ANTHRACYCLINES WITH HIGH AFFINITY FOR LIPID MEMBRANES

Project: Research project

Project Details

Description

Cell membrane events play an important role in modulating the
cytotoxicity and resistance to anthracyline antibiotics.
Membrane-targeted anthracyclines may potentiate the membrane-based
mechanisms of cytotoxicity and result in a lower affinity for the
protein-based mechanisms of drug efflux, which play a major role in
mediating cell resistance. Structural requirements for an optimal
anthracycline-lipid membrane affinity and for overcoming resistance to
doxorubicin have been identified. This information will be used to
design and synthesize new anthracycline antibiotics with a high affinity
for lipid membranes and partially not cross-resistant with doxorubicin.
Since most compounds are expected to be highly lipophilic, liposomes of
different composition and size and with tumor targeting properties will
be explored as natural carriers for the new analogs synthesized. The
antitumor activity, toxicity, pharmacokinetics, organ distribution, and
tumor uptake of several prototype liposomal anthracycline preparations
will be studied and compared with those of doxorubicin and the
non-entrapped drugs. The evaluation of the efficacy of these preparation
in the targeted therapy of liver metastases will receive particular
attention. The affinity for lipid membranes and the effects on the cell
membrane of sensitive and resistant tumor cells will be carefully
examined, and the role of the membrane effects in mediating tumor cell
cytotoxicity assessed. The study will define the potential of liposomes
as carriers of new lipophilic anthracyclines antibiotics and lead to the
selection of candidate preparation for clinical development. The
information generated will be essential in further understanding the role
of the cell membrane in modulating the biological activity of this group
of compounds and in providing rational guidance for improving the design
and use of drug carriers for antitumor agents.
StatusFinished
Effective start/end date1/1/9112/31/99

ASJC

  • Medicine(all)