Toxicity associated with boronophenylalanine and cranial neutron irradiation

Abstract

AbstractBoron neutron capture therapy (BNCT) involves administration of a tumor selective boron compound followed by neutron irradiation directed at the target organ. Several studies have shown antitumor activity in animal models with BNCT using the amino acid analog boronophenylalanine (BPA). This study investigates the pharmacological toxicity of BPA in rabbits and the acute (14 days) and subacute (100 days) radiotoxicity of cranial BNCT with BPA in normal mice. To assess the toxicity of BPA alone the drug was administered orally in either a single dose of 5,000 mg/kg or 5 divided doses of 1,000 mg/kg/day to rabbits which were subsequently sacrificed at 2.5 or 4.5 weeks. To study the radiotoxic effects of BNCT mice were given BPA orally followed by cranial irradiation with a thermal neutron beam 3 hr later, with resulting brain doses ranging from 1,100 to 2,750 cGy‐Eq [compound‐relative biological effectiveness (C‐RBE) of 1.3 for 10B, 3.2 for neutrons, and 1.0 for gammas]. Mice were sacrificed 14 or 100 days after irradiation to study acute and subacute radiation toxicity, respectively. BPA alone demonstrated no discernible toxicity at the doses and schedules administered. BNCT resulted in a dose‐independent acute dilatation of the cerebral ventricles and mild cerebral atrophy. No neurologic deterioration could be detected in animals exposed to 2,200 cGy‐Eq or lower but acute clinical morbidity was evident at 2,750 cGy‐Eq, possibly related to non‐neural toxicity. Mice exposed to a dose of 2,750 cGy‐Eq to the brain also presented with moderately severe gastrointestinal toxicity consisting of epithelial hyperplasia or atrophy and necrosis. Animals exposed to lower doses showed no significant gastrointestinal radiotoxicity. All animals sacrificed at 100 days that received 2,200 cGy‐Eq developed bilateral posterior subcapsular cataracts. Lower doses had a minimal ocular toxic effect. It is concluded that there was no discernible toxicity from BPA administration at daily doses 10 times higher than those required for proposed therapeutic applications. Single‐fraction BNCT irradiations to the head showed significant ocular toxicity with a threshold between 1,650 and 2,200 cGy‐Eq; gastrointestinal toxicity with a threshold between 2,200 and 2,750 cGy‐Eq; and neural toxicity with a threshold ≦l,100 cGy‐Eq for histopathologic lesions. © 1995 Wiley‐Liss, Inc.