SBI Pharma Co.

Minato-ku, Japan

SBI Pharma Co.

Minato-ku, Japan

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Yamamoto J.,University of Occupational and Environmental Health Japan | Kakeda S.,University of Occupational and Environmental Health Japan | Yoneda T.,Kumamoto University | Ogura S.-I.,Tokyo Institute of Technology | And 4 more authors.
Oncology Letters | Year: 2017

Magnetic resonance imaging (MI) with a gadolinium-based contrast agent is the gold standard for high-grade gliomas (HGGs). The compound 5-aminolevulinic acid (5-ALA) undergoes a high rate of cellular uptake, particularly in cancer cells. In addition, fluorescence-guided resection with 5-ALA is widely used for imaging HGGs. 5-ALA is water soluble, while protoporphyrin IX (PpIX) is water insoluble. It was speculated whether converting from 5-ALA to PpIX may relatively increase intracellular water content, and consequently, might enhance the T2 signal intensity in HGG. The aim of the present study was to assess whether 5-ALA-induced PpIX enhances the T2 signal intensity in patients with HGGs. A total of 4 patients who were candidates for HGG surgical treatment were prospectively analyzed with preoperative MRI. Patients received oral doses of 5-ALA (20 mg/kg) 3 h prior to anesthesia. At 2.5 h post-5-ALA administration, T2-weighted images (T2WIs) were obtained from all patients. Subsequently, tumors were evaluated via fluorescence using a modified operating microscope. Fluorescent tumor tissues were obtained to analyze the accumulation of 5-ALA-induced PpIX within the tumors, which was confirmed quantitatively by high-performance liquid chromatography (HPLC) analysis. The MRI T2 signal intensity within the tumors was evaluated prior to and following 5-ALA administration. Three glioblastoma multiformes (GBMs) and 1 anaplastic oligodendroglioma. (AO) were included in the analysis. Intraoperatively, all GBMs exhibited strong fluorescence of 5-ALA-induced PpIX, whilst no fluorescence was observed in the AO sample. HPLC analysis indicated a higher accumulation of 5-ALA-induced PpIX in the GBM samples compared with the AO sample. In total, 48 regions of interest were identified within the tumors from T2-WIs. In the GBM group, the relative T2 signal intensity value within the tumors following 5-ALA administration was significantly increased compared with the T2 signal intensity value prior to 5-ALA administration (1.537±0.021 and 1.577±0.023, respectively; P=0.0055). No significant diffeences were observed in the AO group. These results suggest that the 5-ALA-induced PpIX enhanced the T2 signal intensity in HGG. Therefore, 5-ALA may be a potentially useful MRI contrast reagent for HGG. © 2017, Spandidos Publications. All rights reserved.


Tanaka T.,Cosmo Oil Co. | Nishikawa S.,Cosmo Oil Co. | Watanabe K.,Cosmo Oil Co. | Tanaka T.,SBI Pharma Co. | And 2 more authors.
Seibutsu-kogaku Kaishi | Year: 2015

A Rhodobacter sphaeroides mutant strain (CR-720) produced unknown amino acids in parallel with ALA production when cultured in medium containing 50 mM glucose, 60 mM glycine, 5 mM levulinic acid (LA), and 5 g/L yeast extract. The retention time from the amino acid analysis identified the unknown amino acid as 5-amino-4-hydroxyvaleric acid (AHVA). When CR-720 was cultured at 32° C, 41 mM ALA and 2.9 mM AHVA were obtained. In addition, HPLC analysis and optical resolution revealed the AHVA produced from strain CR-720 to be (S)-(+)-AHVA. When CR-720 was cultured in medium with an optimized temperature of 28° C, 44 mM ALA and 1.1 mM AHVA were produced and cell mass was maintained at OD660 > 10. Furthermore, medium optimization for industrial production was carried out. Finally, CR-720 produced 72 mM ALA with a high productivity rate (1.4-1.5 mM/h) and obtained 1.9 mM AHVA at an optimal temperature (28° C) when dissolved oxygen was at 0.5 mg/L, which was possible by controlling agitation in a 5-kL jar fermenter.


Hayashi M.,Tokyo Institute of Technology | Fukuhara H.,Kochi Medical School | Inoue K.,Kochi Medical School | Shuin T.,Kochi Medical School | And 4 more authors.
PLoS ONE | Year: 2015

Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects. © 2015 Hayashi et al.


Koganei M.,Meiji Co. | Saitou Y.,Meiji Co. | Tsuchiya K.,SBI Pharma Co. | Abe F.,SBI Pharma Co. | And 5 more authors.
Journal of Clinical Biochemistry and Nutrition | Year: 2015

The effects of 5-amino levulinic acid (5-ALA) on obesity were investigated using a murine model (diet-induced obese mice). Diet-induced obese mice were divided into 4 groups: a control group (C group), which was fed a high-fat diet; a low-5-ALA dose (10 mg/kg/day) group (10A group); a moderate-5-ALA dose (30 mg/kg/day) group (30A group); and a high-5-ALA dose (100 mg/kg/day) group (100A group). 5-ALA was administered by mixing the high fat diet for 8 weeks. Body weight increases in the 30A and 100A groups were significantly smaller compared with those of the C group. Body fat measurements by X-ray computed tomography indicated that the 100A group showed a tendency toward low visceral fat quantities during the final week of the study. Visceral fat weights in the 30A and 100A groups were slightly low. The levels of serum alanine aminotransferase (ALT) and total cholesterol (TC) in the 10A group was slightly low, whereas the 30A and 100A groups showed significantly lower ALT and TC values. Liver lipid concentration showed a dose-dependent decrease with ALA. Thus, in this diet-induced obese murine model, administration of 5-ALA had a significantly beneficial impact on the visceral fat, serum ALT and TC, and liver lipid concentration. Copyright © 2015 JCBN.


PubMed | Biomaterial in Tokyo Co., Meiji Co. and SBI Pharma Co.
Type: Journal Article | Journal: Journal of clinical biochemistry and nutrition | Year: 2015

The effects of 5-aminolevulinic acid (5-ALA) on obesity were investigated using a murine model (diet-induced obese mice). Diet-induced obese mice were divided into 4 groups: a control group (C group), which was fed a high-fat diet; a low-5-ALA dose (10mg/kg/day) group (10A group); a moderate-5-ALA dose (30mg/kg/day) group (30A group); and a high-5-ALA dose (100mg/kg/day) group (100A group). 5-ALA was administered by mixing the high fat diet for 8 weeks. Body weight increases in the 30A and 100A groups were significantly smaller compared with those of the C group. Body fat measurements by X-ray computed tomography indicated that the 100A group showed a tendency toward low visceral fat quantities during the final week of the study. Visceral fat weights in the 30A and 100A groups were slightly low. The levels of serum alanine aminotransferase (ALT) and total cholesterol (TC) in the 10A group was slightly low, whereas the 30A and 100A groups showed significantly lower ALT and TC values. Liver lipid concentration showed a dose-dependent decrease with ALA. Thus, in this diet-induced obese murine model, administration of 5-ALA had a significantly beneficial impact on the visceral fat, serum ALT and TC, and liver lipid concentration.


PubMed | Tokyo Institute of Technology, SBI Pharma CO. and Kochi Medical School
Type: Journal Article | Journal: PloS one | Year: 2015

Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects.

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