Evaluation of toxicity following electrically mediated interleukin-12 gene delivery in a B16 mouse melanoma model.
OBJECTIVE
Interleukin-12 (IL-12) has potential as an immunotherapeutic agent for the treatment of cancer but is unfortunately associated with toxicity. Delivery of a plasmid encoding IL-12 with electroporation induces an antitumor effect in the B16 mouse melanoma model without serious side effects. To translate this observation to the clinic, an evaluation of toxicity was done in the mouse model.


METHODS
Weight change, tumor response, blood chemistry and hematology values, and serum IL-12 levels were evaluated. Multiple tissues were analyzed histopathologically.


RESULTS
A pronounced reduction in tumor volume, including a large percentage of complete regressions, was observed after electrically mediated gene therapy. No significant increases in serum IL-12 levels were detected. Tumor-bearing mice showed an increased number of atypical hematology values when compared with normal naive controls. Statistically significant differences in chemistry and hematology values were observed sporadically in most of the standard chemistry and hematology categories in all groups. The only histopathologic abnormality specific to the animals receiving both plasmid and electroporation was inflammation associated with the kidney at the last time point.


CONCLUSIONS
In general, mice that received both plasmid and electroporation showed the least abnormal histopathologic findings and were found to be in the best health, reflecting the reduced burden of disease. No significant toxic effects due to the IL-12 gene therapy were observed.
Heller
Loree
L
Department of Medical Microbiology and Immunology, University of South Florida, Tampa 33612, USA.
Merkler
Kathleen
K
Westover
Jeffrey
J
Cruz
Yolmari
Y
Coppola
Domenico
D
Benson
Kaaron
K
Daud
Adil
A
Heller
Richard
R
D000818:Animals; D004195:Disease Models, Animal; D018274:Electroporation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D007668:Kidney / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D010957:Plasmids; D012878:Skin Neoplasms / Q000628:therapy*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D018664:Interleukin-12