Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts.
N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-beta-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 beta-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 microM (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 x g(-1) after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol x 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 beta-glucuronidase. In this respect, a considerably higher beta-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by beta-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity.
Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
P H
PH
Houba
E
E
Boven
I H
IH
van der Meulen-Muileman
R G
RG
Leenders
J W
JW
Scheeren
H M
HM
Pinedo
H J
HJ
Haisma
D000818:Animals; D019540:Area Under Curve; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005966:Glucuronidase / Q000032:analysis / Q000097:blood; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
C116339:N-(4-(daunorubicin-N-carbonyl-oxymethyl)phenyl)-O-glucuronyl carbamate; D011355:Prodrugs; D005966:Glucuronidase; C000847:daunorubicinol; D003630:Daunorubicin