Bielicki L, Voelcker G, Hohorst H J
J Cancer Res Clin Oncol. 1983;105(1):27-9. doi: 10.1007/BF00391828.
3'-5' Exonucleases from various sources were found to toxicogenate 4-hydroxycyclophosphamide ("activated" cyclophosphamide) by splitting the oxazaphosphorinane ring and releasing an alkylating moiety and acrolein. Neither cyclophosphamide (CP) nor the deactivated metabolites of CP, 4-keto-CP and carboxyphosphamide nor 4-(S-ethanol)-sulfido-CP were attacked by 3'-5' exonucleases. DNA polymerases with proofreading activity, such as DNA polymerase I from E. coli or DNA polymerase delta from rabbit bone marrow, exhibited a tenfold higher specific activity with "activated" CP than "plain" 3'-5' phosphodiesterases such as snake venom phosphodiesterase or 3',5'cyclic AMP phosphodiesterase from bovine heart tissue. High levels of toxicogenating activity were estimated in peripheric human lymphocytes and tissues of lymphatic origin, suggesting that enzymatic toxicogenation plays a key role with respect to the cytotoxic specificity of "activated" CP.
研究发现，来自各种来源的3'-5'核酸外切酶可通过裂解氧氮磷杂环戊烷环并释放烷基化部分和丙烯醛，使4-羟基环磷酰胺（“活化”环磷酰胺）产生毒化作用。环磷酰胺（CP）及其失活代谢产物4-酮基-CP、羧基磷酰胺以及4-(S-乙醇)-硫代-CP均不会受到3'-5'核酸外切酶的作用。具有校对活性的DNA聚合酶，如大肠杆菌的DNA聚合酶I或兔骨髓的DNA聚合酶δ，对“活化”CP的比活性比对“普通”3'-5'磷酸二酯酶（如蛇毒磷酸二酯酶或牛心脏组织的3',5'-环磷酸腺苷磷酸二酯酶）高十倍。在人外周淋巴细胞和淋巴源性组织中检测到高水平的毒化活性，这表明酶促毒化作用在“活化”CP的细胞毒性特异性方面起着关键作用。
