# MECHANISM OF ACTION OF ANTITUMOR DRUGS

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 1990 · $189,238

## Abstract

The purpose of this proposal is to investigate the cell killing
mechanism and associated DNA damage responses of a number of
clinically important antitumor drugs that are known to target
DNA topoisomerase II.  Many lines of evidence have strongly
supported the argument that the primary cellular lesion induced
by these drugs is a new and uncharacterized class of DNA
damage:  a reversible drug-topoisomerase-DNA cleavable
complex.  Preliminary studies have suggested that the cleavable
complexes are likely to be responsible for, in addition to cell
killing, the increased frequencies of sister chromatid exchanges,
the stimulation of the differentiation of murine erythroleukemic
cells in vitro, and the induction of heat shock hsp70 gene
expression.  In order to understand this new type of DNA damage
and its biological consequences associated with the antitumor
action of these topoisomerase-specific drugs, we propose the
following experiments:  (a) to investigate the regulation of the
drug target, DNA topoisomerase II, in normal and neoplastic cells.
(b) to characterize drug-enzyme-DNA cleavable complexes in
cultured cells and purified systems.  (c) to study the cellular
responses to topoisomerase-specific antitumor drugs.  (d) to study
the cell killing mechanism by genetic approaches.  The
understanding of the mechanism of action of topoisomerase II-
specific antitumor drugs is likely to shed light on the cell killing
mechanism of other antitumor drugs and improve drug efficacy in
cancer chemotherapy.

## Key facts

- **NIH application ID:** 3178941
- **Project number:** 5R01CA039662-06
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **SAM.gov UEI:** FTMTDMBR29C7
- **Principal Investigator:** LEROY F LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1990
- **Award amount:** $189,238
- **Award type:** 5
- **Project period:** 1985-04-01 → 1993-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178941

## Citation

> US National Institutes of Health, RePORTER application 3178941, MECHANISM OF ACTION OF ANTITUMOR DRUGS (5R01CA039662-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178941. Licensed CC0.

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