Controlled systemic release of interleukin-12 after gene electrotransfer to muscle for cancer gene therapy alone or in combination with ionizing radiation in murine sarcomas.
BACKGROUND
The present study aimed to evaluate the antitumor effectiveness of systemic interleukin (IL)-12 gene therapy in murine sarcoma models, and to evaluate its interaction with the irradiation of tumors and metastases. To avoid toxic side-effects of IL-12 gene therapy, the objective was to achieve the controlled release of IL-12 after intramuscular gene electrotransfer.


METHODS
Gene electrotransfer of the plasmid pORF-mIL12 was performed into the tibialis cranialis in A/J and C57BL/6 mice. Systemic release of the IL-12 was monitored in the serum of mice after carrying out two sets of intramuscular IL-12 gene electrotransfer of two different doses of plasmid DNA. The antitumor effectiveness of IL-12 gene electrotransfer alone or in combination with local tumor or lung irradiation with X-rays, was evaluated on subcutaneous SA-1 and LPB tumors, as well as on lung metastases.


RESULTS
A synergistic antitumor effect of intramuscular gene electrotransfer combined with local tumor irradiation was observed as a result of the systemic distribution of IL-12. The gene electrotransfer resulted in up to 28% of complete responses of tumors. In combination with local tumor irradiation, the curability was increased by up to 100%. The same effect was observed for lung metastases, where a potentiating factor of 1.3-fold was determined. The amount of circulating IL-12 was controlled by the number of repeats of gene electrotransfer and by the amount of the injected plasmid.


CONCLUSIONS
The present study demonstrates the feasibility of treatment by IL-12 gene electrotransfer combined with local tumor or lung metastases irradiation on sarcoma tumors for translation into the clinical setting.
Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia.
Gregor
G
Tevz
Simona
S
Kranjc
Maja
M
Cemazar
Urska
U
Kamensek
Andrej
A
Coer
Mojca
M
Krzan
Suzana
S
Vidic
Darja
D
Pavlin
Gregor
G
Sersa
D000818:Animals; D003131:Combined Modality Therapy; D018274:Electroporation; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007273:Injections, Intramuscular; D018664:Interleukin-12 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D011839:Radiation, Ionizing; D012513:Sarcoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014162:Transfection
D018664:Interleukin-12