# DNA REPAIR AND RESISTANCE TO PLATINUM DRUG TOXICITY

> **NIH NIH R01** · DARTMOUTH COLLEGE · 1990 · $125,602

## Abstract

This research represents an investigation of the mechanisms of
action of the cancer chemotherapeutic platinum coordination
complexes, as well as an investigation of the mechanism of cellular
sensitivity and resistance.  Three murine leukemia L1210 cell lines
will be used: a) L1210/0, which is sensitive to the action of both
cis-diamminedichloroplatinum(II) (cis-DDP) and 1,2-
diaminocyclohexaneplatinum (DACH-Pt) analogues, b) L1210/DDP, which
is preferentially resistant to cis-DDP, c) L1210/DACH, which is
preferentially resistant to DACH-Pt.  The resistant cells exhibit
some reduced accumulation of cis-DDP, but the majority of
resistance is attributed to enhanced DNA repair.  Two different
assays of DNA repair have been used, one measuring direct removal
of DNA bound adducts, the other measuring the ability of cells to
express a transfected damaged gene.  The latter assay demonstrated
that one adduct was normally sufficient to inhibit transcription,
suggesting this could contribute to the mechanism of toxicity
rather than inhibition of DNA synthesis previously suggested. The
aims are, therefore, to further characterize the DNA repair
process. using DNA repair inhibitors and probe for repair of
specific genes.  Attempts will be made to purify the protein(s)
involved.  An assay for inhibition of transcription on a defined
gene is proposed, which will be compared to DNA repair of adducts
within the same gene.  Recombination, as a mechanism for
replicative bypass of DNA adducts will also be investigated.  In
other experiments, attempts will be made to identify the
chromosome(s) coding for resistance by using chromosome-mediated
gene transfer. This is a preliminary to isolating the genes in-
volved.  Parallel studies will be performed to assess the mechanism
of resistance to DACH-Pt in L1210/DACH and also to assess the
mechanisms of hypersensitivity to cis-DDP in embryonal cells. These
cells are representative of tumors that are very responsive to cis-
DDP therapy.

## Key facts

- **NIH application ID:** 3173546
- **Project number:** 5R01CA036039-08
- **Recipient organization:** DARTMOUTH COLLEGE
- **SAM.gov UEI:** EB8ASJBCFER9
- **Principal Investigator:** ALAN R EASTMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1990
- **Award amount:** $125,602
- **Award type:** 5
- **Project period:** 1983-06-01 → 1990-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3173546

## Citation

> US National Institutes of Health, RePORTER application 3173546, DNA REPAIR AND RESISTANCE TO PLATINUM DRUG TOXICITY (5R01CA036039-08). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3173546. Licensed CC0.

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