Maeda H
Dept. of Microbiology, Kumamoto University School of Medicine.
Gan To Kagaku Ryoho. 1998 Feb;25 Suppl 1:1-9.
During the past five years we observed many advances in the study of the polymer drug, "SMANCS". This first polymeric drug was approved by the Japanese Ministry of Health and Welfare in 1994 as a drug for primary liver cancer, in which the arterial injection of oily formulation in Lipiodol (a lipid contrast medium) is the standard procedure. The advantage of this tactic is the most extraordinary cancer targeting efficiency with the least systemic side effect and very prolonged slow release of SMANCS. The mechanism of tumor selective accumulation of SMANCS and polymeric drugs in general is discussed in view of the so called-EPR (enhanced permeability and retention) effect of solid tumor. The mode of action of SMANCS at the cellular level seems to accompany the generation of superoxide radical which damages DNA; strand break and modification of guaninine by 8-hydroxylguanine. Immunological potentiation involves either the cellular (M phi, T-cell, NK-cell) or molecular level (induction of cytokines, including interferon gamma). The in vivo effect of SMANCS is most pronounced in the tumor vessels where more concentrated SMANCS is accessible due to the EPR effect, and perhaps the generation of O2.-. Nitric oxide generated by both inducible form of NO synthase (iNOS) by the infiltrated macrophages and NOS of endothelial cells, and superoxide from SMANCS will readily react to form peroxynitrite (O2- + NO-->ONOO-), which is a very potent cytotoxic molecule and will damage (nitrate and oxidize) DNA and proteins. Thus, tissue damage and vascular injury or collapse will be the principle tumor toxic mechanism of SMANCS at tissue level. The dose of SMANCS (or grade I-IV tumor filling) and tumor regression parallel each other, and a profile of AFP-value and technical issues of SMANCS/Lipiodol administration intraarterially are also discussed.
在过去五年中，我们观察到聚合物药物“丝裂霉素肝动脉化疗栓塞剂（SMANCS）”的研究取得了许多进展。这种首个聚合物药物于1994年被日本厚生省批准用于治疗原发性肝癌，其中在碘油（一种脂质造影剂）中动脉注射油性制剂是标准治疗方法。这种策略的优点是具有最卓越的癌症靶向效率，全身副作用最小，且SMANCS能非常持久地缓慢释放。鉴于实体瘤的所谓“增强渗透与滞留（EPR）效应”，讨论了SMANCS及一般聚合物药物在肿瘤中选择性蓄积的机制。SMANCS在细胞水平的作用方式似乎伴随着超氧自由基的产生，超氧自由基会损伤DNA；导致DNA链断裂，并使鸟嘌呤被8 - 羟基鸟嘌呤修饰。免疫增强作用涉及细胞水平（巨噬细胞、T细胞、NK细胞）或分子水平（诱导包括干扰素γ在内的细胞因子）。SMANCS的体内效应在肿瘤血管中最为显著，由于EPR效应，在肿瘤血管中可获得浓度更高的SMANCS，并且可能会产生超氧阴离子。浸润的巨噬细胞诱导型一氧化氮合酶（iNOS）和内皮细胞的一氧化氮合酶产生的一氧化氮，与SMANCS产生的超氧阴离子会迅速反应形成过氧亚硝酸盐（O2- + NO→ONOO-），这是一种非常强效的细胞毒性分子，会损伤（使硝酸化和氧化）DNA和蛋白质。因此，组织损伤和血管损伤或塌陷将是SMANCS在组织水平上的主要肿瘤毒性机制。还讨论了SMANCS的剂量（或I - IV级肿瘤填充情况）与肿瘤消退的平行关系，以及甲胎蛋白值的变化情况和动脉内注射SMANCS/碘油的技术问题。
