title: Pre-clinical toxicity assessment of tumor-targeted interleukin-12 low-intensity electrogenetherapy.
abstract: This study's goal was to assess the safety of tumor-targeted interleukin-12 (ttIL-12) when administered by electrogenetherapy in C3H/HeJ mice by identifying an initial safe dose for human dose escalation schemes, toxicity target organs, markers of toxicity, and toxicity reversibility. Tumor-free mice receiving two doses of 0.45% NaCl, 1 μg ttIL-12 DNA in 0.45% NaCl or 5 μg ttIL-12 DNA in 0.45% NaCl, 10 days apart combined with low-intensity electroporation were compared with non-treatment controls over time. All mice had blood cell counts, serum chemistry profiles, plasma interleukin-12 and IFNγ determinations, necropsy and multi-organ histopathology. Mild treatment-associated changes included electroporation-associated muscle changes that resolved by 30 days; decreased total white blood cell counts and infectious disease in the 5 μg ttIL-12 group, but not in the 1 μg group, and liver changes in ttIL-12 groups that correlated with alanine transaminase levels and resolved by 30 days. Dystrophic cardiac calcification seen in older, 5 μg ttIL-12-treated mice was the only serious toxicity. Based on these results and the lack of any effect on wound healing when combined with surgery, low-intensity electrogenetherapy with ttIL-12 appears to be safe and well tolerated.
authors.affiliation: Department of Comparative Biomedical Sciences, LSU School of Veterinary Medicine, Baton Rouge, LA, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Reed
authors.forename: S
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D018274:Electroporation; D005260:Female; D050939:Gene Fusion; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D018664:Interleukin-12 / Q000235:genetics* / Q000633:toxicity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D009929:Organ Size; D010455:Peptides / Q000235:genetics; D018675:Toxicity Tests
chemical_list: D010455:Peptides; D018664:Interleukin-12