Toxicity, biodistribution and radioprotective capacity of L-homocysteine thiolactone in CNS tissues and tumors in rodents: comparison with prior results with phosphorothioates.

Abstract

L-Homocysteine thiolactone (L-HCTL) was evaluated for its potential as an intravenously-administered central nervous system (CNS) radioprotector in C3H mice and F344 rats. Toxicity assessments in the mouse yielded a LD50 of 297 mg/kg and in the rat 389 mg/kg. Biodistribution studies 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 uptake relative to the tumors, the brain/tumor ratio, ranged between 0.5 and 3.3. The cervical spinal cord of non-tumor-bearing rats was irradiated with 32 Gy 137Cs with or without prior treatment with L-HCTL following which the time to forelimb or hindlimb paralysis was measured to determine the relative protective factors (RPFs) for this radiation dose. For forelimb paralysis the RPF was 1.9 (+/- 1.0, SD) and for hindlimb 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 demonstrated a dose modifying factor (DMF) of only 1.15 (+/- 0.16, SE). Rats bearing intracerebral 36B-10 glioma received 137Cs irradiation with or without L-HCTL after which the tumors were similarly assayed in vitro. 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-HCTL is roughly the same as WR2721, WR77913 and WR3689 and that it distributes at higher levels in the CNS after systemic administration. L-HCTL may well equal these phosphorothioates at protecting normal CNS tissue without requiring administration directly into the cerebrospinal fluid-containing spaces and it does not protect the 36B-10 glioma.

• Authors: A M Spence, J S Rasey, L Dwyer-Hansen, Z Grunbaum, J Livesey, L Chin, N Nelson, D Stein, K A Krohn, F Ali-Osman
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 35 Issue 3 Pg. 216-26 (Jun 1995) ISSN: 0167-8140 [Print] Ireland
• PMID: 7480825 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Radiation-Protective Agents
• Homocysteine
• S-2-(3-methylaminopropylamino)ethylphosphorothioic acid
• WR 77913
• homocysteine thiolactone
• Amifostine

Topics

• Amifostine (analogs & derivatives, toxicity)
• Animals
• Brain (metabolism, radiation effects)
• Brain Neoplasms (radiotherapy)
• Female
• Homocysteine (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)
• Male
• Mice
• Mice, Inbred C3H
• Radiation-Protective Agents (pharmacokinetics, pharmacology, toxicity)
• Rats
• Rats, Inbred F344
• Spinal Cord (radiation effects)
• Tissue Distribution
• Tumor Cells, Cultured (radiation effects)