Comparison of the anticancer effect of free and HPMA copolymer-bound adriamycin in human ovarian carcinoma cells.
OBJECTIVE
To study peculiarities and the mechanism of the anticancer effect of free and HPMA copolymer-bound ADR in sensitive and resistant human ovarian carcinoma cells.


METHODS
Sensitive A2780 and ADR resistant A2780/AD cells were exposed to different doses of drugs during 12, 24, 36, 48, 60, and 72 hours. Cell viability, drug accumulation, apoptosis, cellular metabolism, lipid peroxidation, DNA content and gene expression were studied.


RESULTS
HPMA copolymer-bound ADR (P(GFLG)-ADR) possessed a comparable cytotoxicity to free ADR when comparison was based on intracellular concentrations. While free ADR up-regulated genes encoding ATP driven efflux pumps (MDR1, MRP), P(GFLG)-ADR overcame existing pumps and down regulated the MRP gene. Free ADR also activated cell metabolism and expression of genes responsible for detoxification and DNA repair. P(GFLG)-ADR down-regulated HSP-70, GST-pi, BUDP, Topo-IIalpha, beta, and TK-1 genes. Apoptosis, lipid peroxidation and DNA damage were significantly higher after exposure to P(GFLG)-ADR, as reflected by simultaneous activation of p53, c-fos in A2780 cells) or c-jun (A2780/AD) signaling pathways and inhibition of the bcl-2 gene. Differences between free ADR and P(GFLG)-ADR increased with the time of incubation and drug concentration.


CONCLUSIONS
P(GFLG)-ADR overcame drug efflux pumps, more significantly induced apoptosis and lipid peroxidation, inhibited DNA repair, replication, and biosynthesis when compared to free ADR.
Minko
T
T
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA.
Kopecková
P
P
Kopecek
J
J
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011109:Polymethacrylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D004317:Doxorubicin