TOXICITY, BIODISTRIBUTION AND RADIOPROTECTIVE CAPACITY OF L-HOMOCYSTEINE THIOLACTONE IN CNS TISSUES AND TUMORS IN RODENTS - COMPARISON WITHPRIOR RESULTS WITH PHOSPHOROTHIOATES

L-Homocysteine thiolactone (L-HCTL) was evaluated for its potential as an intravenously-administered central nervous system (CNS) radioprote ctor in C3H mice and F344 rats. Toxicity assessments in the mouse yiel ded a LD(50) of 297 mg/kg and in the rat 389 mg/kg. Biodistribution st udies in tumor-bearing mice showed that brain specimens contained more label at 10 min than the tumors but less at 30 or 60 min. Brain uptak e relative to the tumors, the brain/tumor ratio, ranged between 0.5 an d 3.3. The cervical spinal cord of non-tumor-bearing rats was irradiat ed with 32 Gy Cs-137 With or without prior treatment with L-HCTL follo wing which the time to forelimb or hindlimb paralysis was measured to determine the relative protective factors (RPFs) for this radiation do se. For forelimb paralysis the RPF was 1.9 (+/- 1.0, SD) and for hindl imb it was 2.0 (+/- 1.1, SD). 36B-10 glioma cells irradiated in vitro with or without L-HCTL and assayed for colony forming capacity demonst rated a dose modifying factor (DMF) of only 1.15 (+/- 0.16, SE). Rats bearing intracerebral 36B-10 glioma received Cs-137 irradiation with o r without L-HCTL after which the tumors were similarly assayed in vitr o. From this the glioma DMF was 1.2 (+/- 0.30, SE). Compared to prior results with phosphorothioates our data show that the toxicity of L-HC TL is roughly the same as WR2721, WR77913 and WR3689 and that it distr ibutes at higher levels in the CNS after systemic administration. L-HC TL may well equal these phosphorothioates at protecting normal CNS tis sue without requiring administration directly into the cerebrospinal f luid-containing spaces and it does not protect the 36B-10 glioma.