Intracerebral microinfusion (ICM) 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 homogeneous distribution of the infused agent.
Temozolomide is a novel methylating agent with proven efficacy against
malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic
drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with
temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with
temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats 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 challenge still resulted in a 23% increase in median survival in rats treated by ICM of
temozolomide compared with rats treated with i.p.
temozolomide. In addition, overall, 21.7% of rats treated by ICM with
temozolomide survived for > 100 days without clinical or histological evidence of
tumor. The dose of
temozolomide delivered by ICM in this study was limited only by
drug solubility, and no neurological or systemic toxicity could be attributed to ICM with
temozolomide. Therefore, ICM of
temozolomide may offer significant advantages in the treatment of MGs.