# CELLULAR PHARMACOLOGY IN CANCER CHEMOTHERAPY

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 1991 · $187,304

## Abstract

DESCRIPTION (Adapted from the applicant's abstract):  The goal of this
application is to establish pharmacologic and biochemical bases for
understanding clinical response of human leukemia and for guiding protocol
design.  The project concentrates on nucleoside analogues that have proven
(ara-C) or newly discovered activity (fludarabine, 2-chlorodeoxyadenosine)
and one whose activity is under investigation (difluorodeoxycytidine).  The
rational combination of growth factors (GM-CFS) with chemotherapy requires
knowledge of their influence on the pharmacodynamics and pharmacokinetics
of nucleotide analogues in human leukemia cells during therapy.  The
following approaches serve as focal points.  1.  Biochemical modulation.  A
clinical trial has been designed to test the hypothesis that the
schedule-specific infusion of fludarabine and ara-C will augment ara-C
5'-triphosphate accumulation in chronic lymphocytic leukemia cells.  These
investigations will be modeled with in vitro studies to determine the role
of fludarabine 5'-triphosphate and dexoynucleoside triphosphates (dNTP) in
modulating deoxycytidine kinase.  2.  Biological modulation.  The action of
GM-CSF on ara-C 5'-triphosphate pharmacokinetics and pharmacodynamics will
be investigated following ara-C infusions in chronic myelogenous leukemia
(CML) blasts serially before and after three days of GM-CSF treatment.
Colonogenicity will be evaluated ex vivo in parallel for prognostic
significance.  3.Pharmacologic determinants of response.  Correlations are
being sought between clinical response to a pharmacologically guided phase
I trial of difluorodeoxycytidine in relapsed acute leukemia and CML blast
crisis and the metabolism and action of this drug in leukemia cells during
therapy and ex vivo after treatment.  4.  Mechanisms of programmed cell
death.  The action of fludarabine and 2-chlorodeoxyadenosine on cells of
lymphocytic leukemia will be investigated in vitro and during therapy.
These studies will focus on DNA damaging mechanisms known to be active in
programmed cell death:  lowered ATP, dNTP, and NAD+ pools, ADP
ribosylation, and DNA fragmentation.

## Key facts

- **NIH application ID:** 3170682
- **Project number:** 2R01CA032839-09
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **SAM.gov UEI:** S3GMKS8ELA16
- **Principal Investigator:** WILLIAM K PLUNKETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $187,304
- **Award type:** 2
- **Project period:** 1983-08-01 → 1996-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3170682

## Citation

> US National Institutes of Health, RePORTER application 3170682, CELLULAR PHARMACOLOGY IN CANCER CHEMOTHERAPY (2R01CA032839-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3170682. Licensed CC0.

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