Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients

Soo, Ross A.; Wang, Ling Zhi; Ng, Shi Ling; Chong, Pek Yoon; Yong, Wei Peng; Lee, Soo‐Chin; Liu, Jing; Choo, Tai Bee; Tham, Lai San; Lee, How Sung; Goh, Boon Cher; Soong, Richie

doi:10.1016/j.lungcan.2008.04.010

Cited by 62 publications

(54 citation statements)

References 28 publications

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“…The variants of candidate genes, which are involved in the metabolism and transport of gemcitabine, such as CDA, dCK, SLC28A1, SLC28A3, and SLC29A1, as well as those that are target molecules of gemcitabine, including ribonucleotide reductase M1 subunit (RRM1), RRM2, and RRM2B, have been suggested to be associated with clinical outcomes and adverse events in gemcitabine therapy [11][12][13][14][29][30][31][32]. In our GWAS, no SNP in the pharmacokinetics-related candidate genes showed a significant association with the risk of severe leukopenia/neutropenia in the patients receiving gemcitabine monotherapy (P Z 1.07 Â 10 -2 ).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy

Kiyotani

Uno

Mushiroda

et al. 2012

Pharmacogenetics and Genomics

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Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy

Kiyotani

Uno

Mushiroda

et al. 2012

Pharmacogenetics and Genomics

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“…In a restrospective study in advanced breast cancers treated with gemcitabine/carboplatin (n = 41), two RRM1 promoter region alleles (-37C and -524T) predicted for better tumor response, PFS and OS (80 (84). In the same study, SLC28A1 1561G>A was related to increased hematologic toxicity (84) and showed interethnic differences in frequencies (Caucasians, 73%; Chinese, 12%; Malays, 30%; Indians, 35%) and warrants further evaluation (84). Ethnic differences have been observed in DCK with Asians showing a higher frequency of promoter variants -C360G/-C201T than Caucasians, which may predispose to greater gemcitabine toxicities (85).…”

Section: Other Chemotherapy Agentsmentioning

confidence: 99%

Pharmacogenetics in Breast Cancer Therapy

Tan

Lee

Goh

et al. 2008

Clinical Cancer Research

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Interindividual and interethnic variability of drug pharmacokinetics and pharmacodynamics may be contributed by commonly occurring genetic polymorphisms of drug-metabolizing enzymes and transporters. Polymorphisms of CYP2D6 in particular have been associated with effects on tamoxifen disposition and clinical efficacy, with interethnic differences in distribution of functional alleles that affect metabolizer phenotype. Other tamoxifen-related genetic variants of CYP3A4, CYP3A5, and sulfotransferase1A1 (SULT1A1) are also briefly reviewed here. Polymorphisms of CYP19A1 (aromatase gene) have been reported to correlate with clinical outcomes from aromatase inhibitors in small studies but require further confirmation. Many studies on chemotherapy are based on hypothesis-generating association studies and need to be validated through larger-scale cooperative group studies. For anthracyclines, polymorphisms in genes such as carbonyl reductase 3 (CBR3), ATP-binding cassette subfamily B, member 1 (ABCB1), glutathione-related transporter genes, and oxidative stress^related genes have been reported to correlate with clinical outcomes. The pharmacogenetics of taxanes has been extensively investigated, but associations of genetic polymorphisms in drug-metabolizing enzymes and transporters reported in earlier small studies have not been validated in a recent large clinical trial. Allelic variants associated with gemcitabine, capecitabine/5-fluorouracil, vinorelbine, and platinum disposition are reviewed. No pharmacogenetic studies have been published for targeted agents thus far, although several potential candidate genes warrant investigation. Future pharmacogenetic studies will need to focus on integration of multiple drug pathways to allow a more comprehensive analysis of genetic factors influencing drug efficacy and toxicity.

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“…The concentrating nucleoside transporter 1 (CNT1; SLC28A1) has been shown to mediate transport of gemcitabine and Ara-C (Graham et al, 2000). In fact, patients with an SLC28A1 c.1561G.A genetic variant who received gemcitabine experienced significantly higher rates of neutropenia and thrombocytopenia (Soo et al, 2009), which is likely due to an increased intracellular influx of gemcitabine in bone marrow progenitors. CNT3 has also been identified in regulating nucleoside analog uptake, although to a lesser degree compared with ENT1 (Ritzel et al, 2001).…”

Section: Nucleoside Analogsmentioning

confidence: 99%

Uptake Carriers and Oncology Drug Safety

Sprowl

Sparreboom

2013

Drug Metab Dispos

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Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction of oncology drugs with SLC have been restricted to the use of exploratory in vitro model systems, emerging evidence suggests that several SLCs, including OCT2 and OATP1B1, contribute to clinically important phenotypes associated with those agents. Recent literature has indicated that modulation of SLC activity may result in drug-drug interactions, and genetic polymorphisms in SLC genes have been described that can affect the handling of substrates. Alteration of SLC function by either of these mechanisms has been demonstrated to contribute to interindividual variability in the pharmacokinetics and toxicity associated with several oncology drugs. In this report, we provide an update on this rapidly emerging field.

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Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients

Cited by 62 publications

References 28 publications

A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy

A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy

Pharmacogenetics in Breast Cancer Therapy

Uptake Carriers and Oncology Drug Safety

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