Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
J Cancer Res Clin Oncol. 2010 Aug;136(8):1143-50. doi: 10.1007/s00432-010-0761-7. Epub 2010 Jan 13.
Photodynamic therapy (PDT) is a new approach to cancer treatment that utilizes photochemical reactions induced by a combination of an oncophilic photosensitizing agent and laser light. With an aim to apply PDT for intraperitoneal disseminated foci of advanced or recurrent ovarian cancers, the present study was conducted to evaluate the antitumor effect of PDT using a methyl ester of 5-aminolevulinic acid (Methyl-ALA) on various types of human ovarian cancer in a subcutaneous xenograft model in nude mice and to elucidate the mechanism of its antitumor effect.
HTOA, MCAS, and TOV21G cell lines derived from human ovarian serous, mucinous, and clear cell adenocarcinoma, respectively, were used in this study. The mice in the treatment group and in the control group received an intraperitoneal injection of 250 mg/kg of Methyl-ALA and PBS alone, respectively. PDT was administered by 10 min irradiation using a 150 W halogen light, 3 h after Methyl-ALA or PBS injection. Each mouse received PDT twice a week for 3 weeks.
Methyl-ALA-PDT significantly suppressed the growth of HTOA tumors as compared to control, whereas there was no significant effect on the growth of MCAS or TOV21G tumors. Methyl-ALA-PDT significantly increased apoptosis in implanted HTOA tumors as well as cultured cells. Western blot analysis showed that amount of expression of milk fat globule-EGF-factor 8, which binds to apoptotic cells and thereby facilitates their phagocytosis, significantly increased in HTOA tumors receiving Methyl-ALA-PDT, compared with untreated HTOA tumors. In addition, reduced vascular endothelial growth factor and CD34-positive microvessel density were found in solid HTOA tumors treated by Methyl-ALA-PDT, suggesting that the antitumor effect of Methyl-ALA-PDT is due to induction of apoptosis and reduction of angiogenesis. In comparison with HTOA cells, HPLC analysis demonstrated a significantly smaller intracellular amount of protoporphyrin IX (PpIX) in MCAS and TOV21G cells. PpIX is readily converted from Methyl-ALA and elicts photocytotoxicity.
We conclude that Methyl-ALA-PDT could be an effective treatment in ovarian cancer and should be tested to apply intraperitoneally disseminated micro-foci during surgery.
光动力疗法（PDT）是一种利用光化学反应治疗癌症的新方法，该反应由亲肿瘤光敏剂和激光光联合引发。为了将 PDT 应用于晚期或复发性卵巢癌的腹腔播散灶，本研究旨在评估在裸鼠皮下异种移植模型中使用 5-氨基酮戊酸甲酯（Methyl-ALA）对各种类型人卵巢癌细胞的抗肿瘤作用，并阐明其抗肿瘤作用的机制。
本研究使用来源于人卵巢浆液性、黏液性和透明细胞腺癌的 HTOA、MCAS 和 TOV21G 细胞系。治疗组和对照组的小鼠分别腹腔注射 250mg/kg 的 Methyl-ALA 和 PBS。在 Methyl-ALA 或 PBS 注射后 3 小时，用 150W 卤灯光照射 10 分钟进行 PDT。每只小鼠每周接受两次 PDT，共 3 周。
与对照组相比，Methyl-ALA-PDT 显著抑制了 HTOA 肿瘤的生长，而对 MCAS 或 TOV21G 肿瘤的生长无明显影响。Methyl-ALA-PDT 显著增加了植入的 HTOA 肿瘤和培养细胞的凋亡。Western blot 分析显示，与未经处理的 HTOA 肿瘤相比，接受 Methyl-ALA-PDT 治疗的 HTOA 肿瘤中结合凋亡细胞并促进其吞噬的乳脂肪球 EGF 因子 8 的表达量显著增加。此外，在接受 Methyl-ALA-PDT 治疗的实体 HTOA 肿瘤中，血管内皮生长因子和 CD34 阳性微血管密度降低，提示 Methyl-ALA-PDT 的抗肿瘤作用是由于诱导凋亡和减少血管生成。与 HTOA 细胞相比，HPLC 分析显示 MCAS 和 TOV21G 细胞中的原卟啉 IX（PpIX）的细胞内含量明显较小。PpIX 可由 Methyl-ALA 转化而来，并产生光细胞毒性。
我们得出结论，Methyl-ALA-PDT 可能是卵巢癌的一种有效治疗方法，应进行测试以应用于手术期间的腹腔播散微灶。
