Oral paclitaxel chemotherapy for brain tumors: Ideal combination treatment of paclitaxel and P-glycoprotein inhibitor

Abstract

Oral chemotherapy has many advantages over parenteral chemotherapeutics administration. To use the advantages of the oral chemotherapy and maximize anti-tumor effects of the chemotherapeutic agent, we designed HM30181A (a P-glycoprotein inhibitor) and a paclitaxel oral co-administration chemotherapeutic method. HM30181A is used to aid paclitaxel absorption from gut lumen into blood and to inhibit paclitaxel exclusion out of the brain tumor mass by endothelial cells, which inhibits paclitaxel access to tumor cells in the brain parenchyma. We applied HM30181A and paclitaxel oral co-administration methods to the treatment of tumors in the brain using the K1735 melanoma brain metastasis animal model and the U-87 MG glioblastoma animal model. Administrations were performed twice per week for 28 days and the therapeutic effect was examined using tumor volume change. We observed that 32 mg/kg HM30181A and 16 mg/kg of paclitaxel (dose ratio 2:1) oral co-administration showed significant therapeutic effects in both animal models, but when the doses or dose ratio was changed, the effects could not be observed. Therefore, adjustments of doses and dose ratio of the agents seems to be essential in realizing oral HM30181A and paclitaxel treatment in brain tumors. These results suggest that if the doses and dose ratio can be successfully adjusted, the oral co-administration of HM30181A and paclitaxel can be used to treat tumors in the brain.