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Identifying the Safety Profile of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Anticipation of a Phase I Clinical Trial in Patients with Recurrent Ovarian Cancer

  1. Author:
    Matthews, K.
    Noker, P. E.
    Tian, B. H.
    Grimes, S. D.
    Fulton, R.
    Schweikart, K.
    Harris, R.
    Aurigemma, R.
    Wang, M. H.
    Barnes, M. N.
    Siegal, G. P.
    Hemminki, A.
    Zinn, K.
    Curiel, D. T.
    Alvarez, R. D.

  2. Author Address

    Matthews, Kellie, Barnes, Mack N.; Alvarez, Ronald D.] Univ Alabama, Div Gynecol Oncol, Birmingham, AL USA. [Zinn, Kurt] Univ Alabama, Dept Radiol, Birmingham, AL USA. [Wang, Minghui, Curiel, David T.] Univ Alabama, Div Human Gene Therapy, Birmingham, AL USA. [Siegal, Gene P.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Noker, Patricia E.; Tian, Baohong, Grimes, Sheila D.; Fulton, Ronna] So Res Inst, Birmingham, AL 35255 USA. [Schweikart, Karen] Toxicol & Pharmacol Branch, Bethesda, MD USA. [Aurigemma, Rose] NCI, Biol Resources Branch, Frederick, MD 21701 USA. [Harris, Raymond] Sci Applicat Int Corp, Biopharmaceut Dev Program, Frederick, MD USA. [Hemminki, Akseli] Univ Helsinki, Canc Gene Therapy Grp, Mol Canc Biol Program, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Transplantat Lab, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Haartman Inst, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, HUSLAB, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Cent Hosp, Helsinki, Finland.
    1. Year: 2009
  2. Journal: Clinical Cancer Research
    1. 15
    2. 12
    3. Pages: 4131-4137
  4. Type of Article: Article
  1. Abstract:

    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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  2. DOI: 10.1158/1078-0432.ccr-08-3354
  3. PMID: 19509153

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