Analysis of Factors Affecting 5-ALA Fluorescence Intensity in Visualizing Glial Tumor Cells-Literature Review

Abstract

Glial tumors are one of the most common lesions of the central nervous system. Despite the implementation of appropriate treatment, the prognosis is not successful. As shown in the literature, maximal tumor resection is a key element in improving therapeutic outcome. One of the methods to achieve it is the use of fluorescent intraoperative navigation with 5-aminolevulinic acid. Unfortunately, often the level of fluorescence emitted is not satisfactory, resulting in difficulties in the course of surgery. This article summarizes currently available knowledge regarding differences in the level of emitted fluorescence. It may depend on both the histological type and the genetic profile of the tumor, which is reflected in the activity and expression of enzymes involved in the intracellular metabolism of fluorescent dyes, such as PBGD, FECH, UROS, and ALAS. The transport of 5-aminolevulinic acid and its metabolites across the blood-brain barrier and cell membranes mediated by transporters, such as ABCB6 and ABCG2, is also important. Accompanying therapies, such as antiepileptic drugs or steroids, also have an impact on light emission by tumor cells. Accurate determination of the factors influencing the fluorescence of 5-aminolevulinic acid-treated cells may contribute to the improvement of fluorescence navigation in patients with highly malignant gliomas.

Keywords: 5-aminolevulinic acid; glioblastoma; high-grade glioma; intraoperative navigation.

Figure 1

Intracellular metabolism of 5-ALA. The synthesis steps of heme metabolism are labelled by blue arrows (↑). Red indicators (T) point to enzymes and substances that inhibit particular steps of metabolism, whereas green indicators (Ψ) highlight factors that promote them. PEPT 1/2—peptide transporter 1/2, ALAS—ALA synthase, ALAD—ALA dehydratase, PBGD—porphobilinogen deaminase, UROS—uroporphyrinogen III synthase, UROD—uroporphyrinogen III decarboxylase, ABCB6—ATP-binding cassette transporter B6, CPOX—coproporphyrinogen III oxidase, FECH—ferrochelatase, ABCG 2—ATP-binding cassette subfamily G 2 Protein, DFO—deferoxamine mesylate, FBS—fetal bovine serum, SnPP—tin protoporphyrin IX, FTC—fumitremorgin C, 5-ALA (endo)—endogenous 5-ALA, 5-ALA (exo)—exogenous 5-ALA.

Figure 2

The stages of the tricarboxylic acid cycle and the effects of IDH mutations on protoporphyrin IX metabolism. The synthesis steps are indicated by solid arrows, and the regulatory steps by dashed arrows. The shortened conversions are marked by a double-dashed arrow. A red indicator (T) points to a transformation inhibited by another factor. The effects of IDH mutations are highlighted by a yellow glow. S-CoAS—Succinyl-CoA synthetase, SD—succinate dehydrogenase, FH—fumarase, MDH—malate dehydrogenase, CS—citrate synthase, IDH—isocitrate dehydrogenase, α-KGDH—α-ketoglutarate dehydrogenase, ALAS—ALA synthase, FECH—ferrochelatase, HO-1—heme oxygenase-1, 5-ALA—5-aminolevulinic acid, PpIX—protoporphyrin IX, NAD—nicotinamide adenine dinucleotide, NADP—nicotinamide adenine dinucleotide phosphate, GDP—guanosine diphosphate, GTP—guanosine-5′-triphosphate.