title: Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound.
abstract: We have recently proposed a macromolecular prodrug strategy for improved cancer chemotherapy based on two features (Kratz, F.; et al. J. Med. Chem 2000, 43, 1253-1256.): (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration and (b) release of the albumin-bound drug in the acidic environment at the tumor site due to the incorporation of an acid-sensitive bond between the drug and the carrier. To investigate this therapeutic strategy in greater depth, four (maleinimidoalkanoyl)hydrazone derivatives of doxorubicin were synthesized differing in the length of the aliphatic spacer (1, -(CH(2))(2)-; 2, -(CH(2))(3)-; 3, -(CH(2))(5)-; 4, -(CH(2))(7)-). The albumin-binding doxorubicin prodrugs, especially the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (3), are rapidly and selectively bound to the cysteine-34 position of endogenous albumin. 3 was distinctly superior to the parent compound doxorubicin in three animal tumor models (RENCA, MDA-MB 435, and MCF-7) with respect to antitumor efficacy and toxicity.
authors.affiliation: Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany. felix@tumorbio.uni-freiburg.de
authors.forename: Felix
authors.initials: F
authors.lastname: Kratz
authors.forename: André
authors.initials: A
authors.lastname: Warnecke
authors.forename: Karin
authors.initials: K
authors.lastname: Scheuermann
authors.forename: Cornelia
authors.initials: C
authors.lastname: Stockmar
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schwab
authors.forename: Peter
authors.initials: P
authors.lastname: Lazar
authors.forename: Peter
authors.initials: P
authors.lastname: Drückes
authors.forename: Norbert
authors.initials: N
authors.lastname: Esser
authors.forename: Joachim
authors.initials: J
authors.lastname: Drevs
authors.forename: Didier
authors.initials: D
authors.lastname: Rognan
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
authors.forename: Caterina
authors.initials: C
authors.lastname: Hinderling
authors.forename: Gerd
authors.initials: G
authors.lastname: Folkers
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D003545:Cysteine / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D011355:Prodrugs; D012709:Serum Albumin; D004317:Doxorubicin; D003545:Cysteine