Abstract
Photodynamic therapy (PDT) may cause tumour cell destruction by direct toxicity or by inducing cellular hypoxia as a result of microcirculatory shutdown. Aminolaevulinic acid (ALA) causes cellular accumulation of protoporphyrin IX (PPIX) in cells exposed to it in excess. PPIX can be used as a photosensitizer for PDT. Microcirculatory shutdown may be induced by toxicity to the endothelial and vascular smooth muscle (VSM) cells or by release of vasoactive substances. We have studied whether PPIX is produced by endothelial, VSM and tumour cells on exposure to ALA and whether these cell lines are directly damaged by PDT in vitro. Tumour endothelial cells are angiogenic and we have, therefore, investigated the effect of cellular proliferation rates on PPIX generation. Tumour cells generate more PPIX intracellularly than the non-neoplastic cell lines studied and are correspondingly more sensitive to PDT-induced cytotoxicity. Endothelial cells are sensitive to PDT-induced cytotoxicity and accumulate between 1.5 and four times more PPIX when proliferating (as during tumour-induced angiogenesis) than when quiescent. We conclude that PPIX-mediated PDT may exert some of its effects on the microcirculation of treated tissues by direct toxicity to endothelial and VSM cells, and that this toxicity may be enhanced in the tumour microenvironment.
Highlights
The aims of this study are: (1) to investigate whether there is production and accumulation of protoporphyrin IX (PPIX) by vascular endothelial and smooth muscle cells on exposure to Aminolaevulinic acid (ALA) and whether this leads to a direct Photodynamic therapy (PDT)-induced toxicity; (2) to compare the rate of PPIX accumulation between different cell lines; and (3) to study the effect of changes in proliferation rates that may influence PPIX accumulation and PDT sensitivity in the tumour microenvironment
The doubling time of HT1197 was significantly shorter than that of AGS cells (P < 0.03), which in turn was significantly less than the microvascular endothelial cells (MVECs) (P < 0.01) and Human dermal fibroblasts (HDFs) (P < 0.003)
MVECs and human umbilical vein endothelial cells (HUVECs) strongly contact inhibited after reaching confluence and assumed a cobblestone morphology, with a reduced cellular proliferation rate
Summary
The aims of this study are: (1) to investigate whether there is production and accumulation of PPIX by vascular endothelial and smooth muscle cells on exposure to ALA and whether this leads to a direct PDT-induced toxicity; (2) to compare the rate of PPIX accumulation between different cell lines; and (3) to study the effect of changes in proliferation rates that may influence PPIX accumulation and PDT sensitivity in the tumour microenvironment
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