# COMBINATION INTRACAVITARY CHEMOTHERAPY

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 1988 · $169,704

## Abstract

The studies accomplished during the first three years of this grant have
established the feasibility of combination cisplatin-based intraperitoneal
therapy with thiosulfate neutralization.  Current results suggest that this
therapy can salvage patients with small volume drug-resistant disease.  Our
aim is to further improve the therapeutic index of ip chemotherapy by
investigating:  1) the use of selective intraperitoneal biochemical
modulation; and 2) the mechanism by which sodium thiosulfate alters the
metabolism of cisplatin (DDP) so as to provide selective protection of the
kidneys.  The ability of dipyridamole (DP) to enhance the activity of
methotrexate (MTX) has been selected as a mode concentration-dependent
synergistic interaction with which to test the feasibility of producing
selective biochemical modulation in the peritoneal cavity where high local
concentrations of dipyridamole can be attained.  The specific aims of this
project are:  a) to determine the basic parameters of the DP/MTX
interaction in human ovarian carcinoma cell lines, and test the concept of
selective ip biochemical modulation in an ascitic xenograft model of human
ovarian carcinoma; b) to perform a pharmacokinetic study of DP administered
ip to patients with cancer involving the peritoneal cavity; and c) to
undertake a phase I study of the combination of DP and MTX administered
together by the ip route.  In the second project, we will further
investigate the use of iv thiosulfate as a neutralizing agent in
combination with ip administration of DDP.  We will determine how
thiosulfate influences the generation of nephrotoxic species from DDP using
new techniques that permit resolution and quantitation of 8 metabolites.
The specific aims of this project are:  a) to determine how thiosulfate
affects the generation of DDP metabolites in vitro, and how it influences
the pharmacokinetics of DDP metabolites in the plasma of patients receiving
DDP; b) to determine whether iv thiosulfate, at doses sufficient to protect
the kidneys, interferes with the antitumor activity of ip administered DDP
in the Ehrlich ascites tumor model; c) to identify the metabolites which
are most important with respect to toxicity to the kidneys, marrow and
nerves; d) to investigate the changes that DDP produces in plasma
glutathione, cyst(e)ine, and methionine in association with the generation
of DDP metabolites; and e) to study the influence of thiosulfate on the
generation of DDP metabolites inside human ovarian carcinoma cells.

## Key facts

- **NIH application ID:** 3172889
- **Project number:** 5R01CA035309-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **SAM.gov UEI:** UYTTZT6G9DT1
- **Principal Investigator:** STEPHEN B HOWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $169,704
- **Award type:** 5
- **Project period:** 1983-08-01 → 1989-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172889

## Citation

> US National Institutes of Health, RePORTER application 3172889, COMBINATION INTRACAVITARY CHEMOTHERAPY (5R01CA035309-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172889. Licensed CC0.

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