Cisplatin Liposomal(SEQUUS Pharmaceuticals)

The frequent development of cellular resistance to cisplatin in cancer patients is a serious limitation for clinical drug therapy. However, cisplatin resistance is incompletely understood. We have shown that cisplatin-resistant A2780 ovarian cancer cells (A2780cis) can efficiently be eliminated by liposomal cisplatin, which displayed similar cytotoxicity towards both A2780 and A2780cis cells. This may, at least in part, be related to a higher intracellular accumulation of the drug within the resistant cells after liposomal entry. However, the superior cytotoxicity of the liposomal drug was not reflected by DNA platination. This suggests a more complex mode of action of liposomal cisplatin, most likely affecting different signaling pathways. To gain insight into the resistance gene signature, a whole-genome gene expression analysis was performed for A2780cis cells, untreated or treated with half-minimal inhibitory concentration (IC50) of free and liposomal cisplatin. Strong differences in the functional networks affected by free and liposomal cisplatin became evident. p53 was identified as a key factor directing differences in the apoptotic processes. While free cisplatin induced the intrinsic pathway of apoptosis, liposomal cisplatin induced expression of genes of DNA damage pathways and of the extrinsic pathway of apoptosis. These predictions from gene expression data were confirmed at the protein and function level. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal cisplatin as a promising strategy for the treatment of cisplatin-resistant ovarian carcinoma.

Cisplatin (CDDP) is a principal compo­ nent of standard ovarian cancer chemother­ apy. However, the frequent development of cellular resistance to CDDP severely restricts the clinical therapeutic success. The molecu­ lar mechanisms of resistance are manifold and not completely understood [1]. Previously, we reported that liposo­ mal CDDP overcomes CDDP resistance of A2780cis human ovarian cancer cells [2]. However, the superior cytotoxic activi­ ty of liposomal CDDP vs. the free drug in A2780cis cells did not correlate with DNA platination levels, thus suggesting a different mode of action of liposomal CDDP com­ pared to free CDDP. To gain an insight into liposomal CDDP activity, a transcriptome analysis of A2780cis cells, either untreated, or in response to ex­ posure with IC50 values of free or liposomal CDDP has been performed [3]. A process network analysis of up­regulated genes indi­ cated that liposomal CDDP induced a highly different gene expression profile compared to the free drug. p53 was identified as play­ ing a key role in directing transcriptional responses to free or liposomal CDDP. Most interestingly, the transcriptome data showed that liposomal CDDP, in contrast to the free drug, induces expression of genes from the extrinsic pathway of apoptosis, which indi­ cates how liposomal CDDP can overcome chemoresistance of A2780cis cells. The aim of this study was to gain further insight into liposomal CDDP activity and to confirm prior findings on apoptosis induction on a protein and functional level. Materials and methods