Elsevier

Biochemical Pharmacology

Volume 57, Issue 6, 15 March 1999, Pages 673-680
Biochemical Pharmacology

Chemotherapy and Metabolic Inhibitors
Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts

https://doi.org/10.1016/S0006-2952(98)00343-8Get rights and content

Abstract

N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-β-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 μM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol · g−1 after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol · g−1 (P < 0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by β-glucuronidase. In this respect, a considerably higher β-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by β-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity.

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.

References (20)

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