CLINICAL-TRIALS OF WR-2721 PRIOR TO ALKYLATING AGENT CHEMOTHERAPY AND RADIOTHERAPY
CLINICAL-TRIALS OF WR-2721 PRIOR TO ALKYLATING AGENT CHEMOTHERAPY AND RADIOTHERAPY
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DOI：
10.1016/0163-7258(88)90032-0
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发表时间：
1988-01-01
影响因子：
13.5
通讯作者：
GLICK, JH
中科院分区：
文献类型：
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作者：
GLOVER, D;FOX, KR;GLICK, JH
在动物模型中，S-2（3-氨基丙基氨基）乙基硫代酸（WR-2721，硫代磷）选择性地保护正常组织免受辐射和烷基化剂化疗的细胞毒性。辐射和烷基化剂造成的损伤是由自由基及其副产物介导的。氧和其他电子亲和化合物的存在增加了辐射或烷基化剂造成的损害。消耗细胞内的化合物：非蛋白巯基，主要是谷胱甘肽，增加辐射敏感性（Bump et al., 1982; Mitchell et al., 1988）。据推测，巯基化合物通过清除自由基、与氧竞争和促进受损大分子的修复来保护细胞。WR-2721是所测试的1000多种巯基放射性防护剂中最有效和毒性最小的一种。Yuhas和stover（1969）首次报道WR-2721可分别以2.4和2.7倍增加小鼠皮肤和骨髓的抗辐射能力，但不增加小鼠乳腺实体瘤的抗辐射能力。从那时起，该药物的数据已经扩展到包括5个额外的物种，11个额外的正常组织和16个额外的移植或自发肿瘤（Yuhas, 1980; Washburn et al., 1974）。虽然WR-2721对一些实验性肿瘤具有非选择性的保护作用（Harris and Phillips, 1971; Stewart et al., 1983），但对正常组织的差异性保护作用导致对大多数实验性肿瘤几乎没有保护作用（Yuhas and stower, 1969; Phillips et al., 1973; Yuhas, 1983）。除了WR-2721在全身给药时不能保护大脑（Wasburn et al., 1976）或脊髓（Yuhas, 1980）外，WR-2721可以提高实体瘤放疗有效性的基本建议仍然是完整的。WR-2721的选择保护机制尚未完全阐明，但可能与正常组织和恶性组织对WR-2721的不同吸收有关。WR-2721很容易通过促进扩散的过程在大多数正常组织中集中，而大多数实体肿瘤通过被动吸收吸收少量药物（Yuhas, 1980）。Yuhas等人（1982）也证明了药物亲水性是WR-2721在正常组织中选择性吸收的一个主要因素。在动物模型中，WR-2721选择性地保护正常组织免受顺铂、环磷酰胺、氮芥和l -苯丙氨酸芥的细胞毒性（Yuhas and Culo, 1980; Yuhas et al., 1980; Wasserman et al., 1981）。WR-2721改善肾脏对顺铂的耐受性的因子为1.3-1.7 （Yuhas和Culo， 1980）。骨髓对环磷酰胺和氮芥的耐受性分别提高1.5-2和2-4倍。因此，将WR-2721与烷基化剂化疗或放疗相结合，理论上应该允许施用明显更高的剂量，导致更大的肿瘤细胞杀伤，并具有降低宿主毒性的优势。
In the animal model, S-2 (3-aminopropylamino) ethylphosphorothioic acid (WR-2721, ethiofos) selectively protects normal tissues against the cytotoxicities of radiation and alkylating agent chemotherapy. Damage produced by radiation and alkylating agents is mediated by free radicals and their by-products. The presence of oxygen and other electron-affinic compounds increases the damage produced by radiation or alkylating agents. Compounds that deplete intracellular: nonprotein sulfhydryls, predominantly glutathione, increase radiosensitivity (Bump et al., 1982; Mitchell et al., 1988). It is postulated that sulfhydryl compounds protect by scavenging free radicals, competing with oxygen, and promoting repair of damaged macromolecules. WR-2721 was one of the most effective and least toxic of over 1000 sulfhydryl radioprotectors tested. Yuhas and Storer (1969) first reported that WR-2721 could increase the radiation resistance of murine skin and bone marrow by factors of 2.4 and 2.7, respectively without increasing the radiation resistance of the solid mammary tumors borne by those animals. Since that time, data on this drug have been expanded to include five additional species, 11 additional normal tissues, and 16 additional transplanted or spontaneous tumors (Yuhas, 1980; Washburn et al., 1974). Although WR-2721 nonselectively protects some experimental tumors (Harris and Phillips, 1971; Stewart et al., 1983), differential protection in favor of normal tissues has resulted in E: tle or no protection of the majority of experimental tumors (Yuhas and Storer, 1969; Phillips et al., 1973; Yuhas, 1983). Except that WR-2721 does not protect the brain (Wasburn et al., 1976) or the spinal cord (Yuhas, 1980) when administered systemically, the basic proposal that WR-2721 can improve the effectiveness of solid tumor radiotherapy remains intact. The mechanism of selection protection of WR-2721 has not been fully elucidated, but it appears to be related to the differential absorption of WR-2721 by normal and malignant tissues. WR-2721 is readily concentrated in most normal tissues by a process of facilitated diffusion, whereas most solid tumors absorb minimal amounts of the drug by passive absorption (Yuhas, 1980). Yuhas et al.(1982) also demonstrated that drug hydrophilicity is a major factor underlying the ability of WR-2721 to be selectively absorbed in normal tissues. In animal models, WR-2721 selectively protects normal tissues against the cytotoxicities of cis-platinum, cyclophosphamide, nitrogen mustard, and L-phenylalanine mustard (Yuhas and Culo, 1980; Yuhas et al., 1980; Wasserman et al., 1981). WR-2721 improves renal tolerance to cis-platinum by factors of 1.3-1.7 (Yuhas and Culo, 1980). Bone marrow tolerance to cyclophosphamide and nitrogen mustard are improved by factors of 1.5-2 and 2-4, respectively. Thus, combining WR-2721 with alkylating agent chemotherapy or radiotherapy should theoretically permit the administration of significantly higher doses, leading to greater fractional tumor cell kill with the advantage of decreased host toxicity.