Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA)-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors

Abstract

Photodynamic diagnosis (PDD) is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX) exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA) or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new approach of quantitative structure-activity relationship (QSAR) analysis to design potent ABCG2-inhibitors.

In vivo fluorescence navigation of gastric and upper gastrointestinal tumors by 5-aminolevulinic acid mediated photodynamic diagnosis with a laser-equipped video image endoscope

“…The present PDD has been developed on the similar basis of the LASEREO video endoscopic system with a semiconductor laser light source (Fuji Film Medical Co.) [16]. About 410 nm laser (the blue light mode) can offer excitation of ALA-induced PpIX as a photosensitizer to emit red fluorescence of around 635 nm [1][2][3].…”

“…Although underlying mechanism by which ALA-induced PpIX accumulates differentially remains uncertain, it could reflect the diversity in histological types of cancers [17][18][19]. In the heme biosynthesis pathway [1,2], catalytic deficiency of ferrochelatase or higher activity of porphobilinogen deaminase might result in greater production and retention of PpIX [5]. It is suggested that altered expression of peptide transporter PEPT1 and ATP-binding cassette transporter ABCG2 could affect intracellular PpIX levels in gastric cancer cells in vitro [17].…”

“…Photodynamic diagnosis (PDD) is an optical imaging technology and involves administration of photoactive drugs that selectively accumulate in malignant tumors and cause the drug-induced fluorescence [1,2]. Five-aminolevulinic acid (ALA) is a precursor of photosensitizing protoporphyrin IX (PpIX) in the heme biosynthesis pathway.…”

“…Five-aminolevulinic acid (ALA) is a precursor of photosensitizing protoporphyrin IX (PpIX) in the heme biosynthesis pathway. Exogenously administrated ALA increases cellular PpIX levels, and the overproduced PpIX causes evident emission of a red fluorescence at around 635 nm in certain tumors than the non-tumor surrounding tissues with a blue-violet light excitation [1][2][3]. Thus, ALA-mediated PDD relies on the tumor-specific accumulation of PpIX, and has become efficient in the detection of bladder and brain tumors [2,4].…”

Fluorescence guided PDT for optimization of the outcome of skin cancer treatment

“…On the other hand, PpIX photobleaching is dependent on the illuminations parameters [27]. The enzymatic levels involved in the metabolism of porphyrin expression are altered during PDT [28].…”