Koudinova Natalia V, Pinthus Jehonathan H, Brandis Alexander, Brenner Ori, Bendel Peter, Ramon Jacob, Eshhar Zelig, Scherz Avigdor, Salomon Yoram
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Int J Cancer. 2003 May 10;104(6):782-9. doi: 10.1002/ijc.11002.
Small cell carcinoma of the prostate (SCCP), although relatively rare, is the most aggressive variant of prostate cancer, currently with no successful treatment. It was therefore tempting to evaluate the response of this violent malignancy and its bone lesions to Pd-Bacteriopheophorbide (TOOKAD)-based photodynamic therapy (PDT), already proven by us to efficiently eradicate other aggressive non-epithelial solid tumors. TOOKAD is a novel bacteriochlorophyll-derived, second-generation photosensitizer recently, developed by us for the treatment of bulky tumors. This photosensitizer is endowed with strong light absorbance (epsilon(0) approximately 10(5) mol(-1) cm(-1)) in the near infrared region (lambda=763nm), allowing deep tissue penetration. The TOOKAD-PDT protocol targets the tumor vasculature leading to inflammation, hypoxia, necrosis and tumor eradication. The sensitizer clears rapidly from the circulation within a few hours and does not accumulate in tissues, which is compatible with the treatment of localized tumor and isolated metastases. Briefly, male CD1-nude mice were grafted with the human SCCP (WISH-PC2) in 3 relevant anatomic locations: subcutaneous (representing tumor mass), intraosseous (representing bone metastases) and orthotopically within the murine prostate microenvironment. The PDT protocol consisted of i.v. administration of TOOKAD (4 mg/kg), followed by immediate illumination (650-800 nm) from a xenon light source or a diode laser emitting at 770 nm. Controls included untreated animals or animals treated with light or TOOKAD alone. Tumor volume, human plasma chromogranin A levels, animal well being and survival were used as end points. In addition, histopathology and immunohistochemistry were used to define the tumor response. Subcutaneous tumors exhibited complete healing within 28-40 days, reaching an overall long-term cure rate of 69%, followed for 90 days after PDT. Intratibial WISH-PC2 lesions responded with complete tumor elimination in 50% of the treated mice at 70-90 days after PDT as documented histologically. The response of the orthotopic model was also analyzed histologically with similar results. The study with this model suggests that TOOKAD-based PDT can reach large tumors and is a feasible, efficient and well-tolerated approach for minimally invasive treatment of local and disseminated SCCP.
前列腺小细胞癌（SCCP）虽然相对罕见，但却是前列腺癌中侵袭性最强的变体，目前尚无成功的治疗方法。因此，我们很想评估这种恶性肿瘤及其骨病变对基于钯-细菌脱镁叶绿素（TOOKAD）的光动力疗法（PDT）的反应，我们已经证明该疗法能有效根除其他侵袭性非上皮性实体肿瘤。TOOKAD是一种新型的细菌叶绿素衍生的第二代光敏剂，最近由我们开发用于治疗体积较大的肿瘤。这种光敏剂在近红外区域（波长=763nm）具有很强的吸光能力（ε(0)约为10(5) mol(-1) cm(-1)），可实现深部组织穿透。TOOKAD-PDT方案以肿瘤血管系统为靶点，导致炎症、缺氧、坏死并根除肿瘤。该敏化剂在数小时内迅速从循环中清除，不会在组织中蓄积，这与局部肿瘤和孤立转移灶的治疗相适应。简而言之，将雄性CD1裸鼠在3个相关解剖部位移植人SCCP（WISH-PC2）：皮下（代表肿瘤块）、骨内（代表骨转移）以及在小鼠前列腺微环境内原位移植。PDT方案包括静脉注射TOOKAD（4mg/kg），随后立即用氙光源或发射波长为770nm的二极管激光进行照射（650-800nm）。对照组包括未治疗的动物或仅接受光照或TOOKAD治疗的动物。以肿瘤体积、人血浆嗜铬粒蛋白A水平、动物健康状况和生存率作为终点指标。此外，采用组织病理学和免疫组织化学来确定肿瘤反应。皮下肿瘤在28-40天内完全愈合，PDT后随访90天，总体长期治愈率达69%。组织学记录显示，胫骨内WISH-PC2病变在PDT后70-90天，50%的治疗小鼠肿瘤完全消除。对原位模型的反应也进行了组织学分析，结果相似。该模型的研究表明，基于TOOKAD的PDT可以作用于大肿瘤，是一种可行、有效且耐受性良好的局部和播散性SCCP微创治疗方法。
