5-Aminolevulinic acid-induced protoporphyrin IX with multi-dose ionizing irradiation enhances host antitumor response and strongly inhibits tumor growth in experimental glioma in vivo

Yamamoto,Junkoh; Ogura,Shun‑Ichiro; Shimajiri,Shohei; Nakano,Yoshiteru; Akiba,Daisuke; Kitagawa,Takehiro; Ueta,Kunihiro; Tanaka,Tohru; Nishizawa,Shigeru

doi:10.3892/mmr.2014.2991

5-Aminolevulinic acid-induced protoporphyrin IX with multi-dose ionizing irradiation enhances host antitumor response and strongly inhibits tumor growth in experimental glioma in vivo

Authors:
- Junkoh Yamamoto
- Shun‑Ichiro Ogura
- Shohei Shimajiri
- Yoshiteru Nakano
- Daisuke Akiba
- Takehiro Kitagawa
- Kunihiro Ueta
- Tohru Tanaka
- Shigeru Nishizawa
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Affiliations: Department of Neurosurgery, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807‑8555, Japan, Department of Bioengineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226‑8501, Japan, Department of Surgical Pathology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807‑8555, Japan, SBI Pharmaceuticals Co., Ltd., Minato‑ku, Tokyo 106‑6020, Japan
Published online on: November 21, 2014 https://doi.org/10.3892/mmr.2014.2991
Pages: 1813-1819

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Abstract

Ionizing irradiation is a well‑established therapeutic modality for malignant gliomas. Due to its high cellular uptake, 5‑aminolevulinic acid (ALA) is used for fluorescence‑guided resection of malignant gliomas. We have previously shown that 5‑ALA sensitizes glioma cells to irradiation in vitro. The aim of the present study was to assess whether 5‑ALA acts as a radiosensitizer in experimental glioma in vivo. Rats were subcutaneously injected with 9L gliosarcoma cells and administered 5‑ALA. The accumulation of 5‑ALA‑induced protoporphyrin IX was confirmed by high‑performance liquid chromatography (HPLC) analysis. Subcutaneous (s.c.) tumors were subsequently irradiated with 2 Gy/day for five consecutive days. In the experimental glioma model, high‑performance liquid chromatography analysis revealed a high level of accumulation of 5‑ALA‑induced protoporphyrin IX in s.c. tumors 3 h after 5‑ALA administration. Multi‑dose ionizing irradiation induced greater inhibition of tumor growth in rats that were administered 5‑ALA than in the non‑5‑ALA‑treated animals. Immunohistochemical analysis of the s.c. tumors revealed that numerous ionized calcium‑binding adapter molecule 1 (Iba1)‑positive macrophages gathered at the surface of and within the s.c. tumors following multi‑dose ionizing irradiation in combination with 5‑ALA administration. By contrast, the s.c. tumors in the control group scarcely showed aggregation of Iba1‑positive macrophages. These results suggested that multi‑dose ionizing irradiation with 5‑ALA induced not only a direct cytotoxic effect but also enhanced the host antitumor immune response and thus caused high inhibition of tumor growth in experimental glioma.

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1	Mimura S, Ito Y, Nagayo T, et al: Cooperative clinical trial of photodynamic therapy with photofrin II and excimer dye laser for early gastric cancer. Lasers Surg Med. 19:168–172. 1996. View Article : Google Scholar : PubMed/NCBI
2	Mlkvy P, Messmann H, Pauer M, et al: Distribution and photodynamic effects of meso-tetrahydroxyphenylchlorin (mTHPC) in the pancreas and adjacent tissues in the Syrian golden hamster. Br J Cancer. 73:1473–1479. 1996. View Article : Google Scholar : PubMed/NCBI
3	Yamamoto J, Hirano T, Li S, et al: Selective accumulation and strong photodynamic effects of a new photosensitizer, ATX-S10. Na (II), in experimental malignant glioma. Int J Oncol. 27:1207–1213. 2005.PubMed/NCBI
4	Stummer W, Pichlmeier U, Meinel T, et al: Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7:392–401. 2006. View Article : Google Scholar : PubMed/NCBI
5	Muller PJ and Wilson BC: Photodynamic therapy for malignant newly diagnosed supratentorial gliomas. J Clin Laser Med Surg. 14:263–270. 1996.PubMed/NCBI
6	Yamamoto J, Yamamoto S, Hirano T, et al: Monitoring of singlet oxygen is useful for predicting the photodynamic effects in the treatment for experimental glioma. Clin Cancer Res. 12:7132–7139. 2006. View Article : Google Scholar : PubMed/NCBI
7	Schaffer M, Ertl-Wagner B, Schaffer PM, et al: Feasibility of photofrin II as a radiosensitizing agent in solid tumors - preliminary results. Onkologie. 29:514–519. 2006. View Article : Google Scholar : PubMed/NCBI
8	Luksiene Z, Juzenas P and Moan J: Radiosensitization of tumours by porphyrins. Cancer Lett. 235:40–47. 2006. View Article : Google Scholar
9	Berg K, Luksiene Z, Moan J and Ma L: Combined treatment of ionizing radiation and photosensitization by 5-aminolevulinic acid-induced protoporphyrin IX. Radiat Res. 142:340–346. 1995. View Article : Google Scholar : PubMed/NCBI
10	Schaffer M, Schaffer PM, Jori G, et al: Radiation therapy combined with photofrin or 5-ALA: effect on Lewis sarcoma tumor lines implanted in mice. Preliminary results. Tumori. 88:407–410. 2002.PubMed/NCBI
11	Takahashi J, Misawa M, Murakami M, et al: 5-Aminolevulinic acid enhances cancer radiotherapy in a mouse tumor model. Springerplus. 2:6022013. View Article : Google Scholar : PubMed/NCBI
12	Yamamoto J, Ogura S, Tanaka T, et al: Radiosensitizing effect of 5-aminolevulinic acid-induced protoporphyrin IX in glioma cells in vitro. Oncol Rep. 27:1748–1752. 2012.PubMed/NCBI
13	Benda P, Someda K, Messer J and Sweet WH: Morphological and immunochemical studies of rat glial tumors and clonal strains propagated in culture. J Neurosurg. 34:310–323. 1971. View Article : Google Scholar : PubMed/NCBI
14	Schmidek HH, Nielsen SL, Schiller AL and Messer J: Morphological studies of rat brain tumors induced by N-nitrosomethylurea. J Neurosurg. 34:335–340. 1971. View Article : Google Scholar : PubMed/NCBI
15	Barth RF: Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol. 36:91–102. 1998. View Article : Google Scholar : PubMed/NCBI
16	Hagiya Y, Fukuhara H, Matsumoto K, et al: Expression levels of PEPT1 and ABCG2 play key roles in 5-aminolevulinic acid (ALA)-induced tumor-specific protoporphyrin IX (PpIX) accumulation in bladder cancer. Photodiagnosis Photodyn Ther. 10:288–295. 2013. View Article : Google Scholar : PubMed/NCBI
17	Ishizuka M, Hagiya Y, Mizokami Y, et al: Porphyrins in urine after administration of 5-aminolevulinic acid as a potential tumor marker. Photodiagnosis Photodyn Ther. 8:328–331. 2011. View Article : Google Scholar : PubMed/NCBI
18	Cerniglia GJ, Wilson DF, Pawlowski M, Vinogradov S and Biaglow J: Intravascular oxygen distribution in subcutaneous 9L tumors and radiation sensitivity. J Appl Physiol. 82:1939–1945. 1997.PubMed/NCBI
19	Abels C, Heil P, Dellian M, et al: In vivo kinetics and spectra of 5-aminolaevulinic acid-induced fluorescence in an amelanotic melanoma of the hamster. Br J Cancer. 70:826–833. 1994. View Article : Google Scholar : PubMed/NCBI
20	Abels C, Fritsch C, Bolsen K, et al: Photodynamic therapy with 5-aminolaevulinic acid-induced porphyrins of an amelanotic melanoma in vivo. J Photochem Photobiol B. 40:76–83. 1997. View Article : Google Scholar : PubMed/NCBI
21	Bozzini G, Colin P, Betrouni N, et al: Efficiency of 5-ALA mediated photodynamic therapy on hypoxic prostate cancer: a preclinical study on the Dunning R3327-AT2 rat tumor model. Photodiagnosis Photodyn Ther. 10:296–303. 2013. View Article : Google Scholar : PubMed/NCBI
22	Niclou SP, Danzeisen C, Eikesdal HP, et al: A novel eGFP-expressing immunodeficient mouse model to study tumor-host interactions. FASEB J. 22:3120–3128. 2008. View Article : Google Scholar : PubMed/NCBI
23	Prall F, Maletzki C and Linnebacher M: Microdensitometry of osteopontin as an immunohistochemical prognostic biomarker in colorectal carcinoma tissue microarrays: potential and limitations of the method in ‘biomarker pathology’. Histopathology. 61:823–832. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kostron H, Swartz MR, Miller DC and Martuza RL: The interaction of hematoporphyrin derivative, light, and ionizing radiation in a rat glioma model. Cancer. 57:964–970. 1986. View Article : Google Scholar : PubMed/NCBI
25	Ito E, Yue S, Moriyama EH, et al: Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer. Sci Transl Med. 3:67ra72011. View Article : Google Scholar : PubMed/NCBI
26	David S and Kroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 12:388–399. 2011. View Article : Google Scholar : PubMed/NCBI
27	Lynch MA: The multifaceted profile of activated microglia. Mol Neurobiol. 40:139–156. 2009. View Article : Google Scholar : PubMed/NCBI
28	MacMicking J, Xie QW and Nathan C: Nitric oxide and macrophage function. Annu Rev Immunol. 15:323–350. 1997. View Article : Google Scholar : PubMed/NCBI
29	Boehm U, Klamp T, Groot M and Howard JC: Cellular responses to interferon-gamma. Annu Rev Immunol. 15:749–795. 1997. View Article : Google Scholar : PubMed/NCBI
30	Hussain SF, Yang D, Suki D, Grimm E and Heimberger AB: Innate immune functions of microglia isolated from human glioma patients. J Transl Med. 4:152006. View Article : Google Scholar : PubMed/NCBI
31	Li W and Graeber MB: The molecular profile of microglia under the influence of glioma. Neuro Oncol. 14:958–978. 2012. View Article : Google Scholar : PubMed/NCBI
32	Filipazzi P, Huber V and Rivoltini L: Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother. 61:255–263. 2012. View Article : Google Scholar
33	Skivka LM, Gorobets OB, Kutsenok VV, et al: 5-aminolevulinic acid mediated photodynamic therapy of Lewis lung carcinoma: a role of tumor infiltration with different cells of immune system. Exp Oncol. 26:312–315. 2004.
34	Ishizuka M, Abe F, Sano Y, et al: Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy. Int Immunopharmacol. 11:358–365. 2011. View Article : Google Scholar
35	Higashikawa F, Noda M, Awaya T, Tanaka T and Sugiyama M: 5-aminolevulinic acid, a precursor of heme, reduces both fasting and postprandial glucose levels in mildly hyperglycemic subjects. Nutrition. 29:1030–1036. 2013. View Article : Google Scholar : PubMed/NCBI
36	Starke RM, Williams BJ, Hiles C, et al: Gamma knife surgery for skull base meningiomas. J Neurosurg. 116:588–597. 2012. View Article : Google Scholar
37	Torres RC, Frighetto L, De Salles AA, et al: Radiosurgery and stereotactic radiotherapy for intracranial meningiomas. Neurosurg Focus. 14:e52003. View Article : Google Scholar