Self-immolative anthracycline prodrugs for suicide gene therapy.
Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorubicin (12, 14) were designed and synthesized. They are self-immolative prodrugs for suicide gene therapy activation by the enzyme carboxypeptidase G2 (CPG2) subsequently releasing the corresponding anthracyclines, by a 1,6-elimination mechanism. A mammary carcinoma cell line (MDA MB 361) was engineered to express CPG2 intracellularly (CPG2) or extracellularly, tethered to the outer cell membrane (stCPG2(Q)3). The prodrugs derived from doxorubicin showed prodrug/drug cytotoxicity differentials of 21-fold (compound 12) and 23-fold (compound 14). Prodrug 12 underwent an 11-fold activation when assayed in the cell line expressing externally surface-tethered CPG2.
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
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I
Niculescu-Duvaz
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D
Niculescu-Duvaz
F
F
Friedlos
R
R
Spooner
J
J
Martin
R
R
Marais
C J
CJ
Springer
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D003630:Daunorubicin / Q000737:chemistry* / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D011623:gamma-Glutamyl Hydrolase / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D011355:Prodrugs; D004317:Doxorubicin; D011623:gamma-Glutamyl Hydrolase; D003630:Daunorubicin