Selective radioprotection of hepatocytes by systemic and portal vein infusions of amifostine in a rat liver tumor model.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Symon
Z
Z
Department of Radiation Oncology, College of Medicine-College of Pharmacy, University of Michigan, Ann Arbor 48109-0010, USA. symonz@umich.edu
Levi
M
M
Ensminger
W D
WD
Smith
D E
DE
Lawrence
T S
TS
D004999:Amifostine / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D022781:Hepatocytes / Q000187:drug effects* / Q000528:radiation effects*; D007262:Infusions, Intravenous; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D008624:Mercaptoethylamines / Q000008:administration & dosage / Q000378:metabolism; D015162:Micronucleus Tests; D011169:Portal Vein; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine