title: Semisynthetic maytansine analogues for the targeted treatment of cancer.
abstract: Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.
authors.affiliation: ImmunoGen, Inc., 128 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Widdison
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Wilhelm
authors.forename: Emily E
authors.initials: EE
authors.lastname: Cavanagh
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Whiteman
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leece
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kovtun
authors.forename: Victor S
authors.initials: VS
authors.lastname: Goldmacher
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Xie
authors.forename: Rita M
authors.initials: RM
authors.lastname: Steeves
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lutz
authors.forename: Robert
authors.initials: R
authors.lastname: Zhao
authors.forename: Lintao
authors.initials: L
authors.lastname: Wang
authors.forename: Walter A
authors.initials: WA
authors.lastname: Blättler
authors.forename: Ravi V J
authors.initials: RV
authors.lastname: Chari
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004220:Disulfides; D004337:Drug Carriers; D013438:Sulfhydryl Compounds; D008453:Maytansine