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

Abstract

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 coadministration of HM30181A and paclitaxel can be used to treat tumors in the brain.

Valproic Acid Induced Differentiation and Potentiated Efficacy of Taxol and Nanotaxol for Controlling Growth of Human Glioblastoma LN18 and T98G Cells

“…Our study is in agreement with the previous reports that demonstrate Elacridar [35] and Valspodar [10], the strong inhibitors of P-gp, are highly effective in increasing the delivery of TX across the BBB and significantly reducing tumor volume in glioblastoma xenografts. Recently, an oral combination therapy using the P-gp inhibitor HM30181A and TX significantly regressed tumor volume by inhibiting TX efflux in animal model of glioblastoma [11], thereby lending support to the possibility of either VPA ? TX or VPA ?…”

“…Besides, the commercial formulation of 6 mg/ml (7 mM) TX in 1:1 mixture of the solvents Cremophor EL Ò (CrEL, polyoxyethylated castor oil) and ethanol has systemic toxicity, side effects, and short time stability, and is associated with hypersensitivity reactions [8]. TX is a substrate for the P-gp [9] and co-administration of the P-gp inhibitor PSC833 [10] or HM30181A [11] with TX has shown significant therapeutic efficacy in brain tumor.…”

Breast Cancer Resistance Protein and P-Glycoprotein in Brain Cancer: Two Gatekeepers Team Up

“…It has now been shown that elacridar and tariquidar are not P-gp-specific inhibitors, but at higher concentrations also inhibit BCRP [41–43]. A recent study also demonstrated that oral, bi-weekly co-administration of the new P-gp inhibitor HM30181A with paclitaxel decreased tumor volume of K1735 melanoma brain metastases and U-87 MG glioblastoma in cancer animal models [44]. …”

Preclinical approaches to study the biology and treatment of brain metastases

“…Another methodology aimed at increasing permeability of chemotherapeutic agents across the CNS, and which has shown promise in the preclinical setting, is inhibition of BBB efflux transporters such as P-glycoprotein (P-gp) [69,70]. Unfortunately, P-gp inhibitors also target the drug metabolizing cytochrome P4503A (CYP3A) leading to alterations in clearance of chemotherapeutic drugs and increased toxicity [69,71]; a limitation that will have to be addressed before continuing with clinical assessment of this approach, if it is used at all.…”

“…Unfortunately, P-gp inhibitors also target the drug metabolizing cytochrome P4503A (CYP3A) leading to alterations in clearance of chemotherapeutic drugs and increased toxicity [69,71]; a limitation that will have to be addressed before continuing with clinical assessment of this approach, if it is used at all. Similar preclinical successes have been observed by inducing disruption of BBB by means of hypotonic solutions such as mannitol [72].…”