The Synergistic Effects of Combined Hyperthermia and a Nitrosourea in Treatment of a Murine Ependymoblastoma: Some Possible Mechanisms Involved

The effectiveness of heat therapy in combination with 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) on a murine ependymoblastoma was investigated. Based on survival time and the number of survivors, whole-body hyperthermia (40°C) increased the therapeutic effectiveness of CCNU. Heat alone did not modify the course of the tumor. Microscopic evidence of accelerated tumor destruction in hyperthermic mice was apparent within 24 hours of drug administration. A temporary decrease in body weight was observed with hyperthermia at the higher dose levels of drug. Further investigation determined that heat therapy did not enhance the toxicity of CCNU. This was evident in rebound of animal weight loss and in the absence of drug-related deaths at therapeutic doses. Hyperthermia was found to markedly increase the peritoneal absorption of the ionic compound, cyclophosphamide, while exhibiting no comparable effect on the lipophilic compound, antipyrine. In contrast to the brain and spleen tissue levels of cyclophosphamide, levels in tumor tissue more accurately reflected the increase in plasma-drug levels with hyperthermia. There were no distinguishing differences in tissue uptake of antipyrine.