Radioprotection of Normal Tissues against Gamma Rays and Cyclotron Neutrons with WR-2721: LD 50 Studies and 35 S-WR-2721 Biodistribution

Abstract

The ability of WR-2721 to protect mice against two modes of death following whole-body radiation with 137Cs gamma rays or d(22)+Be neutrons was examined. For single fractions, 400 mg/kg WR-2721 was administered prior to irradiation. In two-fraction exposures, the dose was 275 mg/kg given prior to each fraction. Dose modification factors (DMFs) were calculated as ratios of LD50 values. For single fractions of gamma rays, the DMF was 1.74 for the LD50/7 end point and for LD50/30, the DMF for single fractions was 2.25. For two fractions 3 hr apart, it was 1.88. For single fractions of cyclotron neutrons, the DMF was 1.32 for LD50/7. Measured with the LD50/30 end point, the DMF for single neutron doses was 1.41 and for two fractions, 1.19. Substantial radioprotection of bone marrow and intestinal epithelium against cyclotron neutrons was seen in these investigations. Biodistribution studies were done following ip injection of 35S-labeled WR-2721 into C3H mice bearing RIF-1 tumors. Blood levels peaked at 10 min after injection and declined thereafter. Most normal tissues achieved maximum levels of 35S at 30 to 60 min postinjection and high concentrations were retained in most tissues for up to 2 hr. Assuming that all 35S is in parent compound or dephosphorylated radioprotective metabolites, the concentration of protector (milligram per gram tissue) in various organs at 30 min postinjection ranked as follows: kidney greater than submandibular gland much greater than liver = lung greater than gut greater than heart much greater than blood greater than skin greater than tumor greater than brain. High levels of 35S were achieved and retention times were long in certain normal tissues which respond at early or late times postradiation and may be dose limiting in radiotherapy: kidney, liver, salivary gland, and lung. These combined observations suggest that there is potential for protecting dose-limiting, late-responding normal tissue in the radiotherapy of human cancer with both neutrons and conventional radiotherapy.

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

“…The capability of protecting late-responding normal tissues of clinical relevance against radiation damage is of great interest, and 35 S-labeled WR2721 biodistribution and blood clearance studies in C3H mice with RIF-1 tumors after intraperitoneal injection have been reported to identify the tissues and postinjection times that suggest a high level of radioprotection. Rasey et al (1984) reported that the concentration of protector (milligram per gram of tissue) in various organs at 30 minutes after injection ranked in the following order: kidney . liver 5 lung .…”

Inhibition of the Tumor Necrosis Factor-α Pathway Is Radioprotective for the Lung

“…Amifostine decreases radiation toxicity by scavenging free radicals produced immediately after radiation to the parotid gland (4,5). Its use is limited by its toxicity (36) and the requirement that it be administered at the time of radiation.…”

Antisense Oligonucleotide Inhibition of Tumor Necrosis Factor Receptor 1 Protects the Liver from Radiation-Induced Apoptosis

“…Ursodeoxycholic acid, an antithrombotic agent, has been shown to protect endothelial cells and hepatocytes by inhibiting TNF-a and interleukin-1a production, or by increasing glutathione, and thus inhibiting apoptosis (29). Amifostine (WR-2721) is another clinically investigated radioprotector which decreases radiation toxicity in the parotid gland, and, possibly, the lung and esophagus (30,31). We have previously reported that amifostine achieved a radiation dose modification factor of 2.4 to 3.3 in liver with minimal tumor protection (19), and a clinical trial has been initiated based on this concept.…”