A Novel Class of Antitumor Prodrug, 1‐(2′‐Oxopropyl)‐5‐fluorouracil (OFU001), That Releases 5‐Fluorouracil upon Hypoxic Irradiation
A Novel Class of Antitumor Prodrug, 1‐(2′‐Oxopropyl)‐5‐fluorouracil (OFU001), That Releases 5‐Fluorouracil upon Hypoxic Irradiation
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一类新型抗肿瘤前药 1-(2′-氧代丙基)-5-氟尿嘧啶 (OFU001)，在低氧照射下释放 5-氟尿嘧啶
DOI：
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发表时间：
2000
期刊：
影响因子：
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通讯作者：
S. Nishimoto
中科院分区：
文献类型：
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作者：
Y. Shibamoto;Ling Zhou;H. Hatta;M. Mori;S. Nishimoto
我们一直在开发抗癌药物的前药，如5-氟尿嘧啶（5-FU），其在缺氧条件下通过单电子还原被辐射激活。其中，OFU 001 [1-（2′-氧代丙基）-5-氟尿嘧啶]是一种原型辐射活化前药。在这项研究中，我们研究了OFU 001的辐射化学反应性和生物效应。推测该前药通过将水合电子掺入C（1′）-N（1）键的反键σ* 轨道释放5-FU。水合电子是来自水辐解的活性物质，但在有氧辐照条件下，很容易被O2灭活为超氧阴离子自由基（）。因此，在低氧条件下照射后，5-FU释放高度特异性地发生。溶解在磷酸盐缓冲液中的OFU 001在低氧照射后释放5-FU，G-值（吸收1 J辐射能量分解或产生的分子摩尔数）为1.9×10−7 mol/ J，而在有氧照射后释放5-FU的G-值为1.0×10−8 mol/J。然而，OFU 001分解的G值几乎相同，即，低氧照射后为3.4×10−7 mol/J，有氧照射后为2.5×10−7 mol/J。当低氧照射（7.5-30戈伊）OFU 001加入到鼠SCCVII细胞中1-24 h时，观察到显著的细胞杀伤作用。这种细胞毒性的程度与相应浓度的真实5-FU一致。另一方面，细胞毒性是最小的，当细胞用有氧照射或未照射的OFU 001处理。该化合物对SCCVII细胞在有氧或缺氧条件下没有放射增敏作用，当药物在照射后立即除去时。由于缺氧通常在肿瘤中最显著，并且在肿瘤部位施加辐射，因此前药设计的这种概念似乎对选择性肿瘤治疗具有潜在的有用性，并且抗癌剂的副作用最小。
We have been developing prodrugs of anticancer agents such as 5‐fluorouracil (5‐FU) that are activated by irradiation under hypoxic conditions via one‐electron reduction. Among them, OFU001 [1‐(2′‐oxopropyl)‐5‐fluorouracil] is a prototype radiation‐activated prodrug. In this study, we investigated the radiation chemical reactivity and the biological effects of OFU001. This prodrug is presumed to release 5‐FU through incorporation of hydrated electrons into the antibonding σ* orbital of the C(1′)‐N(1) bond. Hydrated electrons are active species derived from radiolysis of water, but are readily deactivated by O2 into superoxide anion radicals () under conditions of aerobic irradiation. Therefore, 5‐FU release occurs highly specifically upon irradiation under hypoxic conditions. OFU001 dissolved in phosphate buffer released 5‐FU with a G‐value (mol number of molecules that are decomposed or produced by 1 J of absorbed radiation energy) of 1.9×10−7 mol/ J following hypoxic irradiation, while the G‐value for 5‐FU release was 1.0×10−8 mol/J following aerobic irradiation. However, the G‐values for decomposition of OFU001 were almost the same, i.e., 3.4×10−7 mol/J following hypoxic irradiation and 2.5×10−7 mol/J following aerobic irradiation. When hypoxically irradiated (7.5–30 Gy) OFU001 was added to murine SCCVII cells for 1–24 h, a significant cell‐killing effect was observed. The degree of this cytotoxicity was consistent with that of authentic 5‐FU at the corresponding concentrations. On the other hand, cytotoxicity was minimal when the cells were treated with aerobically irradiated or unirradiated OFU001. This compound had no radiosensitizing effect against SCCVII cells under either aerobic or hypoxic conditions when the drug was removed immediately after irradiation. Since hypoxia is generally most marked in tumors and irradiation is applied at the tumor site, this concept of prodrug design appears to be potentially useful for selective tumor treatment with minimal adverse effects of anticancer agents.
P450 依赖性异环磷酰胺药代动力学的调节：更好地了解体内药物激活。
影响因子：
8.8
作者：
Brain,EG;Yu,LJ;Gustafsson,K;Drewes,P;Waxman,DJ
通讯作者：
Waxman,DJ
5-碘-2-嘧啶酮-2-脱氧核糖作为小鼠和人体组织中 5-碘-2-脱氧尿苷介导的放射增敏前药的临床前评估。
DOI：
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发表时间：
1998
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
Kinsella,TJ;Kunugi,KA;Vielhuber,KA;Potter,DM;Fitzsimmons,ME;Collins,JM
通讯作者：
Collins,JM