title: Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea.
abstract: OBJECTIVE
  To investigate whether clinically relevant levels of epigallocatechin gallate (EGCG, a component of green tea) or vitamin C (ascorbic acid) could antagonize bortezomib antitumor activity in CWR22 human prostate xenograft tumors.
  
  
  METHODS
  The pharmacokinetics (PK) of EGCG and ascorbic acid were determined in immunocompromised mice and compared with concentrations measured in human PK studies of dietary supplements. Antitumor activity of bortezomib in combination with EGCG or ascorbic acid was determined using several dosing regimens to evaluate different target plasma concentrations of EGCG and ascorbic acid.
  
  
  RESULTS
  Bortezomib dosed twice-weekly at 0.8 mg/kg IV demonstrated tumor growth inhibition (TGI) of 53.9-58.9%. However, when combined with EGCG such that the plasma concentrations of EGCG were >200 μM at the time of bortezomib dosing, all antitumor activity was abrogated (TGI = -17.7%). A lower concentration of EGCG (11-16 μM), which is severalfold higher than measured clinically in humans taking EGCG supplements (0.6-3 μM), was not antagonistic to bortezomib (TGI 63.5%). Pharmacodynamic studies of proteasome inhibition reflected these findings. Ascorbic acid (40 and 500 mg/kg PO daily) was evaluated under a similar study design and did not antagonize bortezomib antitumor activity (TGI 57.2 and 72.2%).
  
  
  CONCLUSIONS
  No antagonism of bortezomib is seen in preclinical in vivo experiments, where EGCG or ascorbic acid plasma concentrations are commensurate with dietary or supplemental intake. The data suggest that patients receiving bortezomib treatment do not need to avoid normal dietary consumption of green tea, vitamin C-containing foods, or EGCG or vitamin C dietary supplements.
authors.affiliation: Millennium Pharmaceuticals, Inc., 40 Landsdowne St., Cambridge, MA 02139, USA.
authors.forename: Bret
authors.initials: B
authors.lastname: Bannerman
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Matthew
authors.initials: M
authors.lastname: Jones
authors.forename: Christopher
authors.initials: C
authors.lastname: Tsu
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Paul
authors.initials: P
authors.lastname: Hales
authors.forename: Johan
authors.initials: J
authors.lastname: Monbaliu
authors.forename: Paul
authors.initials: P
authors.lastname: Fleming
authors.forename: Lawrence
authors.initials: L
authors.lastname: Dick
authors.forename: Mark
authors.initials: M
authors.lastname: Manfredi
authors.forename: Christopher
authors.initials: C
authors.lastname: Claiborne
authors.forename: Joseph
authors.initials: J
authors.lastname: Bolen
authors.forename: Erik
authors.initials: E
authors.lastname: Kupperman
authors.forename: Allison
authors.initials: A
authors.lastname: Berger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002853:Chromatography, Liquid; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013662:Tea / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D013662:Tea; D000069286:Bortezomib; D002392:Catechin; C045651:epigallocatechin gallate; D001205:Ascorbic Acid