title: Tamoxifen paradoxically decreases paclitaxel deposition into cerebrospinal fluid of brain tumor patients.
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.
authors.affiliation: Experimental Therapeutics Program, Division of Medical Oncology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Johnson
authors.initials: J
authors.lastname: Chen
authors.forename: Casilda
authors.initials: C
authors.lastname: Balmaceda
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sisti
authors.forename: May
authors.initials: M
authors.lastname: Huang
authors.forename: Ying Kuen K
authors.initials: YK
authors.lastname: Cheung
authors.forename: Guy M
authors.initials: GM
authors.lastname: McKhann
authors.forename: Robert R
authors.initials: RR
authors.lastname: Goodman
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fine
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000134:cerebrospinal fluid*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000134:cerebrospinal fluid*; D011446:Prospective Studies; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D013629:Tamoxifen; D017239:Paclitaxel