# MECHANISM OF ACTION OF PLATINUM ANTICANCER DRUGS

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 1989 · $89,675

## Abstract

We have proposed to study the mechanism of action of cis
1,2-diaminocyclohexyl malonato platinum (II) [(cisDACH)PT(mal)] and related
compounds in the mouse L-1210 leukemia cell line.  (cisDACH)Pt(mal) is a
second generation platinum compound with comparable effectiveness to
cis-diammino dichloro platinum (II) [cis(NH3)2Pt(Cl)2] but with better
penetration of the blood brain barrier and reduced nephrotoxicity.  It has
already shown promise in some clinical trials.  Our laboratories have
recently developed new techniques to:  1) measure intracellular metabolites
of (cisDACH)Pt(mal) and related platinum compounds; 2) measure platinum-DNA
monoadducts, intrastrand G-G cross-links, and intrastrand G-X-G cross-links
as well as interstrand cross-links; and 3) measure an excision nuclease
activity capable of removing intrastrand cross-links.  These techniques
have not been previously available.  We plan to use these techniques to
answer the following questions:  1) What are the major metabolites of
(cisDACH)Pt(mal) in the cell and are there significant differences between
the metabolism of platinum compounds containing malonate and chloride
leaving ligands?  2) What are the proportions of interand intrastrand
cross-links in L-1210 cells treated with cytotoxic levels of
(cisDACH)-Pt(mal) and related platinum compounds?  3) Do intrastrand
cross-links correlate with the platinum induced inhibition of DNA synthesis
and cytotoxicity?  4) How are intrastrand cross-links removed from the DNA
of mammalian cells?  and 5) What is the mechanism of resistance of the
L-1210/DDP cell line to platinum (II) compounds and why is is not resistant
to platinum compounds containing the DACH carrier ligand?  In view of the
current interest in (cisDACH)Pt(mal) and (transDACH)Pt(mal) as possible
clinical drugs, the metabolic and mechanistic studies with (cisDACH)Pt(mal)
should be particularly valuable at this time.  In view of the widespread
use of cis(NH3)2Pt(Cl)2 in the treatment of human cancers, the experiments
designed to resolve the mechanism of DNA-platinum modification and repair
are important.  Finally, the studies with the resistant cell line of L-1210
may well serve as a model to facilitate the understanding of resistance to
platinum drugs in human tumors.

## Key facts

- **NIH application ID:** 3171827
- **Project number:** 5R01CA034082-06
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **SAM.gov UEI:** D3LHU66KBLD5
- **Principal Investigator:** STEPHEN G CHANEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $89,675
- **Award type:** 5
- **Project period:** 1987-02-01 → 1991-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3171827

## Citation

> US National Institutes of Health, RePORTER application 3171827, MECHANISM OF ACTION OF PLATINUM ANTICANCER DRUGS (5R01CA034082-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3171827. Licensed CC0.

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