TABLE 15

Prodrugs of 5-FU and doxorubicin, their respective enzymes, their activation, their antitumor activity, and their limitations

Drug Side effect Prodrug Enzyme Activation Investigated Antitumor Effect Investigated Limitations
Vitro Vivo Vitro Vivo
5-FU Rapid breakdown in gastrointestinal tract and gastrointestinal toxicity 5-FP Aldehyde oxidase Yes Yes (Mice) No Yes (Mice) No improvement in antitumor activity compared with 5-FU
Ftorafur P450 Yes Yes (human) Yes Yes (human) Nontumor-specific activation, clinically used prodrug
5′-DFUR Thymidine phosphorylase Yes Yes (human) Yes Yes (human) Causes gastrointestinal toxicity,a clinically used prodrug
5-FU glucuronide β-Glucuronidase Yes Yes (mice) Yes Yes (mice) Rapid clearance after i.v. or i.p. injection, intratumoral injection necessary
5-FC Cytosine deaminase Yes Yes (mice) Yes Yes (mice) General ADEPT limitations (see text), promising candidate, in clinical trials
Doxorubicin Cardiotoxicity, acute myelo suppression, nausea, and vomiting N-(4-phosphono- oxy)-phenylacetyl) doxorubicin Alkaline phosphatase Yes No No No Widespread distribution, few data available
HMR 1826 β-Glucuronidase Yes Yes (mice) Yes Yes (mice) Only activated in necrotic sites of the tumor
DOX-GA3 β-Glucuronidase Yes Yes (mice) Yes Yes (mice) Only activated in necrotic sites of the tumor
DPO Penicillin amidase Yes No Yes No Partial prodrug activation, adverse immune effects due to bacterial enzyme
N-(phenyacetyl) doxorubicin Penicillin amidase Yes No No No Poor solubility in aqueous solution, Adverse immune effects due to bacterial enzyme, few data available
C-DOX β-Lactamase Yes Yes Yes Yes (mice) Adverse immune effects due to bacterial enzyme
PRODOX β-Lactamase Yes No Yes No Adverse immune effects due to bacterial enzyme
  • a To overcome this gastrointestinal toxicity, capecitabine was developed (see text).