5-氟吲哚-3-乙酸：被过氧化物酶激活的前药，可能用于靶向癌症治疗。,BIOCHEMICAL PHARMACOLOGY

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5-氟吲哚-3-乙酸：被过氧化物酶激活的前药，可能用于靶向癌症治疗。
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2002-02-14 , DOI: 10.1016/s0006-2952(01)00868-1
Lisa K Folkes ₁ , Olga Greco , Gabi U Dachs , Michael R L Stratford , Peter Wardman

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吲哚-3-乙酸和一些衍生物被辣根过氧化物酶氧化，形成自由基阳离子，该阳离子迅速断裂（消除CO（2））以形成细胞毒性产物。当吲哚-3-乙酸或辣根过氧化物酶以共同形成有效细胞毒素的浓度单独孵育时，未见毒性。出乎意料的是，在存在过氧化物酶的情况下，被辣根过氧化物酶化合物I氧化的5-氟吲哚-3-乙酸比吲哚-3-乙酸慢10倍，对V79仓鼠成纤维细胞的细胞毒性比未取代的吲哚大得多。氟化前药/过氧化物酶的组合在人和啮齿动物的肿瘤细胞系中也显示出强大的细胞毒活性。据认为，细胞毒性部分是由于3-亚甲基-2-氧吲哚（或类似物）的形成而引起的，该亚甲基可以与硫醇结合，也可能与DNA或其他生物亲核试剂结合。腹膜内给药50mg / kg后，鼠癌NT中的氟化前药水平约为200μM。尽管它们比血浆水平（达到1mM）低4-5倍，但在2小时内肿瘤中浓度/时间曲线下的积分面积约为20 mM min，几乎是达到90-99％所需暴露量的两倍尽管人膀胱T24癌细胞株具有更高的耐药性，但在人MCF7乳腺或HT29结肠肿瘤细胞株和CaNT鼠细胞中仍能杀死细胞。

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5-Fluoroindole-3-acetic acid: a prodrug activated by a peroxidase with potential for use in targeted cancer therapy.

Indole-3-acetic acid and some derivatives are oxidized by horseradish peroxidase, forming a radical-cation that rapidly fragments (eliminating CO(2)) to form cytotoxic products. No toxicity is seen when either indole-3-acetic acid or horseradish peroxidase is incubated alone at concentrations that together form potent cytotoxins. Unexpectedly, 5-fluoroindole-3-acetic acid, which is oxidized by horseradish peroxidase compound I 10-fold more slowly than indole-3-acetic acid, is much more cytotoxic towards V79 hamster fibroblasts in the presence of peroxidase than the unsubstituted indole. The fluorinated prodrug/peroxidase combination also shows potent cytotoxic activity in human and rodent tumor cell lines. Cytotoxicity is thought to arise in part from the formation of 3-methylene-2-oxindole (or analogues) that can conjugate with thiols and probably DNA or other biological nucleophiles. Levels of the fluorinated prodrug in the murine carcinoma NT after intraperitoneal administration of 50 mg/kg were about 200 microM. Although these were 4-5-fold lower than plasma levels (which reached 1mM), the integrated area under the concentration/time curve in tumors over 2 hr was approximately 20 mM min, almost double the exposure needed to achieve approximately 90-99% cell kill in human MCF7 breast or HT29 colon tumor cell lines and CaNT murine cells in vitro, although the human bladder T24 carcinoma cell line was more resistant. The high cytotoxicity of 5-fluoroindole-3-acetic acid after oxidative activation suggests its further evaluation as a prodrug for targeted cancer therapy involving antibody-, polymer-, or gene-directed delivery of horseradish peroxidase or similar activating enzymes.

更新日期：2019-11-01

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