Tsutsumi Y, Tsunoda S, Kamada H, Kihira T, Nakagawa S, Kaneda Y, Kanamori T, Mayumi T
Faculty and Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
Br J Cancer. 1996 Oct;74(7):1090-5. doi: 10.1038/bjc.1996.495.
To design hybrid tumour necrosis factor-alpha (TNF-alpha) applicable to systemic anti-tumour therapeutic use, we assessed the relationships among the molecular size of hybrid TNF-alpha, in vitro bioactivity and in vivo anti-tumour potency. Natural human TNF-alpha was covalently modified with polyethylene glycol (PEG) of various number-average molecular weights (Mn = 2000, 5000, 12,000). The in vitro bioactivity of PEG-modified TNF-alpha s decreased with an increase in the degree of PEG modification, irrespective of the molecular weight of PEG. This decrease in the specific bioactivity markedly increased with an increase in the molecular weight of the attached PEG. The in vivo anti-tumour effects of the hybrid TNF-alpha s with a molecular size from 100 to 110 kDa, which had more than 50% of specific bioactivity of native TNF-alpha, were significantly superior to other PEG-TNF-alpha s. These hybrid TNF-alpha s showed over ten times greater anti-tumour effects than native TNF-alpha. Thus, the molecular size, which was determined by the degree of PEG modification and PEG molecular weight, influences the specific activity and anti-tumour effects of hybrid TNF-alpha.
为了设计适用于全身抗肿瘤治疗的杂合肿瘤坏死因子-α（TNF-α），我们评估了杂合TNF-α的分子大小、体外生物活性和体内抗肿瘤效力之间的关系。用各种数均分子量（Mn = 2000、5000、12,000）的聚乙二醇（PEG）对天然人TNF-α进行共价修饰。PEG修饰的TNF-α的体外生物活性随PEG修饰程度的增加而降低，与PEG的分子量无关。随着连接的PEG分子量增加，这种比活性的降低显著增加。分子大小为100至110 kDa且具有超过天然TNF-α 50%比活性的杂合TNF-α的体内抗肿瘤作用明显优于其他PEG-TNF-α。这些杂合TNF-α显示出比天然TNF-α大十倍以上的抗肿瘤作用。因此，由PEG修饰程度和PEG分子量决定的分子大小影响杂合TNF-α的比活性和抗肿瘤作用。
