ANNAMYCIN--MECHANISMS OF ACTION

Project: Research project

Project Details

Description

Annamycin (Ann) is a new lipophilic anthracycline antibiotic with 4
distinct structural features compared with the parent compound doxorubicin
(Dox), which confer to the molecule a high affinity for lipid membranes
and lack of solubility in water. Our initial hypothesis was that because
of its distinct physicochemical characteristics, Ann should be easily
amenable to be formulated in a wide variety of liposomal carriers and
should interact differently with the recognized cellular targets of
anthracyclines. Work performed during the initial funding period has
confirmed this hypothesis. In addition, we have shown that Ann
incorporated in liposomes displays significant lack of cross resistance
with Dox in a panel of 4 tumor cells lines and their MDR counterparts and
a markedly enhanced in vivo antitumor activity compared with Dox against
several murine models including L1210 leukemia, B16 melanoma, M5076
reticulosarcoma, lung Lewis lung carcinoma, and KB/MDR human xenografts in
nude mice. Because of its promising antitumor activity profile, initial
clinical studies with Ann entrapped in multilamellar vesicles are planned
to start at the end of the current funding period at the cellular level,
the lack of cross-resistance properties of Ann have been found to be
associated with (1) similar drug accumulation and retention in sensitive
and resistant cell lines, (2) 20-30 fold higher drug accumulation and
retention compared with Dox in resistant cells, (3) lack of P-glycoprotein
mediated drug efflux, (4) extent of DNA damage in resistant cells similar
to that of Dox in sensitive cells, (5) significant induction of apoptosis
in resistant cells, Dox being ineffective. These results indicate
significant differences in the way Ann and Dox interact with P-
glycoprotein and topoisomerase-II, which are two well recognized cellular
targets of anthracyclines. Ann tissue levels after i.v. administration
show a preferential distribution to lung and s.c. tumors (6 and 10 fold
difference with Dox, respectively), and an ability to cross the blood
brain barrier, while heart levels are similar to those achieved with Dox.
The great flexibility in chosing the appropriate liposome carrier offers
the opportunity of modulating the pharmacokinetics and organ distribution
of Ann for specific therapeutic purposes. The main objectives of this
competing renewal proposal are (1) to develop and test against human
xenografts liposomal formulations of Ann with enhanced tumor targeting
properties and low distribution to heart (small unilamellar liposomes
containing lipids that avoid recognition of the particles by the RES, thus
resulting in a prolonged serum half-life and a preferential distribution
to the tumor), (2) to study the pharmacokinetics, in vivo metabolism, and
cardiotoxicity of selected liposomal-Ann formulations in rabbits, and (3)
to examine in depth the cellular mechanisms of action of Ann at the
different cellular targets of anthracyclines: interaction with
topoisomerase II, signal transduction pathways, cell membrane
interactions, cell cycle regulation, and apoptosis. The results of these
studies will be essential in learning how to optimize the use of Ann and
in planning its clinical development strategy.
StatusFinished
Effective start/end date1/1/9112/31/99

Funding

  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute

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