title: Effects of orally active taxanes on P-glycoprotein modulation and colon and breast carcinoma drug resistance.
abstract: BACKGROUND
  The taxane paclitaxel (Taxol) is often of limited efficacy in chemotherapeutic regimens because some cancer cells express high levels of the efflux pump, P-glycoprotein (Pgp), which removes the drug from the cells. The orally active paclitaxel analog IDN-5109 has been reported to overcome Pgp-mediated drug resistance. We tested whether IDN-5109 acts by modulating Pgp activity.
  
  
  METHODS
  Human MDA435/LCC6mdr1 and MDA435/LCC6 breast carcinoma cells, which express and do not express Pgp, respectively, were incubated with [3H]IDN-5109 and paclitaxel to determine intracellular drug accumulation. Flow cytometry was used to analyze intracellular retention of two Pgp substrates, rhodamine 123 (Rh-123) and doxorubicin, in both breast carcinoma cell lines and in human colon carcinoma cells (SW-620, DLD1, and HCT-15, whose Pgp levels vary) treated with different taxanes. The effects of IDN-5109 and paclitaxel on tumor growth in vivo were studied with the use of tumors established through xenografts of Pgp-expressing SW-620 and DLD1 cells in severe combined immunodeficiency mice. All statistical tests were two-sided.
  
  
  RESULTS
  Pgp-expressing cells treated with IDN-5109 or with the taxane-based drug resistance reversal agent tRA96023, which blocks Pgp activity, retained 8.1- and 9.4-fold more Rh-123 (P =.0001), respectively, and 1.7- and 1.9-fold more doxorubicin (P =.001), respectively, than cells treated with paclitaxel. Non-Pgp-expressing cells treated similarly demonstrated no increased retention of either substrate. MDA435/LCC6mdr1 cells retained 5.3-fold more [3H]IDN-5109 than [3H]paclitaxel after 2 hours (P =.01). IDN-5109 showed statistically significantly higher tumor growth inhibition than paclitaxel against the SW-620 xenograft (P =.003).
  
  
  CONCLUSIONS
  IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Vredenburg
authors.forename: I
authors.initials: I
authors.lastname: Ojima
authors.forename: J
authors.initials: J
authors.lastname: Veith
authors.forename: P
authors.initials: P
authors.lastname: Pera
authors.forename: K
authors.initials: K
authors.lastname: Kee
authors.forename: F
authors.initials: F
authors.lastname: Cabral
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.forename: P
authors.initials: P
authors.lastname: Kanter
authors.forename: W R
authors.initials: WR
authors.lastname: Greco
authors.forename: R J
authors.initials: RJ
authors.lastname: Bernacki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D005453:Fluorescence; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D043823:Taxoids; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D043823:Taxoids; D004317:Doxorubicin; C404743:IDN 5109; D017239:Paclitaxel