Ortel B, Sharlin D, O'Donnell D, Sinha A K, Maytin E V, Hasan T
Wellman Laboratories of Photomedicine WEL-224, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts, MA 02114, USA.
Br J Cancer. 2002 Nov 18;87(11):1321-7. doi: 10.1038/sj.bjc.6600575.
Photodynamic therapy using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) may be applied to the treatment of neoplasms in a variety of organs. In order to enhance existing regimens of photodynamic therapy, we investigated the effects of adding differentiation therapy to photodynamic therapy in human prostate cancer cells in vitro. The objective of differentiation therapy per se is to reverse the lack of differentiation in cancer cells using pharmacological agents. The motivation for this study was to exploit the differentiation-dependent expression of some heme enzymes to enhance tumour cell toxicity of ALA-photodynamic therapy. A short course of differentiation therapy was applied to increase PpIX formation during subsequent ALA exposure. Using the synthetic androgen R1881, isomers of retinoic acid, and analogues of vitamin D for 3 to 4 days, exogenous ALA-dependent PpIX formation in LNCaP cells was increased, along with markers for growth arrest and for differentiation. As a consequence of higher PpIX levels, cytotoxic effects of visible light exposure were also enhanced. Short-term differentiation therapy increased not only the overall PpIX production but also reduced that fraction of cells that contained low PpIX levels as demonstrated by flow cytometry and fluorescence microscopy. This study suggests that it will be feasible to develop protocols combining short-term differentiation therapy with photodynamic therapy for enhanced photosensitisation.
使用5-氨基酮戊酸（ALA）诱导的原卟啉IX（PpIX）的光动力疗法可应用于多种器官肿瘤的治疗。为了增强现有的光动力治疗方案，我们在体外研究了在人前列腺癌细胞中，将分化疗法与光动力疗法相结合的效果。分化疗法本身的目的是使用药物逆转癌细胞中缺乏分化的状态。本研究的动机是利用某些血红素酶的分化依赖性表达来增强ALA光动力疗法对肿瘤细胞的毒性。应用一个短疗程的分化疗法，以增加随后ALA暴露期间PpIX的形成。使用合成雄激素R1881、视黄酸异构体和维生素D类似物处理3至4天，LNCaP细胞中外源性ALA依赖性PpIX的形成增加，同时生长停滞和分化的标志物也增加。由于PpIX水平较高，可见光照射的细胞毒性作用也增强。短期分化疗法不仅增加了总的PpIX产量，还减少了流式细胞术和荧光显微镜显示的低PpIX水平细胞的比例。这项研究表明，开发将短期分化疗法与光动力疗法相结合以增强光敏化的方案是可行的。
