Intracerebral chemotherapy: chronic microinfusion of cisplatin

Cisplatin, a chemotherapeutic agent used to treat tumors in many parts of the body, does not reach brain tissue during systemic injection because of the blood-brain barrier and protein binding in the blood. To allow hydrophilic drugs, such as cisplatin, to reach brain neoplasms with minimal body toxicity, we tested chronic intracerebral microperfusion into the extracellular space of the brain in normal rats. Small stainless steel cannulas connected to osmotic minipumps were stereotactically placed in the midline cerebellum or frontal cortex, and cisplatin was pumped into the brain at the rate of 0.9 microgram/hour for periods of up to 7 days. Brain tissue was then analyzed for the total platinum content, at 1-mm intervals from the cannula tip, using atomic absorption spectroscopy. The results of the animal studies show that a platinum concentration of 2 ng/mg of tissue, wet weight, can be maintained over a 1-cm region of brain. If all of the extracellular platinum has remained in the active cisplatin form, then this would be equivalent to a drug concentration of 10 microM. Cisplatin at this constant level has been shown to have a therapeutic effect against various tumor lines in vitro. To extend these results to human brain neoplasms, we estimate that one cannula would be sufficient to treat a 1-cm tumor or a larger tumor that could be surgically reduced. For inoperable tumors of up to 2 cm in diameter, a multiple cannula system would be required to yield the 10 microM concentration throughout. For larger inoperable tumors, local infusion will not produce high enough drug levels. In conclusion, chronic intracerebral microinfusion can be used to produce adequate and sustained therapeutic drug levels over a considerable region of tissue without the problem of systemic toxicity.