1.
Tamoxifen paradoxically decreases paclitaxel deposition into cerebrospinal fluid of brain tumor patients.
Chen, J, Balmaceda, C, Bruce, JN, Sisti, MB, Huang, M, Cheung, YK, McKhann, GM, Goodman, RR, Fine, RL
Journal of neuro-oncology. 2006;(1):85-92
Abstract
BACKGROUND P-glycoprotein (Pgp) mediates, in part, resistance to natural product chemotherapy drugs which constitute over half of the available drugs for cancer treatment. Tamoxifen (TAM) enhances intracellular deposition of natural product chemotherapy in human cell lines by inhibition of Pgp. Pgp is highly expressed in the choroid plexus and is thought to be a key component of the blood-cerebrospinal fluid barrier (BCSFB). We conducted a prospective, randomized study to assess if Pgp inhibition by TAM alters deposition of paclitaxel in cerebrospinal fluid (CSF). METHODS Ten patients with either primary or metastatic brain tumors were randomized to: paclitaxel alone (175 mg/m2/IV) or a course of TAM (160 mg/m2 PO BID on Days 1-5) followed by paclitaxel (175 mg/m2/IV on Day 5). CSF and plasma samples were obtained following paclitaxel infusion; paclitaxel and TAM concentrations were measured by high-performance liquid chromatography assays. RESULTS Paclitaxel was detected in the CSF of six of the 10 patients. Peak CSF paclitaxel concentrations of the paclitaxel and paclitaxel-TAM groups ranged between 3.5-57.4 and 2.3-24.6 nM, respectively. Though there was a 2.4-fold higher mean CSF paclitaxel concentration and a 3.7-fold higher median peak CSF:plasma paclitaxel ratio for those who received paclitaxel alone as compared to combined paclitaxel-TAM, it was not statistically significant (P = 0.22). In one patient enrolled to both arms, higher CSF concentrations of paclitaxel and higher paclitaxel CSF: plasma ratios were observed when given paclitaxel alone. CONCLUSIONS The trend towards lower paclitaxel CSF concentrations when given with TAM is consistent with the published finding that Pgp's localization in the endothelial cells of the choroid plexus works in an opposite direction and keeps drugs in the CSF. Thus, agents which inhibit Pgp, such as TAM, may increase efflux of Pgp substrates out of the BCSFB and may paradoxically lower CSF concentrations of natural product chemotherapy drugs. Conceptually, this finding implies that the Pgp in the BBB and BCSFB keeps natural toxins such as paclitaxel, from entering the brain (BBB) and, if they do enter the brain, keeps them in the CSF (BCSFB) where they may be less harmful than if they re-entered the brain. Thus, our work supports this novel idea and adds to the understanding of the functions of the BCSFB.
2.
Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: implications for the treatment of metastatic brain tumors.
Fine, RL, Chen, J, Balmaceda, C, Bruce, JN, Huang, M, Desai, M, Sisti, MB, McKhann, GM, Goodman, RR, Bertino, JS, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;(19):5770-6
Abstract
PURPOSE Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. EXPERIMENTAL DESIGN Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m(2)/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. RESULTS Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. CONCLUSIONS Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.