Liver Radioprotection by Systemic of Regional Amifostine

描述（由申请人提供）：虽然高剂量三维计划放射治疗可以改善局灶性肝内癌患者的局部控制，并可能改善生存，但许多患者具有弥漫性疾病。氨磷汀在随机试验中显示可以保护腮腺、肺和食道免受辐射。我们建议优化氨磷汀作为正常肝脏辐射保护剂的使用，这将允许对局灶性和弥漫性疾病患者安全提供更高剂量的辐射。在Specific Aim 1中，我们将对弥漫性肝内癌患者进行系统性氨磷汀剂量递增放射治疗的I期试验。我们的临床前数据表明，全身给药氨磷汀在正常肝脏中比在肝内肿瘤中产生更多的WR-1065，这导致肝脏（而不是肿瘤）的放射保护。因此，我们假设全身氨磷汀将允许正常肝脏有意义的选择性保护，允许辐射剂量增加。在Specific Aim 2中，我们将进行临床前研究以优化选择性（Aim 2A）并估计合适的局部氨磷汀剂量（Aim 2B）。我们的初步数据表明，系统氨磷汀和门静脉氨磷汀都能保护正常肝脏而不保护肿瘤，门静脉氨磷汀产生的活性代谢物WR-1065的正常组织/肿瘤比率明显高于系统氨磷汀。我们假设局部氨磷汀在产生更高的肝肿瘤比WR-1065方面优于全身氨磷汀，对正常肝脏的选择性保护优于肿瘤。在Specific Aim 3中，我们将对弥漫性肝内癌患者进行区域性氨磷汀剂量递增放射治疗的I期试验。我们假设，与全身给药相比，局部给药氨磷汀对正常肝脏的保护作用更大（或同等），而全身毒性相同（或更小）。我们的初步数据、研究团队和将临床前研究结果转化为临床的记录表明，该建议可能会改善弥漫性肝内癌患者的治疗结果。

DESCRIPTION (provided by applicant): Although high dose three dimensionally planned radiation therapy improves local control and, possibly, survival for patients with focal intrahepatic cancers, many patients have diffuse disease. Amifostine has been shown in randomized trials to protect the parotid gland, lung, and esophagus from radiation. We propose to optimize the use of amifostine as a radiation protector of normal liver, which will permit the safe delivery of higher doses of radiation for patients with both focal and diffuse disease. In Specific Aim 1 we will conduct a phase I trial of dose escalating radiation therapy with systemic amifostine for patients with diffuse intrahepatic cancer. Our preclinical data demonstrate that systemic administration of amifostine produces more WR-1065 in the normal liver than in intrahepatic tumor, and that this leads to radioprotection of the liver (and not the tumor). Therefore, we hypothesize that systemic amifostine will permit meaningful selective protection of the normal liver, permitting radiation dose escalation. In Specific Aim 2 we will carry out preclinical studies to optimize selectivity (Aim 2A) and estimate the appropriate dose of regional amifostine (Aim 2B). Our preliminary data demonstrate that both systemic and portal venous amifostine protect normal liver without protecting tumor, and that portal venous amifostine produces significantly higher normal tissue/tumor ratios of the active metabolite WR-1065 than systemic amifostine. We hypothesize that regional amifostine will be superior to systemic amifostine in producing a higher liver to tumor ratio of WR-1065, causing greater selective protection of normal liver compared to tumor. In Specific Aim 3 we will conduct a phase I trial of dose escalating radiation therapy with regional amifostine for patients with diffuse intrahepatic cancer. We hypothesize that regional administration of amifostine will permit greater (or equal) protection of normal liver than is possible by systemic administration, with equal (or less) systemic toxicity. Our preliminary data, research team, and record for translating preclinical findings to the clinic suggest that this proposal is likely to improve the outcome of treatment of patients with diffuse intrahepatic cancer.