Mechanisms Responsible for Reduced Cardiotoxicity of Mitoxantrone Compared to Doxorubicin Examined in Isolated Guinea-Pig Heart Preparations

Abstract

ABSTRACT. We reported previously that doxorubicin, an anticancer agent that has an anthracycline structure, alters Ca 2+ releasing and uptake mechanisms in the sarcoplasmic reticulum of myocardial cells. These effects of doxorubicin are apparently related to its cardiotoxicity. Mitoxantrone is a similar anticancer agent with an anthracenedion structure that has been shown to be significantly less cardiotoxic. In the present study, the effects of mitoxantrone on the functions of the sarcoplasmic reticulum were examined in isolated muscle preparations obtained from the guinea-pig heart. In electrically-stimulated left atrial muscle preparations, incubation in vitro for 4 hr with 30 or 100 µM mitoxantrone significantly prolonged the time to the peak of twitch tension, markedly increased the developed tension observed at lower stimulation frequencies, thereby attenuating the slope of positive force-frequency relationships, and increased the postrest contraction observed after a 60-sec quiescent period. In myocytes isolated from ventricular muscles, 30 µM mitoxantrone increased the peak and the size of intracellular Ca 2+ concentrations ([Ca 2+ ]i), and prolonged the time to peak [Ca 2+ ]i. In skinned muscle fiber preparations obtained from the left ventricular muscle, 30 µM mitoxantrone significantly increased the caffeine-induced contraction without affecting the Ca 2+ sensitivity of contractile proteins. These results suggest that mitoxantrone enhances Ca 2+ release from the sarcoplasmic reticulum in isolated atrial muscle preparations obtained from the guinea-pig heart. Apparent enhancement of the sarcoplasmic reticulum functions, in contrast to anthracyclines that has been shown to suppress these functions, seems to explain the relative lack of marked cardiotoxicity of mitoxantrone. KEY WORDS: caffeine-induced contraction, Ca 2+ release and uptake by sarcoplasmic reticulum, inotropic effects, intracellular Ca 2+ concentration, mitoxantrone.J. Vet. Med. Sci. 70(3): 255-264, 2008 Anthracyclines are efficacious anti-tumor agents; however, their clinical usefulness is limited by serious cardiotoxic effects. Mitoxantrone, an anthracenedion derivative, has been synthesized in an attempt to develop an agent that has a reliable anticancer activity without the compromising cardiotoxic effects [9,35].Human as well as animal studies demonstrated that the cardiotoxic effects of mitoxantrone are significantly less severe at clinically equivalent anticancer doses compared to those observed with anthracyclines [2,9,11,13,20,22,33].We reported previously [7] that in vivo treatment of rats with doxorubicin results in a prolongation of the time to the peak of twitch tension, a reduction of the developed tension observed at lower stimulation frequencies and an attenuation of the postrest contraction (contraction that is evoked by the first stimulus after a brief quiescent period) observed in electrically-stimulated heart muscle preparations obtained from the drug-treated animals. These changes developed slowly with time aft...

Mitoxantrone removal by electrochemical method: A comparison of homogenous and heterogenous catalytic reactions

“…Mitoxantrone (MXT) is a synthetic antineoplastic drug structurally analogous to anthracyclines such as doxorubicin (DOX). MXT has been used in the treatment of various cancers including leukemia, non-Hodgkin lymphoma and breast cancer (29). To the best of our knowledge, there is no report related to the degradation of MXT by the electro-Fenton process.…”

Interaction of Chemotherapy and Radiation

“…Mitoxantrone is an anthracenedione that was designed to function like an anthracycline but have less cardiotoxicity 85 because it is less likely to form free radicals 35 and may affect calcium release differently. 86 Like anthracyclines, mitoxantrone can intercalate in DNA and poison TopII to form DNA double-stranded breaks. This drug is approved for hormone-refractory prostate cancer.…”

Green Tea Catechins Increase the Force of Contraction in Isolated Guinea Pig Atrial Muscle Preparations by Increasing the Amplitude of Intracellular Ca²⁺ Concentration

“…The amplitude of [ca 2+ ] i was calculated by subtraction of the value of the 340/380 nm ratio at the maximal diastolic period from the value of the 340/380 nm ratio at the peak of [ca 2+ ] i [4]. In the experiments with EGcG (20, 100, and 300 µM) and EcG (5 and 50 µM), the force of contraction and [ca 2+ ] i were examined in one muscle preparation using one concentration of each catechin.…”

“…The left atrial muscle preparation showed stable contractions during repeated electrical stimulation throughout a relatively long experiment [4]. In addition, since the muscle tissue is sufficiently thin and the size is appropriate for measurement of [ca 2+ ] i, this experiment has the advantage that simultaneous recordings of the force of contraction are possible from the same area of the myocardial tissue with only a small variation in experimental results.…”