# MECHANISM OF RESISTANCE TO PLATINUM ANTICANCER DRUGS

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 1992 · $151,947

## Abstract

The major goal of this project is to understand how the nature of the
carrier ligand affects resistance platinum drugs.  In particular, we are
interested in carrier ligand effects involving diaminocyclohexane (dach)-Pt
compounds, since one of these compounds, ormaplatin (OP), is currently in
clinical trial. Our data show no significant carrier ligand effects on bulk
DNA repair of Pt adducts in the L1210 cell lines, but do not eliminate the
possibility of carrier ligand effects on gene specific repair.  Thus, we
propose to collaborate with Dr. Vilhelm Bohr to determine whether there are
any carrier ligand effects on gene specific repair in the L1210 cell lines.
We have characterized carrier ligand effects in some detail with the human
cell lines, but have not completely resolved the issue of which of these
carrier ligand effects are most predictive dach-Pt sensitivity in cisplatin
(CP)-resistant tumors.  Thus, we plan to: (a) compare carrier ligand
effects uptake and efflux, tolerance of PT-DNA adducts, repair and bypass
replication for A2780/DDP, which shows no carrier ligand effects on
resistance, and A2780/CP8, another CP-resistant derivative of A2780 which
retains sensitivity to dach-Pt compounds; (b) confirm carrier ligand
effects on repair by an independent assay; and (c) determine carrier ligand
effects on bypass replication.  Recent studies have suggested that
decreased accumulation of platinum may be an important mechanism of
resistance in many 11 lines.  Unfortunately, the mechanism of platinum
accumulation is not known in detail, in part because of the lack of
suitable radiolabeled platinum compounds and in part because of the
difficulty in separating efflux from the metabolism of platinum complexes.
Our data show that the pattern of uptake OP and CP is essentially the same
in the human cell lines we are studying.  Thus, we plan to: (a) use the 3H-
OP we have prepared previously to characterize uptake and efflux in detail;
(b) use the HPLC techniques we have devised to determine the effects of
intracellular metabolism on uptake and efflux; and prepare a
non-metabolizable platinum complex for uptake and efflux studies.  Finally,
our data suggest at both repair and bypass replication may be inducible.
Thus, we plan to: (a) determine the extent to which both repair and bypass
replication are inducible, whether the induction of those processes is
required for the resistant phenotype, and whether carrier ligand effects
are expressed at the level of induction; (b) use the transient
chloramphenical acetyltransferase expression assay to characterize the
induction of gene expression in our cell lines; and (c) determine if the
signal for the induction of gene expression is Pt damage on DNA.  By
identifying the sites and mechanisms of carrier ligand effects on
resistance, it is hoped that is research will: (1) lead to improved
strategies (eg combination chemotherapy) for overcoming resistance with
dach-Pt compounds; (2) help identify the tumor typ...

## Key facts

- **NIH application ID:** 3171823
- **Project number:** 2R01CA034082-07A2
- **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:** 1992
- **Award amount:** $151,947
- **Award type:** 2
- **Project period:** 1987-02-01 → 1994-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3171823

## Citation

> US National Institutes of Health, RePORTER application 3171823, MECHANISM OF RESISTANCE TO PLATINUM ANTICANCER DRUGS (2R01CA034082-07A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3171823. Licensed CC0.

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