# CELL BIOLOGY AND PHARMACOKINETICS OF LOW-DOSE ARA-C

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 1987 · $156,311

## Abstract

This project is designed to improve understanding of the action of low-dose
1-Beta-D-arabinofuranosylcytosine (LD-ARA-C) (20 mg/m2 q 24 hrs) and
2,2'-anhydro-1-Beta-D-arabinofuranosyl-5-fluorocytosine (AAFC) in the
treatment of human acute non-lymphocytic leukemia.  A phase I study will
determine the in vivo dose of AAFC equivalent to LD-ARA-C.  Studies in
patients will be complemented by in vitro investigation using the human
promyelocytic cell line HL-60.  Specifically, effects on cell cycle, RNA
content, chromatin structure in situ, 3H-TdR incoporation will be
investigated with a variety of flow cytometric techniques (FCM) and
autoradiography and will elucidate cell kinetic effects of ARA-C and AAFC
at different dose levels.  Pharmacokinetic studies of LD-ARA-C and AAFC
will include determination of ARA-C and ARA-U levels in plasma and urine by
radioimmunoassay (RIA) and ARA-CTP formation and inhibition of 3H-thymidine
incorporation into DNA of bone marrow cells by ARA-CTP.  Determination of
deoxycytidine kinase and cytidine deaminase in plasma and bone marrow cells
will use deoxycytidine and ARA-C and cytidine and ARA-C respectively as
substrates.  Levels of AAFC and/or its metabolites will be studied by
HPLC.  If required for very low AAFC levels, a RIA for AAFC will be
developed.  ARA-C and AAFC will be compared as to clinical, cell kinetic,
and pharmacokinetic effects.  In vitro studies will evaluate cell kinetic
effects, deaminase and kinase in medium and HL-60 cells, and intracellular
nucleotide formation at different concentrations and time points.  For this
purpose, 3H-ARA-C and 14C-AAFC will be used.

Concomitant studies of differentiation antigens will investigate the effect
of LD-ARA-C and AAFC on the differentiation of leukemic cells.  A panel of
monoclonal antibodies directed against intracellular onc-gene (ras, myb,
mos, myc, sis) products and cell surface antigens will define discrete
steps of onc-gene expression and differentiation of myeloid leukemia and
will be determined serially in vitro and in vivo.  Simultaneous
determination of cellular DNA content and antigen expression and of marrow
cellularity by multiparameter FCM will clearly distinguish differentiation
effects from cytotoxic effects on human leukemic and non-leukemic cells.
We expect these studies to improve our understanding of the mode of action
of ARA-C and AAFC, to correlate pharmacological, cell biological and
clinical effects, to predict response and failure for groups of patients
and to optimize therapeutic effects in individual patients.

## Key facts

- **NIH application ID:** 3177534
- **Project number:** 5R01CA038980-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **SAM.gov UEI:** KUKXRCZ6NZC2
- **Principal Investigator:** MICHAEL ANDREEFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $156,311
- **Award type:** 5
- **Project period:** 1985-07-01 → 1988-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3177534

## Citation

> US National Institutes of Health, RePORTER application 3177534, CELL BIOLOGY AND PHARMACOKINETICS OF LOW-DOSE ARA-C (5R01CA038980-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3177534. Licensed CC0.

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