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Authors: Kenneth H Kim; Igor Dmitriev; Janis P O'Malley; Minghui Wang; Souheil Saddekni; Zhiying You; Meredith A Preuss; Raymond D Harris; Rosemarie Aurigemma; Gene P Siegal; Kurt R Zinn; David T Curiel; Ronald D Alvarez Journal: Clin Cancer Res Date: 2012-04-17 Impact factor: 12.531
Authors: A K M G Muhammad; M Puntel; M Candolfi; A Salem; K Yagiz; C Farrokhi; K M Kroeger; W Xiong; J F Curtin; C Liu; K Lawrence; N S Bondale; J Lerner; G J Baker; D Foulad; R N Pechnick; D Palmer; P Ng; P R Lowenstein; M G Castro Journal: Clin Pharmacol Ther Date: 2010-02-17 Impact factor: 6.875
Authors: J Michael Mathis; Shilpa Bhatia; Alok Khandelwal; Imre Kovesdi; Stephen J Lokitz; Yoshi Odaka; Amol M Takalkar; Tracee Terry; David T Curiel Journal: PLoS One Date: 2011-02-09 Impact factor: 3.240
Authors: Lynda Coughlan; Raul Alba; Alan L Parker; Angela C Bradshaw; Iain A McNeish; Stuart A Nicklin; Andrew H Baker Journal: Viruses Date: 2010-10-13 Impact factor: 5.818