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Abstract：
Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.
摘要：
不可切除的胰腺癌几乎普遍致命，因为化疗和放疗不能完全阻止癌症的生长。在无法切除的疾病中使用放射来近似手术的主要问题是消融胰腺癌所需的放射剂量超过了附近十二指肠的耐受性。WR-2721又称氨磷汀,是一个著名的防辐射装置,但全身给药时具有显著的临床毒性。WR-2721是一种前药，被转化为其活性代谢物，WR-1065，在正常组织中通过碱性磷酸酶。小肠富含这些活化酶，因此，我们推断，在辐射之前口服WR-2721会导致在小肠中局部产生辐射防护WR-1065，提供保护性益处而没有明显的全身副作用。这里,我们表明口服WR-2721在促进病态照射后肠道隐窝克隆原的存活方面与腹膜内WR-2721一样有效。此外，口服WR-2721在12.5Gy×5分的致命上腹部照射后赋予完全的辐射防护和存活（总计62.5Gy，EQD2=140.6Gy)。这种放射防护能够在胰腺癌小鼠模型中进行消融放射治疗，与对照组相比，中位生存期几乎增加了三倍。我们发现口服WR-2721的功效源于其在肠道中的选择性积累，但不是在肿瘤或其他正常组织中，通过体内质谱分析确定。因此，我们证明口服WR-2721是一种耐受性良好的药物，和定量选择性，肠道的放射防护剂，能够使临床相关的上腹部放射剂量无不可接受的胃肠道毒性。
