# CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 1989 · $273,943

## Abstract

The major objective of this research is to elucidate the mechanism of
action of the antitumor drug cis-diamminedichloroplatinum(II), cis-DDP.
Detailed information about how this leading anticancer drug functions will
facilitate both clinical protocols for its use in cancer chemotherapy as
well as the design of more effective drugs.  Several new reagents to
modulate and map the platinum binding sites on DNA, its most likely
biological target, will be prepared and characterized.  These include
chelating diamine platinum(II) complexes linked by a polymethylene or
polyamine chain to intercalators or to a pendant EDTA-containing side
chain.  Addition of Fe(II), O2, and dithiothreitol to the latter will
cleave the DNA backbone near the platinum binding sites, providing an
internal "molecular scissors" by which the platinum loci on DNA can be
mapped through subsequent electrophoresis on DNA sequencing gels.
Platinum-DNA binding locations will also be mapped by using existing and
proposed new mono- and polyclonal antibodies prepared agaist cis-DDP
modified DNAs.  To examine the hypothesis that cis-DDP is selectively
cytotoxic to cancer cells because of their lesser ability, compared with
normal cells, to repair a specific DNA-Pt lesion, such as the intrastrand
d(GpG) crosslink, the genome of M13 virus will be modified with cis-DDP at
a unique, chemically programmable site and introduced into normal and
repair-deficient cells.  Both repair of, and mutagenesis directed by, the
platinum lesion will be studied.  Replication of the cis-DDP modified M13
viral genome will also be investigated in vitro, and in vivo using E. coli
cells mutant in their ability to repair and/or replicate DNA.  These
experiments require the synthesis of oligonucleotides containing bound
cis-diammineplatinum(II).  Platinated oligonucleotides from 2 to 21 monomer
units in length will be synthesized, purified by HPLC chromatography, and
structurally characterized in solution by NMR spectroscopic methods.  Where
possible, X-ray crystal structures of crystalline complexes will be
determined.  Mammalian cells will be infected with SV40 virus, treated with
cis-DDp, and the platinum binding sites on the SV40 minichromosome mapped.
Platinum binding at critical control regions, e.g. enhancer sequences, will
be correlated with inhibition of viral directed processes.  The speciation
of cis-DDp in vivo and in buffers constructed to simulate intracellular
conditions will be studied chemically by 195Pt NMR spectroscopy.  The
chemical characterization of cis-diammine- and ethylenediamineplatinum
Alpha-pyridone blues and their Pt(III) derivatives will be completed.

## Key facts

- **NIH application ID:** 3172770
- **Project number:** 5R01CA034992-07
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **SAM.gov UEI:** E2NYLCDML6V1
- **Principal Investigator:** Stephen J. Lippard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $273,943
- **Award type:** 5
- **Project period:** 1983-01-01 → 1989-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172770

## Citation

> US National Institutes of Health, RePORTER application 3172770, CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS (5R01CA034992-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172770. Licensed CC0.

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