DEVELOPMENT OF L NDDP FOR THE TREATMENT OF CISPLATIN-RES

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date7/1/966/30/00

ASJC

  • Oncology

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.