T. Minko et al., Efficacy of the chemotherapeutic action of HPMA copolymer-bound doxorubicin in a solid tumor model of ovarian carcinoma, INT J CANC, 86(1), 2000, pp. 108-117
Anticancer activity and main mechanisms of action of free doxorubicin (DOX)
and HPMA copolymer-bound DOX (P(GFLG)-DOX) were studied in solid tumor mic
e models of DOX sensitive and resistant human ovarian carcinoma. Free DOX w
as effective only in sensitive tumors decreasing the tumor size about three
times, whereas P(GFLG)-DOX decreased the tumor size 28 and is times in the
sensitive and resistant tumors. An enhanced accumulation of P(GFLG)-DOX in
the tumor was observed, whereas only low concentrations of DOX were detect
ed in other organs following P(GFLG)-DOX administration. This effect was de
pendent on the high permeability of blood vessels in untreated tumors. Afte
r treatment with P(GFLG)-DOX the permeability decreased concomitantly with
the downregulation of VEGF gene expression. P(GFLG)-DOX effectively killed
both types of tumors inducing apoptosis and necrosis through the activation
of p53, Apaf-1, caspase 9, c-fos, or c-jun pathways, and the downregulatio
n of the bcl-2 gene. HPMA copolymer-bound DOX preserved its activity inside
cells, inhibited detoxification and defensive mechanisms encoded by GST-T
pi, BUDP, and HSP-70 genes, and limited DNA repair, replication, and biosyn
thesis by downregulation of Topo-II alpha,beta, and TKI genes. P(GFLG)-DOX
also produced tumor tissue hypoxia and significantly activated lipid peroxi
dation in tumors. No damage to other organs after exposure to P(GFLG)-DOX w
as detectable. On the other hand, free DOX activated lipid peroxidation and
led to tissue hypoxia in many organs. All data relevant to the mechanism o
f anticancer action of P(GFLG)-DOX indicated a higher antitumor activity an
d lower systemic toxicity of HPMA copolymer-bound DOX when compared with fr
ee DOX, Int. J. Cancer 86:108-117, 2000. (C) 2000 Wiley-Liss, Inc.