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Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration.
J Biochem Mol Toxicol 2004; 18(2):78-86JB

Abstract

The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment.

Authors+Show Affiliations

Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. sherif_ibrahem@hotmail.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15122649

Citation

Saad, Sherif Y., et al. "Cardiotoxicity of Doxorubicin/paclitaxel Combination in Rats: Effect of Sequence and Timing of Administration." Journal of Biochemical and Molecular Toxicology, vol. 18, no. 2, 2004, pp. 78-86.
Saad SY, Najjar TA, Alashari M. Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration. J Biochem Mol Toxicol. 2004;18(2):78-86.
Saad, S. Y., Najjar, T. A., & Alashari, M. (2004). Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration. Journal of Biochemical and Molecular Toxicology, 18(2), pp. 78-86.
Saad SY, Najjar TA, Alashari M. Cardiotoxicity of Doxorubicin/paclitaxel Combination in Rats: Effect of Sequence and Timing of Administration. J Biochem Mol Toxicol. 2004;18(2):78-86. PubMed PMID: 15122649.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration. AU - Saad,Sherif Y, AU - Najjar,Tawfeeg A O, AU - Alashari,Mouied, PY - 2004/5/4/pubmed PY - 2004/12/16/medline PY - 2004/5/4/entrez SP - 78 EP - 86 JF - Journal of biochemical and molecular toxicology JO - J. Biochem. Mol. Toxicol. VL - 18 IS - 2 N2 - The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment. SN - 1095-6670 UR - https://www.unboundmedicine.com/medline/citation/15122649/Cardiotoxicity_of_doxorubicin/paclitaxel_combination_in_rats:_effect_of_sequence_and_timing_of_administration_ L2 - https://doi.org/10.1002/jbt.20012 DB - PRIME DP - Unbound Medicine ER -