作用於DNA拓樸異構酶之抗癌藥物   全文下載

DNA Topoisomerases as Targets of Anticancer Drugs

DNA拓模異構?是細胞核內的重要蛋白質，分為第一、第二兩型，可經由切或接DNA而調節DNA的超螺旋結構。故此?幾乎參予了所有DNA的生物反應如複製、轉錄及重組。近年來更發現DNA拓樸異構?是許多抗細菌、真菌、病毒或抗癌藥物的標的物。本文主要介紹以DNA拓樸異構?為標的之抗癌藥物，例如喜樹鹼作用在第一型拓樸異構?（Topo I），而VM26則作用在第二型拓樸異構?（Top II），它們的作用均是抓住DNA和拓樸異構?所形成的切割複合體，使斷裂的DNA無法接合而干擾DNA的複製或轉錄等重要生物反應。然而如同其他的抗癌藥物，癌細胞會產生多種耐藥性機制來逃過這些藥物的作用，例如在細胞表面大量表現多重耐藥蛋白（multiple drug resistance protein 1, MDR 1），將抗癌藥物運送出細胞；或降低細胞內拓樸異構?的濃度，或產生具耐藥性的拓樸異構?突變種等。因此研究抗癌藥物標的物及耐藥性機制，將有助於我國發展新而有效的抗癌藥物。"

Eukaryotic DNA topoisomerases are ubiquitous nuclear enzymes that alter DNA topology by breaking and rejoining DNA strands. There are two classes of DNA topoisomerases; DNA topoisomerase I introduces a transient single- strand DNA break, while topoisomerase II introduces transient double-strand DNA breaks for each catalytic reaction. Both are important for solving topological problems arising during DNA replication, transcription, recombinaion and other cellular functions. Recently, scientists have realized the importance of topoisomerases as new therapeuic targets for antibacterial, antifungal antiparastitic, antiviral and anticancer drugs. The present review focuses on anticancer drugs targeting mammalian DNA topoisomerases, which are named DNA topoisomerase poison. Camptothecin and VM26 (teniposide) are representative DNA topoisomerase poisons that target DNA topoisomerase I and topoisomerase 11, respectively. These drugs alter the breakagereunion reactions of DNA topoisomerases by trapping topoisomerase-DNA cleavable complexes in both the purified system and cultured cells. However, resistance to various DNA topoisomerase poisons has been documented in cancer cells with repect to MDR1 overexpression, reduced topoisomerase levels, drug-resistant mutant topoisomerase, lengthened cell cycle time and altered DNA repair function. A better understanding of the molecular targets for anticancer drugs and the various drug-resistance mechanisms may help us to discover and tailor new drugs for particular drug-resistant tumors.