RADIOPROTECTIVE DRUGS--MECHANISM AND BIOLOGICAL STUDIES

Project: Research project

Project Details

Description

This project will investigate aminoalkylthiol radioprotective drugs
and has two distinct but complementary goals: to study the
mechanisms of these drugs' effects and to develop pragmatic
applications for radiation therapy. Several questions are posed.
How are radioprotective drugs taken up across biological
membranes and distributed at the subcellular, cellular and tissue
level? How are the drugs metabolized and by what mechanisms
do these metabolites ameliorate radiation injury and interact with
endogenous protective substances? How may the effects of these
drugs be quantified in terms of direct radioprotection as well as
other biological endpoints that modify expression of radiation
injury? What can be learned about their application through
pragmatic preclinical studies? The specific aims will address these questions in systems of
increasing complexity, beginning with in vitro cell-free systems
such as liposomes, DNA and enzymes in solution, and homogenates
prepared from normal and malignant cells. Cultured cells from
rodent sarcomas and gliomas and from normal rat and human
neural tissue as well as cell isolated from liver and kidney will be
used to investigate and correlate protector uptake, metabolism,
and protective effect. Protective studies in vivo will emphasize
temporal or spatial localization of radioprotectors to selected
rodent normal tissues but not tumors. Possible differential
protection of normal CNS relative to brain tumors, protection of
liver by drugs targeted to that organ via specific receptor ligands,
and protection of normal tissue against radiation from I-131
labeled monoclonal antibodies prior to their concentration in
tumor will be tested as applications of drug targeting. To support
these biological aims new molecules, including lipophilic
protectors capable of crossing the blood brain barrier, thiols with
less polar latentiating groups, and thiols coupled to receptor
specific ligands will be synthesized and labeled with H-3 or S-35.
Analytical techniques (HPLC, TLC, autoradiography) will be
developed and used.
StatusFinished
Effective start/end date12/1/834/30/94

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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.