N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity.
Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped versions of 4 such as the succinyl derivative 5 can be administered by the iv route at more than 10 times the LD(50) of doxorubicin without inducing the acute toxic reaction, and they are active in vivo.
Fernandez
A M
AM
Laboratory of Cell Biology, Université Catholique de Louvain, Place Croix du Sud 5, B-1348 Louvain-la-Neuve, Belgium. fernandez@bani.ucl.ac.be
Van Derpoorten
K
K
Dasnois
L
L
Lebtahi
K
K
Dubois
V
V
Lobl
T J
TJ
Gangwar
S
S
Oliyai
C
C
Lewis
E R
ER
Shochat
D
D
Trouet
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D004355:Drug Stability; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D012996:Solutions; D023382:Toxicity Tests, Acute; D014407:Tumor Cells, Cultured; D014462:Ultrafiltration; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C438951:N-(succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin; C424942:N-alanyl-leucyl-alanyl-leucyl-doxorubicin; D009842:Oligopeptides; D011355:Prodrugs; D012996:Solutions; D004317:Doxorubicin