HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-adriamycin (ADR) conjugate containing lysosomally degradable oligopeptide (GFLG) side chains terminated in ADR was synthesized. The effect of free and HPMA copolymer-bound ADR on the viability of A2780 sensitive and A2780/AD multidrug resistant human ovarian carcinoma cells was studied in vitro. As expected, the IC50 dose for the HPMA copolymer-ADR conjugate was higher than for free ADR reflecting the difference in the mechanism of cell entry. The resistant A2780/AD cells demonstrated about 40-times higher resistance to free ADR than the sensitive A2780 cells. On the contrary, there was only a small difference in cytotoxicity of the HPMA copolymer-ADR conjugate toward sensitive A2780 or MDR resistant A2780/AD cells. The IC50 value for A2780/AD was only about 20% higher than the value for sensitive A2780 cells. These data seem to indicate that the HPMA copolymer-ADR conjugate may, at least partially, avoid the ATP driven P-glycoprotein (Pgp) efflux pump. The analysis of the expression of the MDR1 gene which encodes the Pgp, has shown that free ADR in high doses stimulated MDR1 gene expression in sensitive A2780 cells. At the same time both free and HPMA copolymer-ADR conjugate partially inhibited the expression of the MDR1 and beta 2 m genes in multidrug resistant A2780/AD cells.