The Role of ABC Transporters in Clinical Practice

Leonard, Gregory D.; Fojo, Tito; Bates, Susan E.

doi:10.1634/theoncologist.8-5-411

Cited by 690 publications

(575 citation statements)

References 88 publications

(60 reference statements)

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“…At present, only ABCC4 has been identified as an efflux pump for 5-azacytidine . Further studies are required because the ABC family represents a well-established factor in cancer drug resistance (Leonard et al, 2003).…”

Section: Metabolic Activation and Cellular Transport Of Dnmt Inhibitorsmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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Section: Metabolic Activation and Cellular Transport Of Dnmt Inhibitorsmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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“…Dysfunctions of these proteins have been causally related to several pathological phenotypes, spanning from neurological or metabolic diseases to drug resistance [115][116][117]. For instance, the most common fatal autosomal recessive genetic disease affecting Caucasian populations, npg cystic fibrosis, is caused by mutations in the ABCC7 transporter (or CFTR), which is a regulated ion channel [118].…”

Section: Abc Transporters and Diseasesmentioning

confidence: 99%

ABC transporters, neural stem cells and neurogenesis – a different perspective

2006

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“…P-glycoprotein, a member of the ATP-binding cassette superfamily of transmembrane transporters, prevents the intracellular accumulation of many natural product-derived cytotoxic agents (Gottesman et al, 2002). As a result, targeted inhibition of P-glycoprotein by agents administered in combination with chemotherapeutic agents has been attempted (Ford et al, 1996;Sikic, 1999;Leonard et al, 2003). One such agent, valspodar (PSC 833), a cyclosporine D analogue, reverses P-glycoprotein-mediated resistance in vitro at concentrations of 1000 ng ml À1 (Twentyman and Bleehen, 1991).…”

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confidence: 99%

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Fracasso¹,

Blum²,

K.³

et al. 2005

Br J Cancer

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Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20 -25 mg m À2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m À2 and escalated in an accelerated titration design to 25 mg m À2 . Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m À2 . The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10 -73) ml h À1 m À2 in cycle 1 to 18 (3 -37) ml h À1 m À2 with the addition of valspodar in cycle 2 (P ¼ 0.009). Treatment with PEG-LD 25 mg m À2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

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The Role of ABC Transporters in Clinical Practice

Cited by 690 publications

References 88 publications

Epigenetic cancer therapy: rationales, targets and drugs

Epigenetic cancer therapy: rationales, targets and drugs

ABC transporters, neural stem cells and neurogenesis – a different perspective

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

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