# MECHANISM OF REVERSAL OF TUMOR DRUG RESISTANCE TO ARA-C

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 1987 · $128,410

## Abstract

Drug resistance of the tumor cells in cancer chemotherapy is very common.
The objective of this proposal is to investigate the mechanisms of reversal
of drug resistance of leukemic cells to Cytarabine (ara-C) by 5-Azacytidine
(5-Aza-C) and its derivatives, dihydro-5-azacytidine (DHAC) and
2'-deoxy-5-Azacytidine (5-Aza-dCyd).  The formation, accumulation and
elimination kinetics of the triphosphates of these compounds will be
determined in tumor (P388/0, L1210/ara-C, and P388/ara-C) and mouse host
tissues (bone marrow (BM) and gastrointestinal mucosa (GI)) by high
pressure liquid chromatography after in vivo injections of the maximally
tolerated doses (MTD) to tumor bearing mice.  The cellular concentrations
of the nucleotide analogs will be correlated with their effects on
inhibition of DNA synthesis and their incorporation into nucleic acids of
the tumor cells.  Our preliminary studies have indicated that partial
reversal of resistance of L1210/ara-C to ara-C by expressing deoxycytidine
kinase (dCyd kinase) is taking place after pretreatment of this tumor line
with DHAC.  This will be investigated in detail with all three drugs on the
L1210/ara-C tumor line.  Further studies of reversal of resistance to ara-C
will examine whether it is a general effect of expressing dCyd kinase to a
small percentage of control or a certain small number of L1210/ara-C cells
are expressing the enzyme as the L1210/0 cells.  Similar studies will be
carried out with the human leukemia cell line CCRF/CEM/O and CCRF/CEM/dCK
(-).  The evolution of tumor resistance to ara-C will be investigated in
relapsed pediatric leukemic patients who will receive one or more high dose
ara-C (HDara-C) treatments.  The pharmacodynamic parameters of HDara-C will
be determined along with the activity of various enzymes that may indicate
presence of resistance to ara-C, such as Cytidine deaminase and
dCyd-kinase.  Once resistance to ara-C has been established, the multiple
relapsed patients will receive 5-Aza-C in vivo.  The pharmacokinetic and
biochemical parameters will then be investigated to determine whether
5-Aza-C treatment alters the tumor resistance to ara-C.  The ultimate goal
of this project is to examine the mechanism of reversal of both murine and
human tumor that becomes resistant to ara-C.

## Key facts

- **NIH application ID:** 3177342
- **Project number:** 5R01CA038905-02
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **SAM.gov UEI:** DVL1CMRMWRN9
- **Principal Investigator:** VASSILIOS AVRAMIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $128,410
- **Award type:** 5
- **Project period:** 1986-04-01 → 1989-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3177342

## Citation

> US National Institutes of Health, RePORTER application 3177342, MECHANISM OF REVERSAL OF TUMOR DRUG RESISTANCE TO ARA-C (5R01CA038905-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3177342. Licensed CC0.

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