The
prodrug N-[4-(
daunorubicin-N-carbonyl-oxymethyl)phenyl] O-beta-glucuronyl
carbamate (DNR-GA3) was synthesized for specific activation by human
beta-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
beta-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 t1/2 = 20 min) than the parent drug (elimination t1/2 = 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.