DRUG SELECTIVITY IN CARDIAC AND MDR TUMOR CELLS

Project: Research project

Description

Adriamycin, a clinical widely used anti-tumor agent, is thought to work as
most other cancer chemotherapeutic drugs by affecting the replicating
machinery of actively dividing tumor and normal cells. Unfortunately, this
agent also affects the non-dividing cells of the heart. In addition,
Adriamycin is recognized by a specific cellular mechanism, termed multi-
drug resistance (MDR). In vitro systems have been developed in our
laboratories in which cardiotoxic as well as tumoricidal and MDR
mechanisms of drugs can be studied, at the cellular and subcellular level.
We have uncovered fundamental differences in the electronegative membrane
potentials of these cells that may in part explain differential cellular
attraction of, and sensitivity to, Adriamycin, which is positively-
charged. We propose to study how charge and lipophilicity of Adriamycin
and related analogs affect their selective accumulation and toxicity in
cardiac-muscle cells (MDR-) and in MDR- and MDR+ tumor cell lines. These anthracyclines however, are complex in structure which makes their
use difficult for investigational structure/function studies of
cardiotoxicity and MDR. We therefore plan to use a series of simple
lipophilic-cationic compounds (guanidiniums and pyridiniums) as a model to
explore mechanisms of drug selectivity in MDR- and MDR+ cells. Recently,
utilizing this strategy we found (Cancer Research 52:6385-6389, 1992) that
an aromatic moiety and a certain degree of lipophilicity are required for
these simple cationic compounds to be recognized by MDR + cells. This
information will be used to further characterize the physical/chemical
requirements for MDR recognition as well as for MDR induction and
modulation. The specific aims of this proposal are to clarify the effects
that chemical charge and lipophilicity impact on these simple compounds as
well as on anthracyclines, to explain their differential accumulation and
consequent cytotoxicity in MDR- and MDR+ cells. The overall goal of these
studies is to increase understanding of the underlying mechanisms involved
in both ADM-induced cardiotoxicity and multiple drug resistance, which
could eventually translate into new designs of clinical protocols using
anthracyclines with maximal activity toward MDR + tumor cells and minimal
detrimental effects on cardiac cells. Our video-computerized system will be used to assay effects of drugs on
sensitive (non-MDR) cardiac cell function and viability in vitro.
Fluorescence microscopy, high pressure liquid chromatography and
radioactive probes will be used to measure intracellular drug accumulation
and transmembrane potentials.
StatusFinished
Effective start/end date7/1/836/30/12

Funding

  • National Institutes of Health: $343,254.00
  • National Institutes of Health: $303,676.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $313,989.00
  • National Institutes of Health
  • National Institutes of Health: $313,989.00
  • National Institutes of Health: $343,254.00
  • National Institutes of Health: $195,454.00
  • National Institutes of Health: $310,320.00
  • National Institutes of Health: $172,384.00
  • National Institutes of Health: $313,989.00
  • National Institutes of Health
  • National Institutes of Health: $188,028.00
  • National Institutes of Health: $343,254.00
  • National Institutes of Health: $343,254.00
  • National Institutes of Health
  • National Institutes of Health: $332,956.00
  • National Institutes of Health
  • National Institutes of Health

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Glycolysis
Neoplasms
Anthracyclines
Glycosylation
Deoxyglucose
Mitochondria
Doxorubicin
Multiple Drug Resistance
Pharmaceutical Preparations
Rhodamines
Rhodamine 123
Myocardium
Leukemia
Proteins
Oxygen
In Vitro Techniques
Carcinoma
valrubicin
Oxidative Phosphorylation
Cardiomyopathies

ASJC

  • Medicine(all)