Irinotecan is an anticancer drug that was approved for use in 1996. It is a modified version of the plant alkaloid camptothecin, and even though it shows significant activity against brain tumors in culture, but in a living body, this drug poorly penetrates the blood-brain barrier. Therefore irinotecan usually does not accumulate to appreciable levels in the brain and is typically not used to treat brain tumors.
That could change, however, if a new strategy published in paper by Marianne Metz and her colleagues from the laboratory of Karen Aboody at the Beckman Research Institute at the City of Hope in Duarte, California, in collaboration with colleagues from several other laboratories.
In this paper, Metz and her co-workers genetically engineered neural stem cells to express enzymes called “carboxylesterases.” These carboxyesterase enzymes convert irinotecan, which is an inactive metabolite, to the active form, which is known as “SN-38.” The efficient conversion of irinotecan to SN-38 in the brain greatly accelerates the therapeutic activity of this drug in the brain. Also, the constant conversion of irinotecan to another molecule accelerates the transport of irinotecan past the blood brain barrier.
To test this strategy. Metz and others grew the engineered neural stem cells in culture and measured their ability to make carboxylesterases in culture, and their ability to convert irinotecan into SN-38 in culture. In both cases, the engineered neural stem cells made a boat-load of carboxylesterase and converted irinotecan into SN-38 in spades. More importantly, the genetically engineered neural stem cells behaved exactly as they did before, which shows that the genetic manipulation of these cells did not change their properties.
Next, Metz others tested the ability of the engineered neural stem cells to kill human brain tumor cells in culture in the presence of irinotecan. Once again, the genetically engineered neural stem cells effectively killed human brain tumor cells in culture in a irinotecan-concentration-dependent manner. When these genetically engineered neural stem cells were injected into the brains of mice with brain tumors, intravenous administration of irinotecan produced high levels of SN-38 in the brain. This shows that these cells have the capacity to increase the production of SN-38 in the brain.
This strategy is similar to other strategies that been used in various clinical trials, but because neural stem cells have a tendency to move into brain tumor tissue and surround it, they represent an efficient and effective way to deliver anticancer drugs to brain tumors. Also, since the particular neural stem cell line used in this experiment (HB1.F3.CD) does not cause tumors and is also not recognized as foreign by the immune system, it is a particularly attractive stem cell line for such an anti-tumor strategy.