Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubicin without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment.
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PMID:The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat. 791 32

Anthracyclines are widely used and effective antineoplastic drugs. Although active against a wide variety of solid tumours and haematological malignancies, their clinical use is hindered by tumour resistance and toxicity to healthy tissue. Modification of the general anthracycline ring structure results in analogues with different but overlapping antitumour and tolerability profiles. Activity of the anthracyclines is related to topoisomerase II inhibition, which occurs as a result of anthracycline intercalation between adjacent DNA base pairs. Production of hydroxyl free radicals is associated with antitumour effects and toxicity to healthy tissues. Myocardial tissue is particularly susceptible to free radical damage. Development of tumour cell resistance to anthracyclines involves a number of mechanisms, including P-glycoprotein-mediated resistance. The classical dose-limiting adverse effects of this class of drugs are acute myelosuppression and cumulative dose-related cardiotoxicity. Anthracycline-induced cardiomyopathy is often irreversible and may lead to clinical congestive heart failure. Other toxicities of the anthracyclines, including stomatitis, nausea and vomiting, alopecia and 'radiation recall' reactions, are generally reversible. Anthracycline-induced cardiotoxicity may be reduced or prevented by an administration schedule that produces low peak plasma drug concentrations. Administration of dexrazoxane also provides cardioprotection. Dose intensification of anthracyclines may partly overcome resistance but is associated with reduced tolerability. Liposomal encapsulation of doxorubicin or daunorubicin alters the pharmacokinetic properties of the drugs. Increased distribution in tumours, prolonged circulation and reduced free drug concentrations in plasma may increase antitumour activity and improve the tolerability of the anthracyclines.
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PMID:Anthracyclines in the treatment of cancer. An overview. 936 55

Anthracyclines, including doxorubicin, are widely used in the treatment of B-cell non-Hodgkin's lymphoma (NHL). However, their clinical potential is limited by their cardiotoxic adverse effects, which include cardiomyopathy and congestive heart failure. Anthracycline-induced cardiotoxicity is cumulative and irreversible. Liposomal doxorubicin has been developed with the aim of improving the therapeutic index of doxorubicin by reducing the drug's cardiotoxicity. Nevertheless, liposomal conjugation of doxorubicin results in preferential distribution of the drug in the tumor compared with normal tissue, maintaining its anti-tumor efficacy. Nonpegylated liposomal doxorubicin produced a promising response rate when substituted for conventional doxorubicin in the cyclophosphamide, doxorubicin, vincristine and prednisolone regimen in the treatment of patients with NHL either at diagnosis or at relapse. The ability of nonpegylated liposomal doxorubicin to overcome excessive drug efflux due to P-glycoprotein (MDR-1) overexpression in NHL might confer on this drug a curative potential for patients with a bad prognosis (e.g., MDR-1 overexpressing, the elderly or frail).
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PMID:Nonpegylated liposomal doxorubicin in the treatment of B-cell non-Hodgkin's lymphoma: where we stand. 1927 12