| Autor: |
Houba, PHJ, Boven, E, van der Meulen-Muileman, IH, Leenders, RGG, Scheeren, JW, Pinedo, HM, Haisma, HJ |
| Přispěvatelé: |
Biopharmaceuticals, Discovery, Design and Delivery (BDDD) |
| Jazyk: |
angličtina |
| Rok vydání: |
1999 |
| Předmět: |
|
| Zdroj: |
Biochemical Pharmacology, 57(6), 673-680. PERGAMON-ELSEVIER SCIENCE LTD |
| ISSN: |
0006-2952 |
| Popis: |
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 p-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 mu M (t = I min). DNR-GAS 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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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