Publications [#168967] of Mark W. Dewhirst

Papers Published

1. F Siddiqui, CY Li, SM Larue, JM Poulson, PR Avery, AF Pruitt, X Zhang, RL Ullrich, DE Thrall, MW Dewhirst, ML Hauck, A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas., Molecular cancer therapeutics, United States, vol. 6 no. 1 (January, 2007), pp. 380-9, ISSN 1535-7163
   (last updated on 2009/12/31)

   Abstract:
   Interleukin-12 (IL-12), a proinflammatory cytokine, shows anticancer properties. Systemically administered IL-12 causes dose-dependent toxicity. To achieve localized intratumoral gene expression, an adenoviral gene therapy vector with IL-12 controlled by a heat-inducible promoter (heat shock promoter 70B) was developed and tested in a phase I clinical trial in cats with spontaneously arising soft tissue sarcoma. A feasibility study was done in 16 cats with soft tissue sarcoma using murine IL-12 and/or enhanced green fluorescent protein adenoviral vectors under cytomegalovirus or heat shock promoter 70 control. Subsequently, we conducted a phase I clinical trial using an adenoviral feline IL-12 construct in 13 cats with soft tissue sarcoma. The soft tissue sarcomas were irradiated (48 Gy/16 fractions) followed by intratumoral injection of adenovirus. Twenty-four hours postinjection, tumors were heated (41 degrees C, 60 min). Tumor expression of feline IL-12 and IFN-gamma was determined. Cats were monitored for systemic toxicity. For the murine IL-12 construct, an association was noted between viral dose and murine IL-12 levels within tumor, whereas serum levels were minimal. Mild toxicity was noted at 10(11) plaque-forming units (pfu). With the feline IL-12 construct, high levels of feline IL-12 mRNA were detected in tumor biopsies with low or absent IFN-gamma mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-gamma mRNA in tumor. It is possible to localize gene expression and limit systemic toxicity of IL-12 using the hyperthermia-induced gene therapy approach. The maximum tolerated dose of the feline IL-12 adenoviral vector was 10(10) pfu/tumor as dose-limiting toxicities were noted at the 4 x 10(10) pfu dose.

   Keywords:
   Adenoviridae • Animals • Cats • Cytomegalovirus • Feasibility Studies • Gene Therapy* • Green Fluorescent Proteins • Hyperthermia, Induced* • Interleukin-12 • Liver • Mice • Promoter Regions, Genetic • Recombinant Proteins • Sarcoma • adverse effects • biosynthesis • blood • drug therapy • genetics • genetics* • metabolism • pathology • radiotherapy • therapeutic use • therapeutic use* • veterinary*