Antineoplastic activity of continuous exposure to dexrazoxane: potential new role as a novel topoisomerase II inhibitor.

Abstract:

:Although originally developed as an antitumor agent in the 1970s, dexrazoxane (DEX) is currently used as a cardioprotective agent in combination with doxorubicin (DOX). Due to concerns about anthracycline-induced cardiotoxicity at higher cumulative doses, many investigators have chosen to administer DOX by prolonged infusion. Therefore, with the ultimate goal of combining infusional DEX and DOX, we performed a phase I study of intravenous DEX alone as a 96-hour infusion. Surprisingly, the maximum tolerated dose of DEX identified in this study was 10- to 15-fold lower than previously determined using different schedules of administration. Results of pharmacokinetic studies in support of the trial have found that steady-state DEX plasma concentrations in the range of 4 to 5 micromol/L can be achieved safely. Because previous experiments have explored the ability of DEX to inhibit the catalytic activity topoisomerase II at low micromolar concentrations and due to a lack of in vitro cytotoxicity data for long-term exposures, we performed further laboratory studies to provide a context for our pharmacokinetic findings. As a result of these correlative studies, we have found that prolonged exposures to DEX are cytotoxic to human leukemic cells at concentrations that are clinically achievable.

journal_name

Semin Oncol

journal_title

Seminars in oncology

authors

Synold TW,Tetef ML,Doroshow JH

subject

Has Abstract

pub_date

1998-08-01 00:00:00

pages

93-9

issue

4 Suppl 10

eissn

0093-7754

issn

1532-8708

journal_volume

25

pub_type

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