# REDUCTION OF TOXICITY IN CANCER CHEMOTHERAPY

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 1991 · $190,166

## Abstract

Cis-platinum is a highly effective and widely used anticancer drug; severe
toxicity, particulary to the kidney and gastrointestinal tract, limits both
the dose and duration of chemotherapy with this promising drug.  We have
demonstrated that diethyldithiocarbamate (DDTC) protects against
cis-platinum toxicity to the kidney, GI tract, and bone marrow in a variety
of animal species, and it inhibits nausea and vomiting in the dog.  These
benefits are achieved without inhibiting the antitumor properties of the
drug, and the protective effects of DDTC allow use of much higher doses of
cis-platinum with impressive increases in tumor response.  Phase I clinical
trials are now underway.  The long range objectives of the research
outlined in this application are to increase our understanding of the
interactions among platinum(II) complexes, the biological ligands with
which they react, and the DDTC ligand, and to utilize this knowledge to
optimize DDTC's efficacy as a clinical chemoprotective agent.  Specific
aims include 1) The utilization of pharmacokinetic data to optimize the
therapeutic index of the DDP-DDTC combination; 2) Determination of the
mechanism by which cis-platinum causes nephrotoxicity and the basis whereby
delayed administration of DDTC protects against this toxicity; 3)
Determination of the mechanism by which platinum drugs cause bone marrow
toxicity, and evaluate the ability of DDTC to inhibit marrow toxicity
induced by the platinum drugs and other cross-linking agents; 4)
Determination of both the generality and the mechanistic basis for DDTC's
ability to potentiate the anti-tumor activity of cis-platinum.
Pharmacokinetics will be measured in Phase I patients and in rodents using
our recently developed HPLC methods; mechanisms of renal toxicity will be
studied using enzyme kinetics, electron microscopy, and low temperature
solids nmr.  Bone marrow experiments will be carried out in mice by direct
measurement of marrow cellularity, assessment of CFU-S and CFU-C activity,
and determination of DNA interstrand cross-linking by alkaline elution.
The basis for DDTC potentiation will be investigated with
platinum-nucleoside complexes as models to study their redox properties and
their reactions with active oxygen species.

## Key facts

- **NIH application ID:** 3172375
- **Project number:** 5R01CA034620-09
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **SAM.gov UEI:** F27KDXZMF9Y8
- **Principal Investigator:** RICHARD F. BORCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $190,166
- **Award type:** 5
- **Project period:** 1982-09-01 → 1995-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172375

## Citation

> US National Institutes of Health, RePORTER application 3172375, REDUCTION OF TOXICITY IN CANCER CHEMOTHERAPY (5R01CA034620-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172375. Licensed CC0.

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