MARKED INTERSPECIES VARIATIONS CONCERNING THE INTERACTIONS OF CAMPTOTHECIN WITH SERUM ALBUMINS - A FREQUENCY-DOMAIN FLUORESCENCE SPECTROSCOPIC STUDY
MARKED INTERSPECIES VARIATIONS CONCERNING THE INTERACTIONS OF CAMPTOTHECIN WITH SERUM ALBUMINS - A FREQUENCY-DOMAIN FLUORESCENCE SPECTROSCOPIC STUDY
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DOI：
10.1021/bi00208a002
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发表时间：
1994-10-25
期刊：
影响因子：
2.9
通讯作者：
BURKE, TG
中科院分区：
文献类型：
--
作者：
MI, ZH;BURKE, TG
喜树碱是一种以其新颖的作用机制和突出的小鼠体内活性而闻名的抗癌剂，迄今为止对人类癌症仅显示出适度的治疗效用。该药物含有一个δ-内酯环部分，在pH 7.4时水解产生一种无生物活性的羧酸盐形式。血浆和纯化血清白蛋白样品中药物稳定性的比较显示，与其他物种的样品相比，人类样品中的开环发生程度要大得多。两种药物形式的固有荧光发射的多频相位调制光谱分析揭示了在人血清白蛋白（HSA）存在下观察到的广泛开环的物理解释：该蛋白质对羧酸盐表现出明显的200倍结合偏好（K = 1.2 × 10（6）M（-1）），相对于内酯（K约为5.5 × 10（3）M（-1）），发现其他物种的血清白蛋白与喜树碱羧酸盐的结合不如HSA紧密。由于人血白蛋白结合喜树碱羧酸盐的独特能力，导致药物广泛转化为其生物学无活性形式，因此似乎该药物在动物模型中根除癌症的成功可能本质上更难以在人体中复制。
Camptothecin, an anticancer agent renown for its novel mechanism of action and outstanding murine in vivo activity, has to date displayed only modest therapeutic utility against human cancers. The drug contains an delta-lactone ring moiety which, at pH 7.4, hydrolyzes to yield a biologically inactive carboxylate form. Comparison of drug stability in both plasma and purified serum albumin samples revealed that ring opening occurred to a much greater extent in human samples versus those of other species. Multifrequency phase-modulation spectroscopic analyses of the intrinsic fluorescence emissions of the two drug forms revealed a physical explanation for the extensive ring opening observed in the presence of human serum albumin (HSA): the protein exhibited a marked 200-fold binding preference for the carboxylate (K = 1.2 x 10(6) M(-1)) relative to the lactone (K approximate to 5.5 x 10(3) M(-1)), Serum albumins from other species were found to bind camptothecin carboxylate not nearly as tightly as HSA. Due to the unique capacity of human albumin to bind camptothecin carboxylate, resulting in extensive conversion of the drug to its biologically inactive form, it appears that the success of the agent in eradicating cancer in animal models may be inherently more difficult to duplicate in man.