Chemotherapy and Metabolic InhibitorsDistribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts
Section snippets
Materials
Daunorubicin (DNR, Société Parisienne d’expansion chimique) was purchased as a powder. The prodrug DNR-GA3 has been characterized [7, ∗]. In this prodrug the anthracycline moiety is linked to the glucuronide via a carbamate spacer with an aromatic center. Stock solutions of DNR and DNR-GA3 were prepared in sterile water and stored at −20°.
Tumor models
Female athymic nude mice (Hsd: athymic nude-nu; Harlan Cpb) were handled under specified pathogen-free conditions. The human ovarian cancer xenografts
Pharmacokinetics in plasma
Administration of DNR to OVCAR-3-bearing mice resulted in a peak concentration of the drug of 12.18 μM (t = 1 min) in plasma and an elimination half-life time of 49 min. After administration of DNR-GA3 to OVCAR-3-bearing mice, the prodrug reached a plasma peak concentration of 390 μM (t = 1 min; Fig. 2) and was eliminated with a half-life time of 17 min. DNR-GA3 administration resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR administration itself,
Discussion
Earlier we observed that inhibition of tumor growth caused by DNR-GA3 was superior to the antitumor effects of equitoxic doses of DNR in three of four human ovarian cancer xenografts. We have now demonstrated that this better tumor growth-inhibiting effect was caused by the specific activation of DNR-GA3 by β-glucuronidase at the tumor site. This led to higher concentrations of DNR in tumor tissue after administration of DNR-GA3, while in plasma and normal tissues the concentrations of DNR were
Acknowledgements
This work was supported by the Dutch Cancer Society.
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