title: A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer.
abstract: The doxorubicin (DOX) prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-beta-glucuronyl carbamate (DOX-GA3) was synthesised for specific activation by human beta-glucuronidase, which is released in necrotic areas of tumour lesions. This novel prodrug was completely activated to the parent drug by human beta-glucuronidase with V(max)= 25.0 micromol x min(-1) x mg(-1) and K(m) = 1100 microM. The pharmacokinetics and distribution of DOX-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3) were determined and compared with DOX. Administration of DOX at 8 mg x kg(-1) i.v. (maximum tolerated dose, MTD) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 16.4 microM (t = 1 min). A 7.6-times lower peak plasma concentration of DOX was measured after injection of DOX-GA3 at 250 mg x kg(-1) i.v. (50% of MTD). In normal tissues the prodrug showed peak DOX concentrations that were up to 5-fold (heart) lower than those found after DOX administration. DOX-GA3 activation by beta-glucuronidase in the tumour yielded an almost 5-fold higher DOX peak concentration of 9.57 nmol x g(-1) (P< 0.05) than the peak concentration of only 2.14 nmol x g(-1) observed after DOX. As a consequence, the area under the curve of DOX calculated in tumour tissue after DOX-GA3 (13.1 micromol x min(-1) x g(-1)) was 10-fold higher than after DOX (1.31 micromol x min(-1) x g(-1)). The anti-tumour effects of DOX-GA3 and DOX were compared at equitoxic doses in OVCAR-3 xenografts at a mean tumour size of 125 mm(3). The prodrug given i.v. at 500 mg x kg(-1) weekly x 2 resulted in a maximum tumour growth inhibition of 87%, while the standard treatment with DOX at a dose of 8 mg x kg(-1) i.v. weekly x 2 resulted in a maximum tumour growth inhibition of only 56%. Treatment with DOX-GA3 was also given to mice with larger tumours containing more necrosis. For tumours with a mean size of 400 mm(3) the specific growth delay by DOX-GA3 increased from 2.7 to 3.9. Our data indicate that DOX-GA3 is more effective than DOX and suggest that the prodrug will be specifically advantageous for treatment of advanced disease.
authors.affiliation: Department of Medical Oncology, University Hospital Vrije Universiteit, P.O. Box 7057, Amsterdam, MB, 1007, The Netherlands.
authors.forename: P H
authors.initials: PH
authors.lastname: Houba
authors.forename: E
authors.initials: E
authors.lastname: Boven
authors.forename: I H
authors.initials: IH
authors.lastname: van der Meulen-Muileman
authors.forename: R G
authors.initials: RG
authors.lastname: Leenders
authors.forename: J W
authors.initials: JW
authors.lastname: Scheeren
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: H J
authors.initials: HJ
authors.lastname: Haisma
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005965:Glucuronates / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009374:Neoplasms, Experimental; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D005965:Glucuronates; C407038:N-(4-doxorubicin-N-carbonyl(oxymethyl)phenyl)-O-glucuronyl carbamate; D004317:Doxorubicin