title: A methylester of the glucuronide prodrug DOX-GA3 for improvement of tumor-selective chemotherapy.
abstract: The glucuronide prodrug of doxorubicin, DOX-GA3, can be selectively activated in tumors by extracellular human beta-glucuronidase, resulting in a better therapeutic index than doxorubicin. DOX-GA3, however, is rapidly excreted by the kidney. We hypothesized that slow release of DOX-GA3 from its methylester, DOX-mGA3, by esterase activity in blood would result in improved circulation half-life (t(1/2)) of DOX-GA3. DOX-mGA3 was synthesized more efficiently with an overall yield of 60% as compared to 37% in the case of DOX-GA3. We showed that DOX-mGA3 was enzymatically converted to DOX-GA3 with a t(1/2) of approximately 0.5 min in mouse plasma to 2.5 h in human plasma, which was in agreement with differences in esterase activity between species. DOX-mGA3, similar to DOX-GA3, was at least 37-fold less potent than the parent drug doxorubicin in growth inhibition of four different human malignant cell lines in vitro. Incubation of OVCAR-3 cells with DOX-mGA3 in combination with an excess of human beta-glucuronidase (0.05 U mL(-1)) resulted in a similar growth inhibition to that of doxorubicin. Intravenous administration of DOX-mGA3 in FMa-bearing mice resulted in an area under the concentration versus time curve (AUC) of DOX-GA3 in tumor and most normal tissues that was 2.5- to 3-fold higher than after the same dose of DOX-GA3 itself. In tumor tissue, this was accompanied by a 2.7-fold increase in the AUC of doxorubicin from DOX-mGA3 than from DOX-GA3. In conclusion, an advantage of DOX-mGA3 over DOX-GA3 is that this prodrug can be produced with a higher yield. Another important advantage is the improved pharmacokinetics of the lipophilic DOX-mGA3 as compared to that of the hydrophilic DOX-GA3. This effect may even be more pronounced in man, because of the lower plasma esterase activity than measured in mice.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: de Graaf
authors.forename: Tapio J
authors.initials: TJ
authors.lastname: Nevalainen
authors.forename: Hans W
authors.initials: HW
authors.lastname: Scheeren
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004952:Esters / Q000737:chemistry; D005260:Female; D005965:Glucuronates / Q000493:pharmacokinetics*; D020719:Glucuronides / Q000737:chemistry; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism* / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004952:Esters; D005965:Glucuronates; D020719:Glucuronides; C407038:N-(4-doxorubicin-N-carbonyl(oxymethyl)phenyl)-O-glucuronyl carbamate; D011355:Prodrugs; D004317:Doxorubicin