Beta-Glucuronidase-Mediated Drug Release

Michelle   de   Graaf; Epie      Boven; Hans   W.   Scheeren; Hidde   J.   Haisma; Herbert   M.   Pinedo

doi:10.2174/1381612023394485

Abstract

The selective activation of a relatively non-toxic prodrug by an enzyme present only in the tumour should enhance the drug concentration at the tumour site and result in a better anti-tumour effect and a reduction in systemic toxicity as compared to conventional chemotherapy. β-Glucuronidase is such an enzyme. It is normally expressed in the lysosomes of cells. In larger tumours, however, high levels of the enzyme are present in necrotic areas. Several glucuronide prodrugs have been synthesised that can be activated by β- glucuronidase. They are relatively non-toxic due to their hydrophilic nature, which prevents them from entering cells and thus from contact with lysosomal β-glucuronidase. The main problem of glucuronide prodrugs for clinical use is their fast renal clearance. Special attention should be paid to the development of new less hydrophilic prodrugs with slower clearance, as this would result in a prolonged exposure to β- glucuronidase at the site of the tumour and a reduction of the amount of prodrug needed. A number of interesting anthracyclin-based glucuronide prodrugs have been synthesised and have shown favourable therapeutic effects compared to treatment with the parent drug. The tumoural levels of β-glucuronidase can even be enhanced by two-step approaches, in which exogenous enzyme is targeted to the tumour by an antibody (ADEPT) or by the gene encoding the enzyme in transduced tumour cells (GDEPT). The ADEPT and GDEPT approaches in combination with glucuronide prodrugs have shown enhanced efficacy in experimental tumour models. Further improvement of ADEPT and GDEPT is warranted to optimise the tumour uptake and retention of antibody-enzyme fusion proteins and the efficiency and safety of current gene delivery methods. In conclusion, it is clear that glucuronide prodrugs hold promise for future use in the treatment of cancer in patients as monotherapy. Enhancement of the therapeutic effects of glucuronide prodrugs, also in patients with small tumour lesions, may possibly be achieved by techniques that target β-glucuronidase specifically to the site of the tumour.

Keywords: glucuronidase, glucuronide prodrug, molecular chemotherapy, suicide gene, adept, gdept

« Previous Next »