MECHANISMS OF PORPHYRIN ACCUMULATION BY CANCEROUS CELLS

卟啉光疗法已经成功地用于治疗某些疾病。 肿瘤，包括其他不可手术的支气管癌症。 当荧光照射时，卟啉在癌细胞中积累， 能够检测负载卟啉的癌细胞， 局部杀肿瘤作用。 生物化学机制和后果 卟啉与正常和癌细胞成分的相互作用 组织尚未得到充分评估。 卟啉结合蛋白和 卟啉代谢酶可能是重要的因素， 卟啉的细胞积累或消除， “捕获储库”或改变外源卟啉的代谢。 此外，通过与重要的细胞成分相互作用，外源性 卟啉可能影响正常组织。 目的之一是鉴定和定量细胞内的马兜铃蛋白结合蛋白 在正常和肿瘤组织中。 最初的重点将放在 由于使用了几种卟啉， 临床上抑制这些酶。 相关的蛋白质将被分离出来 通过亲和层析，并用于产生抗体，用于随后的 在感兴趣的组织中进行鉴定和定量。 另一个目的是 以评估外源性卟啉的代谢。 细胞内 卟啉的代谢可能影响它们被细胞保留， 卟啉会倾向于积聚在组织中， 代谢它们。 外源性卟啉对细胞凋亡的不同影响 线粒体铁螯合酶和相当低水平的这种酶 在Morris肝癌7288C组织中也发现了比正常肝组织中更高的C含量， 外源卟啉与亚铁螯合酶相互作用及其 血红素加氧酶的血红素类似物，以及这些酶在 将测量正常和癌组织。 对细胞的影响 正常细胞暴露于外源性卟啉的代谢也将被 评估。 Morris肝癌被用作模型系统，因为这些 细胞可以在培养物中生长或在大鼠中作为实体瘤生长。 此外，本发明还提供了一种方法， 它们是肝源性细胞，它们的代谢可以与 正常肝脏，其在卟啉代谢中起重要作用。 一个主要 目的是基于人类肿瘤进行类似的研究， 在大鼠研究中开发的知识和工具。

Porphyrin phototherapy has been used with some success to treat certain neoplasias, including otherwise inoperable cancers of the bronchus. Prophyrins accumulated in cancerous cells when illuminated fluoresce, enabling detection of porphyrin-loaded cancerous cells and also produce localized tumoricidal effects. The biochemical mechanisms and consequences of porphyrin interactions with cellular components of normal and cancerous tissues have not been fully assessed. Porphyrin-binding proteins and porphyrin-metabolizing enzymes are likely to be important factors in the cellular accumulation or elimination of porphyrins acting either as "trapping reservoirs" or altering the metabolism of exogenous porphyrins. Moreover, by interacting with important cellular components, exogenous porphyrins are likely to affect normal tissues. One aim is to identify and quantitate cellular prophyrin-binding proteins in normal and neoplastic tissues. The initial focus will be on the cytosolic glutathione-S-transferases since several porphyrins used clinically inhibit these enzymes. The proteins involved will be isolated by affinity chromatography and used to raise antibodies for subsequent identification and quantitation in the tissues of interest. Another aim is to evaluate the metabolism of exogenous porphyrins. Intracellular metabolism of porphyrins is likely to affect their retention by cells since porphyrins would tend to accumulate in tissues which cannot readily metabolize them. Differential effects of exogenous porphyrins on mitochondrial ferrochelatase and considerably lower levels of this enzyme in Morris hepatoma 7288 C tissue than normal liver have been found. The interaction of exogenous porphyrins with ferrochelatase and of their heme-analogs with heme oxygenase, and the activity of these enzymes in normal and cancerous tissues will be measured. The effects on cellular metabolism of exposure of normal cells to exogenous porphyrins will also be assessed. The Morris hepatoma is used as a model system because these cells can be grown in culture or as a solid tumor in rats. In addition, they are liver-derived cells and their metabolism can be compared with normal liver, which plays a vital role in porphyrin metabolism. A prime objective is to carry out similar research with human tumors based on the knowledge and tools developed in the studies with the rat.