CAN WR-2721 BE IMPROVED UPON
CAN WR-2721 BE IMPROVED UPON
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DOI：
10.1016/0163-7258(88)90057-5
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发表时间：
1988-01-01
影响因子：
13.5
通讯作者：
SHAW, LM
中科院分区：
文献类型：
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作者：
BROWN, DQ;GRAHAM, WJ;SHAW, LM
1.在1959年至1973年期间由美国陆军医学研究和发展司令部赞助的抗辐射药物开发计划合成和测试的4400种化合物中，发现S-2721（S-2（3-氨基丙基氨基）乙基硫代磷酸，乙硫磷）是最有效的化学辐射保护剂（Piper等人，1969; Davidson等人，1980; Sweeney，1979）。WR-2721作为化学辐射保护剂对小鼠造血和胃肠道（GI）死亡模式的有效性首先由Yuhas和Storer（1969 a）报道。这些研究者还报告称，与肿瘤（小鼠乳腺癌）相比，WR-2721对正常组织（造血组织、GI系统和皮肤）提供了高度选择性差异放射防护（Yuhas和Storer，1969 b）。在此后的几年中，WR-2721的辐射保护作用已在几个其他物种中得到证实：大鼠、豚鼠和猴（Yuhas，1980 b）、狗（Thrall等人，1980; Davidson等人，1980）和人（Tanaka和Sugahara，1980; Constine等，1986年）。已观察到WR-2721对许多其他组织和终点具有显著的放射保护作用（表1），但通常不适用于中枢神经系统（CNS）或大型实体瘤。从一个组织/器官到另一个组织/器官的辐射防护的这些大的变化主要与以下有关：（a）WR-2721的摄取，其例如在下颂腺中是大的（Rasey等人，1984），而在CNS和大多数实体瘤中较小（Washburn等，1974;乌特利和凯恩，1980; Rasey等人，1986年）。(b)根据辐射保护的竞争模型，组织和细胞P02水平过高（例如肺）或过低（例如肿瘤），无法与辐射保护剂进行有效竞争（Travis等人，1984; Chapman等人，1973年）。(c)碱性磷酸酶水平的组织特异性变化（Bourne，1943），其将WR-2721活化（即脱磷酸化）为活性巯基保护剂WR-1065 [2-（3-氨基丙基氨基）-乙硫醇]。对这一想法的支持来自WR-2721被碱性磷酸酶而不是酸性磷酸酶去磷酸化的证明（Shaw等人，1984; Calabro-Jones等人，1985;中村等人，1987年）。这与WR-2721对胃肠道、肝细胞、脉管系统和腮腺的实质性辐射保护（表1）以及培养物中细胞通常缺乏WR-2721摄取和辐射保护一致（Ritter等人，1982; Purdie，1979）。
1. BACKGROUNDWR-2721 (S-2 (3-aminopropylamino) ethylphosphorothioic acid, ethiofos) was found to be the most effective chemical radioprotector of 4400 compounds synthesized and tested by the Antiradiation Drug Development Program sponsored by the US Army Medical Research and Development Command over the period 1959 to 1973 (Piper et al., 1969; Davidson et al., 1980; Sweeney, 1979). The effectiveness of WR-2721 as a chemical radioprotector against the hematopoietic and gastrointestinal (GI) modes of death of mice was first reported by Yuhas and Storer (1969a). These investigators also reported that WR-2721 provided highly selective differential radioprotection of normal tissues (hematopoietic tissue, GI system and skin) in comparison with tumor (mouse mammary carcinoma)(Yuhas and Storer, 1969b). In the years since then, radioprotection by WR-2721 has been demonstrated in several additional species: rats, guinea pigs and monkeys (Yuhas, 1980b), dogs (Thrall et al., 1980; Davidson et al., 1980) and man (Tanaka and Sugahara, 1980; Constine et al., 1986). Substantial WR-2721 radioprotection has been observed for a number of additional tissues and endpoints (Table 1) but usually not for the central nervous system (CNS) or for large solid tumors. These large variations in radioprotection from one tissue/organ to another are related primarily to:(a) Uptake of WR-2721, which is, for example, large in submandibular glands (Rasey et al., 1984) and small in the CNS and in most solid tumors (Washburn et al., 1974; Utley and Kane, 1980; Rasey et al., 1986).(b) Tissue and cell P02 levels that are either too high (eg lung) or too low (eg tumors) to permit effective competition with a radioprotector according to the competition model of radioprotection (Travis et al., 1984; Chapman et al., 1973).(c) Tissue-specific variations in levels of alkaline phosphatase (Bourne, 1943), which activates (ie dephosphorylates) WR-2721 to the active sulfhydryl protector WR-1065 [2-(3-aminopropylamino)-ethanethiol]. Support for this idea comes from demonstrations that WR-2721 is dephosphorylated by alkaline phosphatase, not acid phosphatase (Shaw et al., 1984; Calabro-Jones et al., 1985; Nakamura et al., 1987). This is consistent with the substantial WR-2721 radioprotection of the GI tract, liver hcpatocytes, vasculature and parotid gland (Table 1) and the usual lack of WR-2721 uptake and radioprotection of cells in culture (Ritter et al., 1982; Purdie, 1979).