5-Aminolevulinic acid (ALA) has been widely used as an intravital fluorescence marker in the fluorescence-guided resection of malignant gliomas. Although not a photosensitizer itself, 5-ALA is a prodrug that accumulates protoporphyrin IX (PpIX) in the mitochondria of glioma cells; PpIX acts as a photosensitizer. Fluorescence-guided resection for malignant gliomas has some pitfalls. Moreover, 5-ALA is not merely a fluorescence marker but has potential as a mitochondria-targeting drug for malignant glioma therapy. In this article, we review the literature related to 5-ALA, discuss the pitfalls of fluorescence-guided resection using 5-ALA for malignant gliomas, and describe the application of 5-ALA for malignant glioma therapy with personal opinions.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of intracranial tumor. However, PCNSL is radiosensitive; thus, whole‑brain radiotherapy (WBRT) is often selected as an alternative consolidation therapy. WBRT‑related delayed neurotoxicity can affect the quality of life of the elderly. 5‑aminolevulinic acid (ALA) is a natural precursor of heme and has been widely used as a live molecular fluorescence marker in brain tumor surgery. Experimental studies have demonstrated that combination therapy with 5‑ALA and ionizing irradiation (IR), denoted radiodynamic therapy (RDT), resulted in tumor suppression in cancer, including glioma, melanoma, colorectal cancer, prostate cancer, breast cancer and lung cancer; however, to the best of our knowledge, this method has not been investigated in lymphoma. The present study aimed to investigate the radiodynamic effect of 5‑ALA on lymphoma cells in vitro. The synthesis of 5‑ALA‑induced protoporphyrin IX (PpIX) was assessed under normal and hypoxic conditions in lymphoma cells (Raji, HKBML and TK). Subsequently, the radiodynamic effect of 5‑ALA was evaluated using a colony formation assay and reactive oxygen species (ROS) production after RDT was examined using flow cytometry. Finally, the mitochondrial density in the lymphoma cells was evaluated. Lymphoma cells exhibited a high accumulation of 5‑ALA‑induced PpIX in the flow cytometric analysis, and a decrease in the surviving fraction under IR in cells with 5‑ALA treatment compared with cells not treated with 5‑ALA in the colony formation assay under normal and hypoxic conditions. Although ROS production 12 h after IR was increased compared with that immediately after IR (0 h), pretreatment with 5‑ALA enhanced the delayed ROS production in each lymphoma cell line under normoxic conditions. Raji and TK cells exhibited an increase in ROS production 12 h after IR compared with that at 0 h in the 5‑ALA‑untreated cells under hypoxic conditions. Raji, HKBML and TK cells exhibited an increase in ROS production 12 h after IR compared with that at 0 h in the 5‑ALA‑treated cells, while TK cells exhibited enhancement of ROS production 12 h after IR in 5‑ALA‑treated cells compared with 5‑ALA‑untreated cells under hypoxic conditions. Other studies have demonstrated that impaired mitochondria damaged by IR produce ROS via the metabolic process, then damage the rest of the surrounding normal mitochondria, consequently propagating oxidative stress within tumor cells and leading to cell death. Thus, we hypothesized that the propagating oxidative stress after IR was associated with mitochondrial density in tumor cells. Namely, high accumulation of 5‑ALA‑indcued PpIX may promote ROS production in mitochondria of tumor cells after IR, and suppress the cell surviving fraction via the propagation of oxidative stress. In the colony formation assay, Raji cell colony formation was suppressed by RDT with 5‑ALA. Simultaneously, the mitochondrial density in the Raji cells was higher than that in other cell lines. Pretreatment with 5‑ALA enhanced delayed ROS production after IR in lymphoma cells under normoxic conditions. Under hypoxic conditions, only TK cells exhibited enhancement of ROS production 12 h after IR in the 5‑ALA‑treated group compared with the 5‑ALA‑untreated group. Although further studies evaluating the effect of hypoxic conditions in lymphoma cells are needed, the results suggested that RDT with 5‑ALA could suppress colony formation under normal and hypoxic conditions in lymphoma cells. Therefore, RDT with 5‑ALA is a potential treatment option for PCNSL.

Nilotinib, a second‑generation tyrosine kinase inhibitor, is considered as one of the most effective drugs for the treatment of chronic myeloid leukemia (CML); however, the use of nilotinib has been reported to be associated with vascular adverse events, such as peripheral arterial occlusive disease and ischemic heart disease. Moreover, there are few reports on cerebral vascular disease associated with nilotinib use. We herein describe the case of a 55‑year‑old male patient with CML, who presented with cerebral infarction and severe cerebrovascular stenosis that developed during nilotinib treatment. The patient was diagnosed with cerebral infarction and severe stenosis of the intracranial arteries associated with nilotinib use. Vessel wall magnetic resonance imaging (VW‑MRI) revealed diffuse concentric thickening of the vessel wall, unlike ordinary patterns of atherosclerosis. The patient underwent direct revascularization (superficial temporal artery to middle cerebral artery bypass) and was successfully treated without recurrence. Based on this rare case, VW‑MRI may be used to detect the morphological changes of the intracranial arteries that are associated with nilotinib use. Moreover, surgical revascularization may improve the prognosis of nilotinib‑associated cerebrovascular diseases, such as severe stenosis or occlusion of the main trunk of the cerebral arteries, that cause brain ischemia.