title: Taxol-oligoarginine conjugates overcome drug resistance in-vitro in human ovarian carcinoma.
abstract: OBJECTIVE
  Multidrug resistance is the major cause of failure of many chemotherapeutic agents. While resistance can arise from several factors, it is often dominated by drug efflux mediated by P-glycoprotein (P-gp), a membrane-bound polysubstrate export pump expressed at high levels in resistant cells. While co-administration of pump inhibitors and a drug could suppress efflux, this two-drug strategy has not yet advanced to therapy. We recently demonstrated that the reversible attachment of a guanidinium-rich molecular transporter, polyarginine, to a drug provides a conjugate that overcomes efflux-based resistance in cells and animals. This study is to determine whether this strategy for overcoming resistance is effective against human disease.
  
  
  METHODS
  Tumor samples from ovarian cancer patients, both malignant ascites cells and dissociated solid tumor cells, were exposed to Taxol-oligoarginine conjugates designed to release free drug only after cell entry. Cell viability was determined via propidium-iodide uptake by flow cytometry. To analyze bystander effect, toxicity of the drug conjugates was also tested on peripheral blood leucocytes.
  
  
  RESULTS
  Human ovarian carcinoma specimens resistant to Taxol in vitro demonstrated increased sensitivity to killing by all Taxol-transporter conjugates tested. These studies also show that the drug conjugates were not significantly more toxic to normal human peripheral blood leukocytes than Taxol.
  
  
  CONCLUSIONS
  These studies with human tumor indicate that oligoarginine conjugates of known drugs can be used to overcome the efflux-based resistance to the drug, providing a strategy that could improve the treatment outcomes of patients with efflux-based drug-resistance.
authors.affiliation: Department of Chemistry, Stanford University, CA 94305, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Galliher
authors.forename: Neelima M
authors.initials: NM
authors.lastname: Bhat
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Pillow
authors.forename: Marcia M
authors.initials: MM
authors.lastname: Bieber
authors.forename: Nelson N H
authors.initials: NN
authors.lastname: Teng
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D011355:Prodrugs; D001120:Arginine; D017239:Paclitaxel