Potentiation of in vivo Antitumor Effects of Recombinant Interleukin‐1α by Gelatin Conjugation

Chemical conjugation of a recombinant human interleukin‐1α (IL‐1) with gelatin was conducted using a water‐soluble carbodiimide in an attempt to augment the indirect effect of IL‐1 on in vivo tumor cell growth in mice. Chromatographic studies of the IL‐1‐gelatin conjugate demonstrated that the apparent molecular weight of IL‐1 was increased by the gelatin conjugation and about 60% of IL‐1 activity was retained in the prepared conjugate. Intraperitoneal (i.p.) injection of the conjugate significantly suppressed the intraperitoneal growth of a subline of Meth A fibrosarcoma cells (RR1 cells), compared with the effect of free IL‐1 at the same dose, although the cells per se were resistant not only to free IL‐1 but also to gelatin‐conjugated IL‐1. Simple mixing of gelatin with free IL‐1 did not augment the in vivo antitumor effect as compared with that of free IL‐1. Gelatin conjugation improved the in vivo stability of IL‐1. Prolonged retention of IL‐1 activity in the peritoneal cavity as well as the circulation of mice was observed after i.p. injection of the IL‐1‐gelatin conjugate in comparison with free IL‐1 injection, irrespective of the presence of tumor cells. Gelatin conjugation was effective in augmenting the in vivo antitumor effects of IL‐1 to activate host cells, e.g. macrophages (Mø). The i.p. injection of the conjugate enhanced Mø infiltration into the peritoneal cavity of tumor‐bearing mice and peritoneal Mø were strongly activated to inhibit the in vitro growth of RR1 cells. Thus, gelatin conjugation was effective in augmenting the indirect effect of IL‐1 via host cells, leading to a high suppressive effect on in vivo growth of tumor cells.