DEVELOPMENT OF L NDDP FOR THE TREATMENT OF CISPLATIN-RES

DESCRIPTION: (Applicant's Abstract) Ovarian carcinoma is a human malignancy in which acquired resistance to cisplatin has a major clinical impact. Because ovarian carcinoma tends to remain confined to the peritoneal cavity, intraperitoneal (i.p.) therapy is, in addition to systemic therapy, a rational therapeutic approach that has recently been shown to have an impact on survival. Cis-bis-neodecanoato-trans- R,R-1,2-diaiminocyclohexane platinum (II) (NDDP) is a lipophilic cisplatin analog designed to be incorporated in liposomes. Liposome- entrapped NDDP (L-NDDP) is not cross-resistant with cisplatin in several in vitro and in vivo systems. L-NDDP has shown a significant pharmacologic advantage over cisplatin when administered i.p. in rats. In humans, L-NDDP given i.v. is less emetogenic than cisplatin, non- nephrotoxic, its dose-limiting toxicity is myelosuppression, and its maximum tolerated dose is 300 mg/m2. When given intrapleurally, it does not cause myelosuppression at a dose of 550 mg/m2 and has shown promising antitumor activity. The main goals of this application are (1) to develop liposomal formulations with enhanced tumor penetration properties (for i.p. administration) and tumor targeting properties (for i.v. administration) of one isomer of NDDP (NDDP-1) for the treatment of cisplatin-resistant ovarian carcinoma, and (2) to investigate the cellular mechanisms of lack of cross-resistance between these two agents. Liposomal formulations with enhanced tumor targeting properties will consist of small unilamellar vesicles composed of a mixture of lipids with a high transition temperature and lipids that avoid the recognition of the vesicles by phagocytes; promising preliminary studies have shown an enhanced tumor targeting and antitumor activity properties of formulations using such type of vesicles as carriers of NDDP. Optimization of formulations for i.p. therapy will be accomplished by examining the effect of lipid composition, size, and the addition of different penetration enhancers in increasing tumor drug penetration. A major emphasis will be placed on understanding the mechanisms of lack of cross-resistance between L-NDDP-1 and cisplatin. The basic hypothesis is that the lack of cross-resistance between both agents is the combined result of (a) differences in kinetics of nuclear drug accumulation secondary to the high lipophilicity of NDDP-1 and liposome delivery, and (b) decreased ability of cells resistant to cisplatin to repair Pt-DNA adducts induced by L-NDDP. Subcellular and subnuclear drug distribution and induction and repair of Pt-DNA adducts will be studied in whole cell systems and cell extracts using different plasmids damaged upon platination with cisplatin or NDDP-1, and compared with those obtained with cisplatin and other DACH-Pt compounds in a series of cell lines with acquired resistance to cisplatin or L-NDDP-1 and with high and low expression of EGFR. The elucidation of the mechanisms of action of L- NDDP-1 and the selection of formulations with optimal tumor penetration and targeting properties will greatly enhance the clinical development of L-NDDP-1 for the treatment of cisplatin-resistant ovarian carcinoma.