The efficacy of the anthracycline prodrug daunorubicin-GA3 in human ovarian cancer xenografts

P. H J Houba, E. Boven, C. A M Erkelens, R. G G Leenders, J. W. Scheeren, H. M. Pinedo, H. J. Haisma

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


The prodrug N-[4-(daunorubicin-N-carbonyl-oxymethyl)phenyl] O-β-glucuronyl carbamate (DNR-GA3) was synthesized for specific activation by human β-glucuronidase, released in necrotic areas of tumour lesions. In vitro, DNR-GA3 was 18 times less toxic than daunorubicin (DNR) and the prodrug was completely activated to the parent drug by human β-glucuronidase. The maximum tolerated dose of DNR-GA3 in nude mice bearing s.c. human ovarian cancer xenografts was 6-10 times higher than that of DNR. The prodrug was cleared more rapidly from the circulation (elimination t(1/2) = 20 min) than the parent drug (elimination t(1/2) = 720 min). The anti-tumour effects of DNR-GA3 and DNR were investigated in four different human ovarian cancer xenografts OVCAR-3, FMa, A2780 and MRI-H-207 at a mean tumour size between 100 and 200 mm3. In three out of four of these tumour lines, the prodrug given i.v. at the maximum tolerated dose ranging from 150 to 250 mg kg-1 resulted in a maximum tumour growth inhibition from 82% to 95%. The standard treatment with DNR at a dose of 8 mg kg-1 given i.v. weekly x 2 resulted only in a maximum tumour growth inhibition from 40% to 47%. Tumour line FMa did not respond to DNR, nor to DNR-GA3. Treatment with DNR-GA3 was also given to mice with larger tumours that would contain more necrosis (mean size 300-950 mm3). The specific growth delay by DNR-GA3 was extended from 2.1 to 4.4 in OVCAR-3 xenografts and from 4.4 to 6.0 in MRI-H-207 xenografts. Our data indicate that DNR-GA3 is more effective than DNR and may be especially of use for treatment of tumours with areas of necrosis.

Original languageEnglish (US)
Pages (from-to)1600-1606
Number of pages7
JournalBritish Journal of Cancer
Issue number12
StatePublished - 1998
Externally publishedYes


  • Anthracycline-glucuronide prodrug
  • Daunorubicin
  • Human β-glucuronidase
  • Human ovarian cancer xenografts
  • Targeting
  • Tumour therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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