Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non-small-cell lung cancer.
ABSTRACT ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the c.421C > A ABCG2 gene polymorphism was associated with gefitinib-induced diarrhea in Caucasian patients with non-small-cell lung cancer. Since c.421C > A ABCG2, resulting in p.Q141K substitution, is more prevalent in Asian populations, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in Japanese patients. c.376C > T, resulting in truncated, non-functional ABCG2, was also investigated.
ABCG2 gene polymorphisms were evaluated in 75 patients with non-small-cell lung cancer treated with gefitinib 250 mg/day orally, and results were correlated with treatment-related adverse effects.
Forty (53.3%) patients harbored c.421A ABCG2 on at least one allele, while the remaining 35 (46.7%) were wild type for c.421C > A. No significant group difference was observed in frequency of gefitinib-related diarrhea or other adverse effects. In addition, the only one patient homozygous for the c.421A allele in this study was not affected with gefitinib-induced diarrhea or interstitial lung disease. Two patients (2.7%) were found to harbor the c.376T allele heterozygously. One of the two patients harbored both the c.376T and the c.421A genotypes on distinct alleles. Gefitinib-related interstitial lung disease and severe diarrhea were noted in neither of the two patients.
In this Japanese population, we did not find an evident association between ABCG2 polymorphisms, c.376C > T and c.421C > A, and susceptibility to gefitinib-induced adverse effects.
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ABSTRACT: INTRODUCTION: Anticancer tyrosine kinase inhibitors (TKIs) are small molecule hydrophobic compounds designed to arrest aberrant signaling pathways in malignant cells. Multidrug resistance (MDR) ATP binding cassette (ABC) transporters have recently been recognized as important determinants of the general ADME-Tox (absorption, distribution, metabolism, excretion, toxicity) properties of small molecule TKIs, as well as key factors of resistance against targeted anticancer therapeutics. AREAS COVERED: The article summarizes MDR-related ABC transporter interactions with imatinib, nilotinib, dasatinib, gefitinib, erlotinib, lapatinib, sunitinib and sorafenib, including in vitro and in vivo observations. An array of methods developed to study such interactions is presented. Transporter-TKI interactions relevant to the ADME-Tox properties of TKI drugs, primary or acquired cancer TKI resistance, and drug-drug interactions are also reviewed. EXPERT OPINION: Based on the concept presented in this review, TKI anticancer drugs are considered as compounds recognized by the cellular mechanisms handling xenobiotics. Accordingly, novel anticancer therapies should equally focus on the effectiveness of target inhibition and exploration of potential interactions of the designed molecules by membrane transporters. Thus, targeted hydrophobic small molecule compounds should also be screened to evade xenobiotic-sensing cellular mechanisms.Expert Opinion on Drug Metabolism & Toxicology 03/2011; 7(5):623-42. · 2.94 Impact Factor
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ABSTRACT: : The treatment of many malignancies has been improved in recent years by the introduction of molecular targeted therapies. These drugs interact preferentially with specific targets that are mutated and/or overexpressed in malignant cells. A group of such targets are the tyrosine kinases, against which a number of inhibitors (tyrosine kinase inhibitors, TKIs) have been developed. Imatinib, a TKI with targets that include the breakpoint cluster region-Abelson (bcr-abl) fusion protein kinase and mast/stem cell growth factor receptor kinase (c-Kit), was the first clinically successful drug of this type and revolutionized the treatment and prognosis of chronic myeloid leukemia and gastrointestinal stromal tumors. This success paved the way for the development of other TKIs for the treatment of a range of hematological malignancies and solid tumors. To date, 14 TKIs have been approved for clinical use and many more are under investigation. All these agents are given orally and are substrates of a range of drug transporters and metabolizing enzymes. In addition, some TKIs are capable of inhibiting their own transporters and metabolizing enzymes, making their disposition and metabolism at steady-state unpredictable. A given dose can therefore give rise to markedly different plasma concentrations in different patients, favoring the selection of resistant clones in the case of subtherapeutic exposure, and increasing the risk of toxicity if dosage is excessive. The aim of this review was to summarize current knowledge of the clinical pharmacokinetics and known adverse effects of the TKIs that are available for clinical use and to provide practical guidance on the implications of these data in patient management, in particular with respect to therapeutic drug monitoring.Therapeutic drug monitoring 10/2013; 35(5):562-87. · 2.43 Impact Factor
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ABSTRACT: Adenine triphosphate (ATP)-binding cassette (ABC) transporter proteins, such as ABCB1/P-glycoprotein (P-gp) and ABCG2/breast cancer resistance protein (BCRP), transport various structurally unrelated compounds out of cells. ABCG2/BCRP is referred to as a "half-type" ABC transporter, functioning as a homodimer, and transports anticancer agents such as irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), gefitinib, imatinib, methotrexate, and mitoxantrone from cells. The expression of ABCG2/BCRP can confer a multidrug-resistant phenotype on cancer cells and affect drug absorption, distribution, metabolism, and excretion in normal tissues, thus modulating the in vivo efficacy of chemotherapeutic agents. Clarification of the substrate preferences and structural relationships of ABCG2/BCRP is essential for our understanding of the molecular mechanisms underlying its effects in vivo during chemotherapy. Its single-nucleotide polymorphisms are also involved in determining the efficacy of chemotherapeutics, and those that reduce the functional activity of ABCG2/BCRP might be associated with unexpected adverse effects from normal doses of anticancer drugs that are ABCG2/BCRP substrates. Importantly, many recently developed molecular-targeted cancer drugs, such as the tyrosine kinase inhisbitors, imatinib mesylate, gefitinib, and others, can also interact with ABCG2/BCRP. Both functional single-nucleotide polymorphisms and inhibitory agents of ABCG2/BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of these molecular cancer treatments, so the pharmacogenetics of ABCG2/BCRP is an important consideration in the application of molecular-targeted chemotherapies.Pharmacogenomics and Personalized Medicine 01/2014; 7:53-64.