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

The prodrug N-[4-(daunorubicin-N-carbonyl-oxymethyl)phenyl] O-beta-glucuron yl carbamate (DNR-GA3) was synthesized for specific activation by human bet a-glucuronidase, released in necrotic areas of tumour lesions. In vitro, DN R-GA3 was 18 times less toxic than daunorubicin (DNR) and the prodrug was c ompletely activated to the parent drug by human P-glucuronidase. The maximu m tolerated dose of DNR-GAS 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 pa rent 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 20 0 mm(3). 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 i n a maximum tumour growth inhibition from 82% to 95%. The standard treatmen t 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-GAS was also given to m ice with larger tumours that would contain more necrosis (mean size 300-950 mm(3)). 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.