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通过与明胶结合增强重组白细胞介素-1α的体内抗肿瘤作用。

Potentiation of in vivo antitumor effects of recombinant interleukin-1 alpha by gelatin conjugation.

作者信息

Tabata Y, Uno K, Ikada Y, Kishida T, Muramatsu S

机构信息

Research Center for Biomedical Engineering, Kyoto University.

出版信息

Jpn J Cancer Res. 1993 Jun;84(6):681-8. doi: 10.1111/j.1349-7006.1993.tb02029.x.

Abstract

Chemical conjugation of a recombinant human interleukin-1 alpha (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 (M phi). The i.p. injection of the conjugate enhanced M phi infiltration into the peritoneal cavity of tumor-bearing mice and peritoneal M phi 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.

摘要

使用水溶性碳二亚胺将重组人白细胞介素-1α(IL-1)与明胶进行化学偶联,以增强IL-1对小鼠体内肿瘤细胞生长的间接作用。对IL-1-明胶偶联物的色谱研究表明,明胶偶联使IL-1的表观分子量增加,并且在制备的偶联物中保留了约60%的IL-1活性。与相同剂量的游离IL-1相比,腹腔注射该偶联物可显著抑制Meth A纤维肉瘤细胞亚系(RR1细胞)的腹腔内生长,尽管这些细胞本身不仅对游离IL-1耐药,而且对明胶偶联的IL-1也耐药。与游离IL-1相比,将明胶与游离IL-1简单混合并不会增强体内抗肿瘤效果。明胶偶联提高了IL-1的体内稳定性。与注射游离IL-1相比,腹腔注射IL-1-明胶偶联物后,无论是否存在肿瘤细胞,均可观察到IL-1活性在小鼠腹腔以及循环中的持续保留时间延长。明胶偶联在增强IL-1激活宿主细胞(如巨噬细胞(M phi))的体内抗肿瘤作用方面是有效的。腹腔注射该偶联物可增强M phi向荷瘤小鼠腹腔的浸润,并且腹腔M phi被强烈激活以抑制RR1细胞的体外生长。因此,明胶偶联在增强IL-1通过宿主细胞产生的间接作用方面是有效的,从而对体内肿瘤细胞生长产生高度抑制作用。

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