Self-immolative prodrugs: candidates for antibody-directed enzyme prodrug therapy in conjunction with a nitroreductase enzyme.
The synthesis and properties of some prodrug candidates for antibody-directed enzyme prodrug therapy (ADEPT) are described. These compounds have been designed to generate the corresponding active drug upon interaction with a bacterial nitroreductase that can be conjugated to antibodies that recognize tumor-selective antigens. The active drugs included in the study are actinomycin D, mitomycin C, doxorubicin, 4-[bis(2-chloroethyl)amino]aniline and 4-[bis(2-chloroethyl)amino]phenol. The prodrugs were all 4-nitrobenzyloxycarbonyl derivatives of these drugs, which upon enzymatic reduction, generated the drug through self-immolation of the 4-(hydroxyamino)benzyloxycarbonyl group. In the case of actinomycin D, the ratio of the dose required between drug and prodrug to give the same cytotoxicity was greater than 100. The prodrug was also much less toxic (20-100x) than actinomycin D to mice in vivo. Therefore this self-immolative prodrug has a potential application in the treatment of cancer using an ADEPT-type approach.
Mauger
A B
AB
CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, Sutton, Surrey, U.K.
Burke
P J
PJ
Somani
H H
HH
Friedlos
F
F
Knox
R J
RJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D000922:Immunotoxins / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009601:Nitroreductases / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000922:Immunotoxins; C090021:N-(4-nitrobenzyloxycarbonyl)actinomycin D; D011355:Prodrugs; D003609:Dactinomycin; D009601:Nitroreductases