Wybranowski Tomasz, Ziomkowska Blanka, Cyrankiewicz Michał, Kruszewski Stefan
Acta Pol Pharm. 2016 Jan-Feb;73(1):29-34.
The study can be useful for understanding the interaction of camptothecin with human serum albu- min. There are two forms of camptothecin (the carboxylate form (CPT-C) and the lactone form (CPT-L)) but only the lactone one is pharmacologically active. It was reported earlier that in the presence of HSA, the active lactone form of camptothecin changes to inactive carboxylate form and it reduces the antitumor activities of camptothecin. However, those studies were performed at physiological pH (7.4) and with non-oxidized and non-glycosylated albumin. The aim of this study was to investigate the effect of oxidative stress, glycosylation, pH changes and competitor drugs on inactivation of lactone form of camptothecin in albumin solution using measurements of fluorescence anisotropy spectroscopy. It was tried to prove that in vivo camptothecin may be present in higher amount in lactone form than previously thought. Due to a reduction of pH value, a decreased rate of hydrolysis from CPT-L to CPT-C was observed. It was found in vitro a significant reduction in bound fraction of CPT-C to HSA oxidized by chloramine T or glycosylated by glucose. Moreover, as a result of block- ing binding of CPT-C to HSA by competitive compound (flurbiprofen), a decrease in the fluorescence anisotropy of the HSA-CPT complex was found. This study opens the way to review an application of CPT and its derivatives in therapy.
该研究对于理解喜树碱与人血清白蛋白的相互作用可能具有重要意义。喜树碱有两种形式（羧酸盐形式（CPT-C）和内酯形式（CPT-L）），但只有内酯形式具有药理活性。此前有报道称，在人血清白蛋白存在的情况下，喜树碱的活性内酯形式会转变为无活性的羧酸盐形式，这会降低喜树碱的抗肿瘤活性。然而，这些研究是在生理pH值（7.4）以及非氧化和非糖基化的白蛋白条件下进行的。本研究的目的是通过测量荧光各向异性光谱，研究氧化应激、糖基化、pH值变化和竞争药物对白蛋白溶液中喜树碱内酯形式失活的影响。试图证明在体内喜树碱内酯形式的含量可能比之前认为的要高。由于pH值降低，观察到从CPT-L水解为CPT-C的速率下降。在体外发现，经氯胺T氧化或葡萄糖糖基化的人血清白蛋白与CPT-C的结合分数显著降低。此外，由于竞争性化合物（氟比洛芬）阻断了CPT-C与人血清白蛋白的结合，发现人血清白蛋白-CPT复合物的荧光各向异性降低。本研究为重新审视喜树碱及其衍生物在治疗中的应用开辟了道路。
