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specific changes in the RAR/RXR ratio, that will cause a decrease in the expression of proapoptotic proteins and increase in the expression of antiapoptotic proteins thus resulting in the prevention of apoptosis; and 5) High dose of retinoic acid (1pM) reduced oxidative stress but did not modulate the changes in RAR/RXR receptor ratio due to adriamycin, thus failing to protect against adriamycin-induced apoptosis. It is concluded that retinoic acid signaling may play a intermediating role in oxidative stress-induced apoptosis due to adriamycin. Thus it may be involved in the patho genesi s o f adriamycin-induced c ardiomyop athy and heart fai lure.
LITERATURE REVIE\il I. Adriamycin induced cardiomvopathy I.a. Background information I.a.l.Brief History: The first representative of antineoplastic antibiotic anthracycline family, daunomycin, was isolated from the micro-organism Steptomyces peucetius in 1957 (Ghione M. 1975). This newly discovered antibiotic created excitement as an antibiotic effective against a wide array of tumors (Boiron et al. 1969; Di Marco et al. 1963; Jacquillat et al. 1966; Tan C. and Tasaka H. 1965). Because of its severe cardiotoxicity (Tan et al. 1967) a new, red-pigmented compound was isolated from a mutated strain of Steptomycesbactena named Streptomyces peucetius var. caesius. This compound, l4-hydroxy analogue of daunorubicin, was later named doxorubicin (adriamycin). Although adriamycin was more efficacious, its administration was shown to result in the increased general toxicity compared to its parent drug. Large clinical trials, initiated in 1968 and in the first half of 1970's demonstrated high potential for clinical usage of adriamycin in the treatment of cancer patients (Ghione M. 1975). However, the initial enthusiasm was shadowed by the reports of adriamycin-induced cardiotoxicity. This cardiotoxicity is charactenzed by the development of delayed and insidious cardiomyopathy, which (in some cases) leads to the development of congestive heart failure and results in death. The mortality was high in patients who received cumulative doses of adriamycin that exceeded 550 mglm2 (Gottlieb and Lefrak 1973; Lefrak et al. 1973; Praga et al. 1979). The research focus was then tumed towards finding a new
Page 1 and 2: il\VOLVEMENT OF RETII\OIC ACID II{
Page 3 and 4: Title: AKNOWLEDGMENTS DEDICATION LI
Page 5 and 6: IV.b.3. The uptake to peripheral ti
Page 7 and 8: II.a. Total RAR and total RXR recep
Page 9 and 10: ACKNO\ryLEDGMENTS I must say that m
Page 11 and 12: DEDICATION To my toughest critic, m
Page 13 and 14: Figure: LIST OF FIGURES Page: 1. Ch
Page 15 and 16: 30. A and B The expression of anti-
Page 17 and 18: treated (ADR), trolox treated (TROL
Page 19 and 20: INTRODUCTION Adriamycin, an anthrac
Page 21: apoptosis, which will ultimately pr
Page 25 and 26: Binding and alkylation of DNA Inter
Page 27 and 28: myocardial inflammation which was s
Page 29 and 30: 1990; Kusuoka et al. l99l; Olson et
Page 31 and 32: levels of antioxidant enzymes (Odom
Page 33 and 34: causing the increased leakage of el
Page 35 and 36: mechanisms which are involved in th
Page 37 and 38: to protect against adriamycin-induc
Page 39 and 40: The usage of Probucol.' Most promis
Page 41 and 42: II. Oxidative stress II.a. Introduc
Page 43 and 44: of a large array of cellular abnorm
Page 45 and 46: menstruation (Kokawa et al. 1996),
Page 47 and 48: DNA(Cohen 1997; Saikumar et al. 199
Page 49 and 50: pathogenesis of heart failure. A nu
Page 51 and 52: elonging to spontaneous hlpertensiv
Page 53 and 54: AlþTrsns Retlnolc Acld fAfRAl g€
Page 55 and 56: dehydrogenase (SDR), alcohol dehydr
Page 57 and 58: (Bavik et a|. 1991). Soon after its
Page 59 and 60: et al. 1994; Napoli 1996). The func
Page 61: is achieved through its binding to
Page 64 and 65: Retinoic acid signaling pathwaybegi
Page 66 and 67: (Bavik et al. 1997). One of the mos
Page 68 and 69: cells (Gaetano et ai. ZOot¡. The s
Page 70 and 71: neuroblastoma, genn cell tumors and
Page 72 and 73:
presence of two distinctive pathway
Page 74 and 75:
cytochrome C release from mitochond
Page 76 and 77:
peroxidation (Sultana et a|.2004).
Page 78 and 79:
adipose tissue and to a lesser exte
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such as; increased generation of re
Page 82 and 83:
physiological and pathological proc
Page 84 and 85:
Protective effects of PPAR y agonis
Page 86 and 87:
IIYPOTHESIS This study tests the hy
Page 88 and 89:
I.c.Collection of Tissues Hearts we
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thoracotomy was performed and heart
Page 92 and 93:
Il.c.Western Blot Analvsis Western
Page 94 and 95:
green were counted as dead cells. T
Page 96 and 97:
RESULTS I.In Vivo Studies I.a.Gener
Page 101:
Lc. Retinoic acid receptors Three w
Page 108:
The RAR o and PPAR-õ receptors RNA
Page 113 and 114:
significantly decreased when compar
Page 116:
IL b.7. RAR alPha recePtor levels T
Page 120:
ILb. 3. RAR sammø recEtor levels F
Page 124:
ILb. 5. RXR baa recEúor levels The
Page 129:
visible staining were accounted as
Page 137 and 138:
DISSCUSION I. Adriamvcin CardiomvoP
Page 139 and 140:
Treatment with adriamycin has been
Page 141 and 142:
High RA 1 Adriamycin I oxidative st
Page 143 and 144:
study as well as in others (Kumar e
Page 145 and 146:
It is reported that PPAR y receptor
Page 147 and 148:
expression. These effects of trolox
Page 149 and 150:
REFERENCES Abdul Hamied,T.A., D.Par
Page 151 and 152:
Bashor,M.M., D.O.Toft, and F.Chytll
Page 153 and 154:
distribution of PPAR-alpha, -beta,
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colbert,M.C., D.G.Hall, T.R.Kimball
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Diep,Q.N., M'El Mabrouk, J.S.Cohn,
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Evans,R.M. 1988. "The steroid and t
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Ghione M. Development of Adriamycin
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Herman,E., R.Young, and S.Krop . Ig
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morphogenetic protein-2 inhibits se
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peroxisome proliferator-activated r
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