# MECHANISM OF ACTION OF ANTITUMOR DRUGS

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 1987 · $125,671

## Abstract

The purpose of this proposed research is to study the molecular mechanism
of cell killing by anti-cancer drugs which are known to produce
protein-linked DNA breaks in vivo.  Our long term goal is to understand the
regulatory mechanism of cell proliferation and cell death.  The proposed
research focuses on the phenomenon of protein-linked DNA breaks which
represents a novel type of DNA damage produced by many potent antitumor
agents.  Relatively little is known about the biological consequences of
this particular DNA damage.  Recently, there is increasing evidence that
mammalian DNA topoisomerase II may be the intracellular target of these
antitumor drugs and the formation of protein-linked DNA breaks may be the
direct result of drug-topoisomerase or drug-topoisomerase-DNA interaction.
In vitro studies have suggested that many antitumor drugs may interfere
with the breakage-reunion reaction of mammalian DNA topoisomerase II by
blocking the reunion of transiently broken DNA.  Whether the observed in
vitro reaction reflects drug action in vivo has not been fully
established.  Furthermore, the molecular mechanism of rapid cell killing by
these antitumor drugs is still not known.  In order to answer these
questions, both genetic and biochemical experiments will be performed to
identify mammalian DNA topoisomerase II as the cytotoxic target.  Genetic
analyses of drug resistant mutants will be used to identify mammalian
topoisomerase II as the primary cytotoxic target of these antitumor drugs.
Localization of the protein-linked DNA breaks on human chromosomes will be
carried out by an indirect end labeling mapping procedure.  The nucleotide
sequences around the breakage sites will be determined by cloning and
sequencing.  DNA clones containing the strong breakage sites will be used
for in vitro studies using purified HeLa topoisomerase II.  Human cells
treated with epipodophyllotoxin, VP-16, will be used as a model system for
the analyses of the biological consequences leading to cell death.

## Key facts

- **NIH application ID:** 3178939
- **Project number:** 5R01CA039662-03
- **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:** 1987
- **Award amount:** $125,671
- **Award type:** 5
- **Project period:** 1985-04-01 → 1988-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178939

## Citation

> US National Institutes of Health, RePORTER application 3178939, MECHANISM OF ACTION OF ANTITUMOR DRUGS (5R01CA039662-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178939. Licensed CC0.

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