Symon Z, Levi M, Ensminger W D, Smith D E, Lawrence T S
Department of Radiation Oncology, College of Medicine-College of Pharmacy, University of Michigan, Ann Arbor 48109-0010, USA.
Int J Radiat Oncol Biol Phys. 2001 Jun 1;50(2):473-8. doi: 10.1016/s0360-3016(01)01522-x.
The tolerance of the liver to radiation is too low to permit an effective dose to be delivered to patients who have diffuse intrahepatic cancer. In this study we evaluated whether systemic or portal venous administration of the aminothiol compound, amifostine, could protect the normal liver from the effects of ionizing radiation without compromising tumor cell kill in a rat liver tumor model.
Rats implanted with liver tumors were infused with 200 mg/kg amifostine over 15 min via the femoral or portal vein. The livers were irradiated with a single 6-Gy fraction 15-20 min after the termination of amifostine infusion. Protection of the liver was assessed by an in vitro hepatocyte micronucleus assay and tumor protection by an in vivo-in vitro clonogenic survival assay. Tissue levels of the active metabolite, free WR-1065, were determined in the tumor and in the normal liver using a specific HPLC assay with electrochemical detection.
After a 6-Gy fraction, the frequency of hepatocyte micronuclei after administration of saline, systemic amifostine, and portal venous amifostine was 18.7+/-1%, 6.8+/-1%, and 9.9+/-2%, respectively, corresponding to a radiation equivalent effect of 6 Gy +/- 0.5, 1.8 Gy +/- 0.3, and 2.5 Gy +/- 1.3, respectively. Both amifostine conditions showed considerably less radiation effect than saline-treated controls (p < 0.01); the two amifostine conditions did not differ (p = 0.3). The surviving fraction of tumor cells was not affected by amifostine treatment and was 0.03+/-0.02 and 0.05+/-0.03 for systemic and portal venous delivery and 0.06+/-0.02 for control animals (ANOVA analysis showed no significant difference of the means p = 0.34). Portal venous delivery produced significantly less WR-1065 in the tumor compared to systemic administration (54 microM +/- 36 vs. 343 microM +/- 88, respectively, p = 0.03).
Both systemic and portal venous administration of amifostine effectively protect hepatocytes from ionizing radiation without compromising tumor cell kill in a clinically relevant animal model. These findings suggest that amifostine may be a selective normal tissue radioprotectant in liver cancer and that regional/portal infusions may be preferable to systemic dosing.
肝脏对辐射的耐受性过低，以至于无法向患有弥漫性肝癌的患者输送有效剂量的辐射。在本研究中，我们评估了在大鼠肝肿瘤模型中，全身或门静脉给予氨磷汀这种氨硫醇化合物，是否能在不影响肿瘤细胞杀伤的情况下，保护正常肝脏免受电离辐射的影响。
将植入肝肿瘤的大鼠通过股静脉或门静脉在15分钟内输注200mg/kg氨磷汀。在氨磷汀输注结束后15 - 20分钟，对肝脏进行单次6Gy的照射。通过体外肝细胞微核试验评估肝脏的保护情况，通过体内 - 体外克隆形成存活试验评估肿瘤的保护情况。使用具有电化学检测的特定高效液相色谱法测定肿瘤和正常肝脏中活性代谢物游离WR - 1065的组织水平。
给予6Gy照射后，给予生理盐水、全身氨磷汀和门静脉氨磷汀后肝细胞微核频率分别为18.7±1%、6.8±1%和9.9±2%，分别对应于等效辐射效应6Gy±0.5、1.8Gy±0.3和2.5Gy±1.3。两种氨磷汀给药情况均显示出比生理盐水处理的对照组明显更小的辐射效应（p < 0.01）；两种氨磷汀给药情况之间无差异（p = 0.3）。氨磷汀处理对肿瘤细胞的存活分数没有影响，全身给药和门静脉给药时肿瘤细胞存活分数分别为0.03±0.02和0.05±0.03，对照动物为0.06±0.02（方差分析显示均值无显著差异，p = 0.34）。与全身给药相比，门静脉给药在肿瘤中产生的WR - 1065明显更少（分别为54μM±36和343μM±88，p = 0.
