Recombinant interleukin‐12 and interleukin‐18 antitumor therapy in a guinea‐pig hepatoma cell implant model

• Published in: Cancer science 2007-12, Vol.98 (12), p.1936-1942
• Main Authors: Shiratori, Ikuo, Suzuki, Yasuhiko, Oshiumi, Hiroyuki, Begum, Nasim A., Ebihara, Takashi, Matsumoto, Misako, Hazeki, Kaoru, Kodama, Ken, Kashiwazaki, Yasuo, Seya, Tsukasa
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Disease Models, Animal; Gastroenterology. Liver. Pancreas. Abdomen; Guinea Pigs; Humans; Immunotherapy - methods; Interleukin-12 - genetics; Interleukin-12 - therapeutic use; Interleukin-18 - genetics; Interleukin-18 - therapeutic use; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Recombinant Proteins - therapeutic use; Toll-Like Receptors - immunology; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2007.00614.x

Interleukin (IL)‐12 and IL‐18 are secreted by myeloid cells activated with adjuvants such as Bacillus Calmette‐Guérin (BCG) cell wall. They induce T‐helper 1 polarization in the host immune system and upregulate production of lymphocyte interferon‐γ, which leads to the induction of an antitumor gene program. It has been reported that humans have an immune system that more closely resembles that of the guinea pig in adjuvant‐response features rather than the mouse system, which prevents the mouse results being extrapolated to human immunotherapy. Here we have constructed a tumor‐implant system in guinea pigs to evaluate the antitumor potential of guinea pig IL‐12 (gpIL‐12) and guinea pig IL‐18 (gpIL‐18). Purified recombinant gpIL‐12 and gpIL‐18 were prepared and applied intraperitoneally to tumor‐bearing (line 10 hepatoma) guinea pigs as the basis of the adjuvant immunotherapy. Intraperitoneal administration of gpIL‐12 and gpIL‐18 led to retardation of primary tumor growth and suppression of lymph‐node metastasis in tumor‐bearing guinea pigs. The permissible range of IL‐12 appeared wider in guinea pigs than in mice. Even at an IL‐12 dose higher than that in mice, there was no evidence of side‐effects until day 26, when the guinea pigs were killed. gpIL‐18 augmented the antitumor effect of gpIL‐12 but exerted less ability to suppress lymph‐node metastasis. The effects of gpIL‐12 and gpIL‐18 on the tumors implanted in guinea pigs will encourage us to use IL‐12‐ and IL‐18‐inducible adjuvants for immunotherapy in human patients with solid cancer. (Cancer Sci 2007; 98: 1936–1942)