Cardiotoxicity in the SCID mouse following administration of doxorubicin and cyclosporin A

Bellamy, William; Peng, Yuyang; Odeleye, A; Ellsworth, L; Xu, Miqing; Grogan, Thomas M.; Weinstein, R. S.

doi:10.1097/00001813-199512000-00004

Cited by 13 publications

(13 citation statements)

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“…The tissue distribution of doxorubicin is previously examined in mice treated in combination with GF120918, cyclosporin A or SDZ PSC 833 (Hyafil et al, 1993;Colombo et al, 1994;Bellamy et al, 1995;Gonzalez et al, 1995). Co-administration of these reversal agents did only slightly change the tissue distribution of doxorubicin, which corresponds with the results of our experiments in mdr1a(-/-) mice.…”

Section: Discussionsupporting

confidence: 87%

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

et al. 1998

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P-glycoprotein is a large plasma membrane protein that can cause multidrug resistance in tumour cells by actively extruding substrate drugs out of the cell. These substrates include many anticancer drugs, such as vinca alkaloids, taxanes, epipodophyllotoxins and anthracyclines (reviewed in Endicott and Ling, 1989). The discovery that verapamil was able to reverse multidrug resistance in murine leukaemia cell lines (Tsuruo et al, 1981) initiated the search for reversal agents, which are compounds capable of blocking or inhibiting P-glycoprotein. A major concern for the clinical application of effective reversal agents are the potential consequences of inhibition of endogenous P-glycoprotein. To predict possible adverse effects of reversal agents and to gain more insight into the physiological role of endogenous P-glycoproteins, mice with homozygously disrupted P-glycoprotein genes have been generated at our institute (Schinkel et al, 1994.In humans, only one P-glycoprotein (MDR1) plays a role in multidrug resistance, whereas in mice both mdr1a and mdr1b P-glycoproteins are involved. The tissue distribution of these proteins suggests that the two murine isoforms together perform the same function as the single human MDR1 protein. The mdr1a gene is predominantly expressed in the intestines and in the capillaries of the brain and the testis, mdr1b is mainly expressed in the adrenal gland, pregnant uterus and ovarium. Significant levels of both mdr1a and mdr1b P-glycoprotein are present in liver, kidney, lung, heart and spleen (Cordon-Cardo et al, 1989;Croop et al, 1989). Based on the results of tissue distribution studies, it has been suggested that P-glycoprotein plays a role in the protection of the organism against potentially toxic agents, e.g. by limiting the absorption of orally ingested compounds, by mediating the elimination of substrates from the body and by protecting essential organs such as the brain and the testis against toxic substances in the circulation (Thiebaut et al, 1987;Cordon-Cardo et al, 1989). Recent studies confirmed that P-glycoprotein in the blood-brain barrier protects the brain against the entry of toxic compounds, whereas P-glycoprotein in the intestinal epithelium has been shown to limit the uptake of substrates from the intestinal lumen and to mediate their direct excretion from the bloodstream (Schinkel et al, 1994(Schinkel et al, , 1995Mayer et al, 1996;Sparreboom et al, 1997).To gain a detailed insight into the pharmacokinetic consequences of blocking P-glycoprotein in normal tissues, we previously performed a comprehensive analysis of the plasma pharmacokinetics, tissue distribution and excretion of vinblastine and its metabolites in wild-type and mdr1a(-/-) mice . However, it is of importance to obtain also comparable data on other widely used substrate drugs because it is likely that the impact of endogenous P-glycoprotein on the pharmacokinetics is substrate dependent. Here, we report on the comparative pharmacokinetics of doxorubicin and metabolites in wild-type and mdr1a(-/-...

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Section: Discussionsupporting

confidence: 87%

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

et al. 1998

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“…Other studies in rodents demonstrated that cyclosporin A or its analog PSC 833 could increase doxorubicin (Colombo et al, 1994;Bellamy et al, 1995;Gonzalez et al, 1995;Colombo et al, 1996a) and etoposide concentrations (Cá rcel-Trullols et al, 2004) in several tissues including the heart. This increase may be correlated with a higher incidence and severity of myocardial damage when cyclosporin A and doxorubicin were administered in combination (Bellamy et al, 1995). The mechanism responsible for the enhanced cardiotoxicities is probably related to an accumulation of drugs in the heart due to the inhibition of P-gp or other ABC transporters by agents such as verapamil, cyclosporin A, or PSC 833.…”

Section: B Cardiotoxicity Related To Atp-binding Cassette Transportersmentioning

confidence: 97%

“…A study performed approximately in the same period showed that the coadministration of verapamil and doxorubicin in mice increased the peak concentration of doxorubicin in the heart by 40%, augmented the incidence and severity of degenerative changes in cardiac tissue, and decreased the survival rate compared with doxorubicin alone (Sridhar et al, 1992). Other studies in rodents demonstrated that cyclosporin A or its analog PSC 833 could increase doxorubicin (Colombo et al, 1994;Bellamy et al, 1995;Gonzalez et al, 1995;Colombo et al, 1996a) and etoposide concentrations (Cá rcel-Trullols et al, 2004) in several tissues including the heart. This increase may be correlated with a higher incidence and severity of myocardial damage when cyclosporin A and doxorubicin were administered in combination (Bellamy et al, 1995).…”

Section: B Cardiotoxicity Related To Atp-binding Cassette Transportersmentioning

confidence: 97%

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The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

Couture

Nash²,

Turgeon³

2006

Pharmacol Rev

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“…[30][31][32] This observation was not confirmed in clinical trials of chemosensitizing agents. 33,34 In the present study, two of the 40 patients who received the CHVP/cinchonine regimen demonstrated a mild and asymptomatic decrease of their left ventricular ejection fraction during the course of the study and none demonstrated symptomatic heart failure.…”

Section: Discussionmentioning

confidence: 87%

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

Solary

Mannone²,

Moreau³

et al. 2000

Leukemia

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Cardiotoxicity in the SCID mouse following administration of doxorubicin and cyclosporin A

Cited by 13 publications

References 0 publications

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

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