Prodrug monotherapy

Y. L. Leu, S. R. Roffler, J. W. Chern, Design and Synthesis of Water-Soluble Glucuro-nide Derivatives of Campothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT) , J. Med. Chem. 1999, 42, 3623 - 3628. 

PRODRUGS OF NATURAL ANTHRACYCLINES SUITED FOR ANTIBODY DIRECTED ENZYME PRODRUG THERAPY (ADEPT) AND PRODRUG MONOTHERAPY... 

In contrast, using enzyme histochemical methods, it was observed that lysosomal (3-glucuronidase was liberated in necrotic tumor areas as functionally active enzyme (75). The cells responsible for the liberation of the enzyme are mainly acute and chronic inflammatory cells, as shown by immunochemistry (74). These observations led to the development of the new concept of prodrug monotherapy (PMT) (74, 75). 

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events. There are two forms of diarrhea an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2-10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases. 

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