Semisynthetic maytansine analogues for the targeted treatment of cancer.
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.
Widdison
Wayne C
WC
ImmunoGen, Inc., 128 Sidney Street, Cambridge, Massachusetts 02139, USA.
Wilhelm
Sharon D
SD
Cavanagh
Emily E
EE
Whiteman
Kathleen R
KR
Leece
Barbara A
BA
Kovtun
Yelena
Y
Goldmacher
Victor S
VS
Xie
Hongsheng
H
Steeves
Rita M
RM
Lutz
Robert J
RJ
Zhao
Robert
R
Wang
Lintao
L
Blättler
Walter A
WA
Chari
Ravi V J
RV
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
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004220:Disulfides; D004337:Drug Carriers; D013438:Sulfhydryl Compounds; D008453:Maytansine