Photosensitization of pancreatic tumour cells by delta-aminolaevulinic acid esters.
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.
Whitaker
C J
CJ
Department of Pharmacology, University of Cambridge, UK.
Battah
S H
SH
Forsyth
M J
MJ
Edwards
C
C
Boyle
R W
RW
Matthews
E K
EK
D000622:Aminolevulinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000378:metabolism; D004952:Esters / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000074011:Peptide Transporter 1; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011524:Protoporphyrins / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D027981:Symporters; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D004952:Esters; D000074011:Peptide Transporter 1; D017319:Photosensitizing Agents; D011524:Protoporphyrins; C489940:Slc15a1 protein, rat; D027981:Symporters; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX