Whitaker C J, Battah S H, Forsyth M J, Edwards C, Boyle R W, Matthews E K
Department of Pharmacology, University of Cambridge, UK.
Anticancer Drug Des. 2000 Jun;15(3):161-70.
A series of straight chain, branched and cyclo-delta-aminolaevulinic acid (ALA) esters have been synthesized and their photosensitizing properties analysed using an in vitro system of rat pancreatoma cells. Structurally favourable ALA esters not only induced the formation of more of the endogenous photosensitizer, protoporphyrin IX (PpIX), but they did so at a faster rate than ALA itself. This action was reflected in a substantial increase in photocytotoxicity of some 270 times, using the more potent ALA esters. An important structural feature was identified in two of the ALA esters which greatly limited PpIX production, i.e. a branch point located next to the site of ester cleavage. Experiments on the transport of ALA and of ALA esters across the cell membrane showed that ALA, but not ALA esters, gain access to the cell via the di- and tripeptide transporter, PEPTI. Finally, these results show that the esterification of ALA can greatly increase its cellular uptake, so generating more intracellular PpIX, improved tumour cell photosensitization and enhanced photocytotoxicity.
已经合成了一系列直链、支链和环δ-氨基乙酰丙酸（ALA）酯，并使用大鼠胰腺癌细胞的体外系统分析了它们的光敏特性。结构上有利的ALA酯不仅能诱导形成更多的内源性光敏剂原卟啉IX（PpIX），而且其诱导速率比ALA本身更快。使用更有效的ALA酯时，这种作用表现为光细胞毒性大幅增加约270倍。在两种ALA酯中发现了一个重要的结构特征，该特征极大地限制了PpIX的产生，即酯裂解位点旁边的一个分支点。关于ALA和ALA酯跨细胞膜转运的实验表明，ALA通过二肽和三肽转运体PEPTI进入细胞，而ALA酯则不能。最后，这些结果表明，ALA的酯化可以大大增加其细胞摄取，从而产生更多的细胞内PpIX，改善肿瘤细胞的光敏化并增强光细胞毒性。
