title: Disposition of conjugate-bound and free doxorubicin in tumor-bearing mice following administration of a BR96-doxorubicin immunoconjugate (BMS 182248).
abstract: OBJECTIVE
  The chimeric BR96-doxorubicin (DOX) immunoconjugate, BMS 182248, has induced remissions and cures of human lung adenocarcinoma (L2987) implanted in athymic mice. The purpose of this study was to evaluate the biodistribution of DOX after BMS 182248 administration to tumor-bearing mice and to evaluate the ability of BMS 182248 to target DOX to tumors.
  
  
  METHODS
  For this evaluation, L2987-implanted mice were given BMS 182248 (5 mg DOX/kg; three doses 4 days apart) and the levels of both conjugate-bound and free DOX in plasma, tumor, liver and heart were determined.
  
  
  RESULTS
  Conjugate-bound DOX comprised the majority of plasma DOX, with relatively low levels of free DOX present. From plasma, conjugate-bound DOX distributed to the tissues examined with the order of concentration (per gram of tissue) being tumor > liver > heart. Free DOX was also detected in liver and heart, but at concentrations lower than those present after an equivalent DOX dose (5 mg/kg; three doses 4 days apart). The total exposure of heart to free DOX after BMS 182248 administration was about one-quarter of that found after the administration of DOX alone. The elimination kinetics of both conjugate-bound and free DOX from heart and liver after BMS 182248 administration paralleled those observed from plasma, indicating that equilibrium had been attained between these nontumor tissues and plasma. The elimination kinetics of both entities from tumors, however, were different from those from plasma, liver and heart. BMS 182248 produced sustained levels of both conjugate-bound and free DOX which were present throughout the experiment. This suggested that, in contrast to normal tissues, tumor tissue retention of BMS 182248 by antigen-promoted binding had occurred and that kinetics of free DOX in the tumors were controlled by the rate of release of DOX from tumor-associated BMS 182248. As a result of this retention, the tumor concentrations of free DOX after BMS 182248 administration exceeded those produced by i.v. administration of DOX at the same dose, a finding consistent with the greater antitumor activity of BMS 182248 relative to DOX. BMS 182248 also liberated DOX upon incubation with rat liver lysosomes and was accumulated by L2987 cells in culture, with the subsequent intracellular release of DOX.
  
  
  CONCLUSIONS
  BMS 182248 effectively delivered DOX to L2987 xenografts implanted in athymic mice and produced higher and more prolonged tumor concentrations of free DOX than the administration of DOX alone. Following BMS 182248 administration, normal tissues (liver and heart) were exposed to lower overall concentrations of free DOX than were produced by administration of an equivalent DOX dose.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research Institute, Wallingford, CT 06410, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Mosure
authors.forename: A J
authors.initials: AJ
authors.lastname: Henderson
authors.forename: L J
authors.initials: LJ
authors.lastname: Klunk
authors.forename: J O
authors.initials: JO
authors.lastname: Knipe
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009368:Neoplasm Transplantation
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C092612:BR96-doxorubicin immunoconjugate; D018796:Immunoconjugates; D004317:Doxorubicin