# MECHANISM OF RADIOPROTECTION BY AMINOTHIOLS

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 1987 · $159,907

## Abstract

The most effective radioprotective drug now available is
S-2(3-aminopropylamino)-ethyl phosphorothioic acid (WR-2721, RSP), a drug
currently undergoing clinical trials as an agent which radioprotects and
chemoprotects normal but not tumor tissue.  Studies of the mechanism of
action have been hindered by the lack of methods for measurement of RSP,
its hydrolysis product (WR-1065, RSH), corresponding disulfide forms (RSS),
other metabolites, and also by the failure to achieve good protection in
cultured cell systems where key factors such as temperature, oxygen
tension, and drug level can be accurately known and controlled.  Using
recently developed methods based upon fluorescent labeling and HPLC
analysis for determination of RSP, RSH, and RSS we have found that alkaline
phosphatase added to culture media containing RSP rapidly converts it to
RSH and RSS, and promotes intracellular accumulation of RSH, with
accompanying radioprotection, in fully oxygenated V-79 cells.  We propose
to exploit and expand this advance in the technology in order to:  (1)
establish the mechanisms of transport of RSP and its metabolites, (2)
elaborate the mechanisms of toxicity associated with the drug, and (3)
identify the drug forms and the mechanisms involved in radioprotection.
The rates at which RSP, RSH, and specific RSS forms are taken up and
exported by cells will be determined.  The forms of the drug responsible
for cell toxicity will be examined.  The mechanism of radioprotection of
V-79 cells will be investigated by determining the relationship between
radioprotection and intracellular drug level under both oxic and anoxic
conditions, and determining whether protection involves initial damage or
biochemical repair processes.  Equilibrium binding of specific drug forms
to calf thymus DNA will be used as an initial probe to assess the
importance of DNA-drug interactions.  Significant findings with V-79 cells
will be tested in other normal cell lines to assess species and tissue
variation, and in selected tumor cell lines to ascertain whether the in
vivo difference between normal vs tumor cells has a biochemical basis that
can be measured in vitro.  The results of these studies should greatly
clarify our understanding of how WR-2721 functions, will identify key
factors to be monitored in clinical studies, and may indicate features to
be considered in improved drug design.

## Key facts

- **NIH application ID:** 3178729
- **Project number:** 5R01CA039582-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **SAM.gov UEI:** UYTTZT6G9DT1
- **Principal Investigator:** ROBERT C FAHEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $159,907
- **Award type:** 5
- **Project period:** 1985-04-01 → 1988-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178729

## Citation

> US National Institutes of Health, RePORTER application 3178729, MECHANISM OF RADIOPROTECTION BY AMINOTHIOLS (5R01CA039582-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178729. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*