Capizzi R L, Scheffler B J, Schein P S
U.S. Bioscience, West Conshohocken, Pennsylvania 19428.
Cancer. 1993 Dec 1;72(11 Suppl):3495-501. doi: 10.1002/1097-0142(19931201)72:11+<3495::aid-cncr2820721617>3.0.co;2-b.
Amifostine (US Bioscience, West Conshohocken, PA; Ethyol, WR-2721), a phosphorylated thiol developed by the United States Army as a protective agent for military personnel in the event of nuclear warfare, has shown protection of normal tissues from the cytotoxic effects of therapeutic radiation and chemotherapy with preservation of cytotoxic effects on the tumor. The basis of this selective protection derives from the relatively rapid uptake and anabolism of Amifostine into normal tissues and minimal, slower uptake into tumor tissue. Preclinical investigations have demonstrated protection of bone marrow stem cells from the toxic effects of radiation and chemotherapy. Several controlled clinical trials demonstrated this hematoprotective effect. In patients given 1.5 g/m2 cyclophosphamide and month later given Amifostine (740 mg/m2) followed by the same dose of cyclophosphamide, the median nadir neutrophil count was significantly increased and duration of neutropenia was significantly reduced by pretreatment with Amifostine. In women with stage III/IV ovarian cancer treated with 1 g/m2 cyclophosphamide and 100 mg/m2 cisplatin +/- Amifostine 910 mg/m2, treatment with Amifostine before cyclophosphamide and cisplatin resulted in a significant decrease in both the incidence and duration of hospital stays for neutropenic fever compared to cyclophosphamide and cisplatin alone. There were equivalent rates of response and duration of survival in both groups. Other studies have shown Amifostine protects bone marrow purged in vitro with 4-hydroperoxycyclophosphamide before autologous bone marrow transplantation. This preservation of marrow stem cells resulted in a statistically significant decrease in time to marrow engraftment, need for platelet transfusions and antibiotics, and duration of hospital stay. Amifostine-mediated protection of normal bone marrow illustrated in preclinical experiments is also evident in clinical trials. Amifostine preserves trilineage stem cells (red blood cells, platelets, and white blood cells) in contrast to the lineage-specific effects of the colony-stimulating factors. Theoretically, Amifostine and the colony-stimulating factors should provide complementary benefits to bone marrow recovery and function after cytotoxic therapies. These observations offer the promise of using high doses of chemotherapy to exploit antitumor, dose-response relationships in clinical trials.
氨磷汀（美国生物科学公司，宾夕法尼亚州韦斯特康舍霍肯；Ethyol，WR - 2721），一种由美国陆军研发的用于在核战争情况下保护军事人员的磷酸化硫醇，已显示出能保护正常组织免受治疗性放疗和化疗的细胞毒性作用，同时保留对肿瘤的细胞毒性作用。这种选择性保护的基础源于氨磷汀相对快速地被正常组织摄取和合成代谢，而进入肿瘤组织的摄取量极少且较慢。临床前研究已证明氨磷汀可保护骨髓干细胞免受放疗和化疗的毒性作用。多项对照临床试验证实了这种血液保护作用。在给予患者1.5 g/m²环磷酰胺，一个月后给予氨磷汀（740 mg/m²），随后再给予相同剂量环磷酰胺的试验中，氨磷汀预处理显著提高了中性粒细胞计数最低点的中位数，并显著缩短了中性粒细胞减少的持续时间。在接受1 g/m²环磷酰胺和100 mg/m²顺铂 +/ - 910 mg/m²氨磷汀治疗的III/IV期卵巢癌女性患者中，与单独使用环磷酰胺和顺铂相比，在环磷酰胺和顺铂之前使用氨磷汀治疗导致中性粒细胞减少性发热的住院发生率和住院时间均显著降低。两组的缓解率和生存期相当。其他研究表明，氨磷汀可保护在体外经4 - 氢过氧环磷酰胺净化的骨髓，用于自体骨髓移植。这种骨髓干细胞的保存导致骨髓植入时间、血小板输注和抗生素需求以及住院时间在统计学上显著减少。临床前实验中所阐述的氨磷汀介导的对正常骨髓的保护作用在临床试验中也很明显。与集落刺激因子的谱系特异性作用不同，氨磷汀可保留三系干细胞（红细胞、血小板和白细胞）。从理论上讲，氨磷汀和集落刺激因子应该为细胞毒性治疗后的骨髓恢复和功能提供互补的益处。这些观察结果为在临床试验中使用高剂量化疗来利用抗肿瘤剂量反应关系带来了希望。
