Additive effect of concomitant multiple low-dose doxorubicin and thoracic irradiation on ex vivo cardiac performance of the rat heart

Wondergem, J.; Franken, Nicolaas A.P.; Chin, Alim; Ravels, F.J.M. Van; Leer, J.W.H.

doi:10.1007/s004320050148

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…Little is known about a possible interaction between anthracyclines and radiation on cardiovascular damage. There are some indications from rat studies that the interaction between doxorubicin and local heart irradiation is additive when the treatments are given concomitantly (Wondergem et al, 1998). Several clinical studies showed that anthracycline-containing therapy may further increase the radiation-related risk of congestive heart failure and valvular disorders two-to three-fold compared with radiotherapy alone (Moser et al, 2006;Aleman et al, 2007); this effect may be more than additive .…”

Section: Anthracyclinesmentioning

confidence: 99%

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs — Threshold Doses for Tissue Reactions in a Radiation Protection Context

Stewart¹,

Akleyev²,

et al. 2012

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This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

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Section: Anthracyclinesmentioning

confidence: 99%

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs — Threshold Doses for Tissue Reactions in a Radiation Protection Context

Stewart¹,

Akleyev²,

et al. 2012

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“…Doxorubicin is applied in myeloblastic leukaemia, lymphoblastic leukaemia (Wondergem et al 1998;Ibrahim et al 1999), breast cancer (Nielsen et al 2000), ovarian tumour, urinary bladder cancer, small-cell lung tumour, bone and soft tissue sarcoma, lymphomas and thyroid and stomach cancer treatment (Gnewuch & Sosnovsky 2002). After intravenous injection, the antibiotic quickly disappears from the plasma, which indicates a dynamic distribution of doxorubicin to the organs and tissues.…”

Section: The Characteristics Of Selected Drugs Causing Multidrug Resimentioning

confidence: 99%

“…Radiation therapy to the mediastinum (Wondergem et al 1998), advanced age and pre-existing cardiac disorders (Ibrahim et al 1999) augment the cardiotoxicity. To increase the safety of doxorubicin, combination with other drugs has been investigated (Herman et al 2000).…”

Section: The Characteristics Of Selected Drugs Causing Multidrug Resimentioning

confidence: 99%

“…Some of the adverse effects of this drug are bone marrow depression and cardiotoxicity, which result primarily from the generation of damaging free oxygen radicals but might also be partly due to the inhibition of topoisomerase II (Hande 1998;Wu et al 2001). Radiation therapy to the mediastinum (Wondergem et al 1998), advanced age and pre-existing cardiac disorders (Ibrahim et al 1999) augment the cardiotoxicity. To increase the safety of doxorubicin, combination with other drugs has been investigated (Herman et al 2000).…”

Section: The Characteristics Of Selected Drugs Causing Multidrug Resimentioning

confidence: 99%

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A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Sawicka

Kalinowska

Skierski

et al. 2004

Journal of Pharmacy and Pharmacology

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It is assumed that proteins from the ABC family (i.e., glycoprotein P (Pgp)) and a multidrug resistance associated protein (MRP) play a main role in the occurrence of multidrug resistance (MDR) in tumour cells. Other factors that influence the rise of MDR are mechanisms connected with change in the effectiveness of the glutathione cycle and with decrease in expression of topoisomerases I and II. The aim of this review is to characterize drugs applied in anti-tumour therapy and to describe the present state of knowledge concerning the mechanisms of MDR occurrence, as well as the pharmacological agents applied in reducing this phenomenon.

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Myocardial enzyme activities in plasma after whole-heart irradiation in rats

Franken

Strootman

Hollaar

et al. 2000

J Cancer Res Clin Oncol

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Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after radiotherapy. Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) were determined in the plasma and left ventricular myocardium of rats following local heart irradiation with a single dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and to reduce survival times of the animals. Cardiac enzyme assays were performed directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH, AST and alpha-HBDH levels were increased between 2 h and 24 h after irradiation. Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between 24 h and 16 days after radiation, did not differ between irradiated and control animals, although acute (first 12 h) reductions were observed in the irradiated group. The elevated enzyme levels in plasma appeared to correlate with the acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20 Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that fractionated radiation, as applied clinically for treatment of solid tumors, will induce plasma enzyme elevations that are large enough to indicate the extent of cardiac damage occurring acutely or chronically.

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Additive effect of concomitant multiple low-dose doxorubicin and thoracic irradiation on ex vivo cardiac performance of the rat heart

Cited by 4 publications

References 23 publications

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs — Threshold Doses for Tissue Reactions in a Radiation Protection Context

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs — Threshold Doses for Tissue Reactions in a Radiation Protection Context

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Myocardial enzyme activities in plasma after whole-heart irradiation in rats

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