Lw. Seymour et al., TUMOR TROPISM AND ANTICANCER EFFICACY OF POLYMER-BASED DOXORUBICIN PRODRUGS IN THE TREATMENT OF SUBCUTANEOUS MURINE B16F10 MELANOMA, British Journal of Cancer, 70(4), 1994, pp. 636-641
Doxorubicin (5 mg kg(-1)) was administered intravenously to C57 mice b
earing subcutaneous B16F10 melanomas, distributing into the tumour wit
h an area under the concentration-time curve (0-48 h; AUC) of 8.7 mu g
h g(-1). Injection of doxorubicin-N-(2-hydroxypropyl)methacrylamide (
HPMA) copolymer conjugate, containing 5 mg of doxorubicin equivalent p
er kg, mediated an AUC for free doxorubicin (i.e. doxorubicin released
from the conjugate) of 15.2 mu g h g(-1) and for total doxorubicin (i
.e. free plus conjugated) of 149.1 mu g h g(-1). An increased dose of
doxorubicin-HPMA copolymer conjugate (18 mg of doxorubicin equivalent
per kg) produced AUC values of 40.1 mu g h g(-1) and 671.7 mu g h g(-1
) for free and total doxorubicin respectively. Hence administration of
doxorubicin-HPMA copolymer conjugate achieved rises of 1.7- to 4.6-fo
ld in tumour AUC (free doxorubicin) and 17.1- to 77.0-fold in tumour A
UC (total doxorubicin). HPMA copolymers bearing fluorescein isothiocya
nate accumulated in vascularised stromal regions, particularly in new
growth sites at the tumour periphery. Treatment of mice with doxorubic
in-HPMA copolymer conjugate achieved treated/control lifespans up to 3
20% (three doses of 27 mg of doxorubicin equivalent per kg) compared w
ith only 133% using aggressive regimens of free doxorubicin (3 x 5 mg
kg(-1)).