Antitumor effects of a new interleukin-2 slow delivery system on methylcholanthrene-induced fibrosarcoma in mice

The interleukin-2 (IL-2) mini-pellet, the carrier material of which is a biocompatible and biodegradable atelocollagen refined from bovine skin, contains 1 x 10(6) units of IL-2 and can release IL-2 slowly in vivo by diffusion and dissolution. We have evaluated the antitumor effects of the IL-2 mini-pellet on an established solid murine tumor, methylcholanthrene-induced fibrosarcoma (Meth A). The subcutaneous administration of the IL-2 mini-pellet alone on days 8 and 11 after tumor inoculation significantly inhibited tumor growth. A significant inhibition was also seen when it was combined with the intravenous injection of 5 x 10(7) lymphokine-activated killer (LAK) cells, in comparison to the untreated controls. Moreover, therapy with the IL-2 mini-pellet alone or in combination with LAK cells also prolonged the survival of mice bearing Meth A fibrosarcoma. In order to determine the precise mechanism of action of these antitumor effects, we tested splenocytes of treated mice for cytotoxic activity in vitro and investigated tumor tissues by an immunohistochemical method. On day 2 after the administration of the IL-2 mini-pellet, the lytic activity of splenocytes against both YAC-1 and JTC-11 cells (i.e. NK and LAK activity) was significantly augmented, and on day 7 a massive accumulation of lymphocytes, which were mainly like Thy1+ and/or asialo-GM1+ LAK cells, was seen in the tumor. These findings indicate that the IL-2 mini-pellet is an appropriate system for local administration of IL-2 and can induce LAK-like effector cells at the target site.