Application of the ADEPT strategy to the MDR resistance in cancer chemotherapy.
New prodrugs consisting of a beta-D-glucuronic acid linked to a MDR reversal agent (verapamil, quinine or dipyridamole) through a self-immolative spacer were synthesized. Four of them were selected for their reduced cytoxicity and beta-glucuronidase enzymatic efficient hydrolysis. Combined use of these prodrugs with a beta-D-glucuronyl-spacer-doxorubicin (HMR1826) according to an ADEPT strategy restored in vitro the sensibility of a MDR resistant strain.
Desbene
S
S
Laboratoire de Pharmacognosie, URA CNRS 1310, Université Paris V, France.
Van
H D
HD
Michel
S
S
Tillequin
F
F
Koch
M
M
Schmidt
F
F
Florent
J C
JC
Monneret
C
C
Straub
R
R
Czech
J
J
Gerken
M
M
Bosslet
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004176:Dipyridamole / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004355:Drug Stability; D004926:Escherichia coli / Q000201:enzymology; D005965:Glucuronates / Q000737:chemistry; D020723:Glucuronic Acid; D005966:Glucuronidase / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007939:Leukemia L1210 / Q000473:pathology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011803:Quinine / Q000737:chemistry / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D005965:Glucuronates; D011355:Prodrugs; D004176:Dipyridamole; D004317:Doxorubicin; D020723:Glucuronic Acid; D011803:Quinine; D014700:Verapamil; D005966:Glucuronidase