A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
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发表时间：
1986-12
期刊：
影响因子：
11.2
通讯作者：
Y. Matsumura;H. Maeda
中科院分区：
文献类型：
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作者：
Y. Matsumura;H. Maeda
我们以前发现，一种与抗癌蛋白新制癌素结合的聚合物，名为smancs，在肿瘤组织中比新制癌素积累更多。为了确定smancs和其他蛋白质的这种致瘤性积累的一般机制，我们使用了各种分子大小（Mr 12，000至160，000）和其他性质的放射性（51 Cr标记）蛋白质。此外，我们使用染料络合的血清白蛋白来可视化荷瘤小鼠肿瘤中的积累。许多蛋白质在这些小鼠的肿瘤组织中进行性积累，并且在19至72小时内获得肿瘤中的蛋白质浓度与血液中的蛋白质浓度之比为5。像免疫球蛋白G这样的大蛋白质需要更长的时间才能达到这个值5。肿瘤中的蛋白质浓度与血液中的蛋白质浓度之比既不为1也不为5，而新制癌素是一种代表性的小蛋白质（Mr 12，000）。我们推测，这些蛋白质的致瘤性积累是由于血管过度，甚至大分子的渗透性增强，以及通过血管或淋巴管的恢复很少。在静脉注射白蛋白-染料复合物（Mr 69，000）以及注射到正常组织和肿瘤组织后，也发现了肿瘤中大分子的这种积聚。该复合物仅在肿瘤组织中长时间保留。从肿瘤组织中淋巴回收的大分子很少。本研究结果对大分子肿瘤的治疗和诊断具有潜在的应用价值。
We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.