FLUDARABINE INHIBITS DNA-REPLICATION - A RATIONALE FOR ITS USE IN THE TREATMENT OF ACUTE LEUKEMIAS

被引：24

作者：

GANDHI, V

HUANG, P

PLUNKETT, W

机构：

[1] Department of Clinical Investigation, The University of Texas M.D. Anderson Cancer Center, Houston, TX

来源：

LEUKEMIA & LYMPHOMA | 1994年 / 14卷

关键词：

ARABINOSYLCYTOSINE; ARA-CTP; FLUDARABINE; F-ARA-ATP; SELF-POTENTIATION;

D O I：

10.3109/10428199409052689

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Fludarabine is a prodrug that must enter cells and be phosphorylated to the nucleoside triphosphate, F-ara-ATP, to elicit biological activity. F-ara-ATP serves as an inhibitory alternative substrate in several key processes involved in DNA synthesis. The enzymes required in DNA synthesis and affected by F-ara-ATP are ribonucleotide reductase, DNA primase, DNA polymerases, 3'-5' exonuclease activity of DNA polymerases delta and epsilon, and DNA ligase I. The action of fludarabine on DNA replication provides a compelling rationale to use this agent for leukemias where target cells are actively synthesizing DNA, for example acute myelogenous leukemia. Additionally, the role of F-ara-ATP to potentiate the activity of deoxycytidine kinase makes it an appropriate candidate to use in combination with other nucleoside analogs which require deoxycytidine kinase for their activation. The present article reviews the effect of fludarabine on enzymes involved in DNA synthesis and the role of fludarabine in combination with arabinosylcytosine for the treatment of diseases other than indolent leukemias.

引用

页码：3 / 9

页数：7

共 49 条

[1]

Montgomery J.A., Hewson K., Nucleosides of 2-fluo-roadenine, J. Med. Chem., 12, pp. 498-504, (1969)

[2]

Malspeis L., Grever M.R., Staubus A.E., Pharmacokinetics of 2-Fara-A (9-β-D-arabinofuranosyl-2-fluo-roadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate, Semin. Oncol., 17, Suppl. 8, pp. 18-32, (1990)

[3]

Danhauser L., Plunkett W., Keating M., 9-β-D-ara-binofuranosyl-2-fluoroadenine 5′-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma, Cancer Chemother. Pharmacol., 18, pp. 145-152, (1986)

[4]

Plunkett W., Huang P., Gandhi V., Metabolism and action of fludarabine phosphate, Semin. Oncol., 17, Suppl. 8, pp. 3-17, (1990)

[5]

Plunkett W., Saunders P.P., Metabolism and action of purine nucleoside analogs, Pharmacol. Ther., 49, pp. 239-268, (1991)

[6]

Plunkett W., Gandhi V., Cellular metabolism of nucleoside analogs in CLL: Implications for drug development, Chronic Lymphocytic Leukemia. Scientific Advances and Clinical Developments, pp. 197-219, (1992)

[7]

Kemena A., Gandhi V., Shewach D.S., Inhibition of fludarabine metabolism by arabinosylcytosine during therapy, Cancer Chemother. Pharmacol., 31, pp. 193-199, (1992)

[8]

Gandhi V., Estey E., Keating M.J., Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy, J. Clin. Oncol., 11, pp. 116-124, (1993)

[9]

Gandhi V., Kemena A., Keating M.J., Cellular pharmacology of fludarabine triphosphate in chronic lymphocytic leukemia cells during fludarabine therapy, Leukemia Lymphoma, 10, pp. 49-56, (1993)

[10]

Plunkett W., Gandhi V., Huang P., Fludarabine: Pharmacokinetics, mechanisms of action, and rationales for combination therapies, Semin. Oncol., 20, pp. 2-12, (1993)

← 1 2 3 4 5 →