5-aminolevulinic-acid-hexyl-ester and Lung-Neoplasms

Photodynamic therapy (PDT) with porphyrin precursors is an established therapy for certain tumors. This study aimed to explore the use of hexaminolevulinate (HAL), a porphyrin precursor, for photodynamic purging of BM grafts contaminated with cells of the 4T1 breast carcinoma cell line. The optimal PDT dose was not effective in eradicating 4T1 cells when the tumor cells were mixed with murine marrow cells in vitro. However, the number of pulmonary metastases was reduced, and the survival of experimental animals was prolonged substantially when they were subjected to TBI followed by transplantation of syngeneic BM containing metastasized 4T1 cells that had been treated ex vivo by HAL-PDT. Despite the failure of in vitro experiments, HAL-based photodynamic purging could be a useful modality for treating animals bearing an experimental breast carcinoma.

Topics: Aminolevulinic Acid; Animals; Bone Marrow; Bone Marrow Purging; Cell Line, Tumor; Female; Hematopoietic Stem Cell Transplantation; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Photochemotherapy; Photosensitizing Agents; Protoporphyrins; Tumor Cells, Cultured

The purpose of this study was to investigate the photoefficacies of protoporphyrin IX (PpIX) generated by drug precursor 5-aminolevulinic acid (ALA) and its hexyl ester (H-ALA) on two human non-small lung carcinoma cell lines (H460/Bcl-2 and H460/neo).. Drug uptake and the photoefficacies of PpIX were measured by flow cytometry and MTT assay; while the mode of cell death and alternation of signal transduction pathways were studied with 4',6-diamidino-2-phenylindole (DAPI) staining and Western blot analysis, respectively.. The flow cytometric analysis of H-ALA (5μM) uptake revealed optimal fluorescent intensity at 8h incubation, while ALA (0.5mM) was still far from saturation. The LD(30) of H-ALA-PDT was 30μM, 2J/cm(2), while the LD(30) of ALA-PDT was 3mM, 2J/cm(2). The dark toxicities mediated by both pro-drug H-ALA and ALA were negligible. By DAPI staining, apoptotic cell death was observed. In addition, by Western blot analysis, H-ALA- and ALA-mediated PDT initiated apoptotic cell death via the up-regulation and activation of p38 mitogen activated protein kinase (MAPK), the stress-activated c-jun N-terminal kinases (JNK) and ERK.. These results suggested that H-ALA and ALA mediated PDT displayed similar photocytotoxicities towards the two non-small lung cancer cells. Our present study also demonstrates H-ALA or ALA mediated PDT in H460 cells are closely related to the activation of p38 MAPK and JNK signalling pathway.

Topics: Aminolevulinic Acid; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Line, Tumor; Coloring Agents; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Flow Cytometry; Fluorescent Dyes; Humans; Indoles; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Photochemotherapy; Photosensitizing Agents; Prodrugs; Protoporphyrins; Signal Transduction; Tetrazolium Salts; Thiazoles; Up-Regulation