Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats

Intracerebral microinfusion (TCM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homoge neous distribution of the infused agent, Temozolomide is a novel methylatin g agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely me tastasize, systemic drug delivery is unnecessary. Therefore, we evaluated t he efficacy and toxicity of ICM with temozolomide in an athymic rat model o f human MGs, Treatment of rats by ICM with temozolomide 3 days after intrac erebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with r ats treated with i,p, saline, and by 100% compared with rats treated with i ,p, temozolomide (P < 0,001), Delay of treatment until 9 days after tumor c hallenge still resulted in a 23% increase in median survival in rats treate d by ICM of temozolomide compared with rats treated with i,p, temozolomide, In addition, overall, 21.7% of rats treated by ICM with temozolomide survi ved for >100 days without clinical or histological evidence of tumor. The d ose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed t o ICM with temozolomide, Therefore, ICM of temozolomide may offer significa nt advantages in the treatment of MGs.