CYP450 polymorphisms predict clinic outcomes to vinorelbine-based chemotherapy in patients with non-small-cell lung cancer

Pan, Jihong; Han, Jinxiang; Wu, Jianmei; Sheng, Lijun; Huang, Hai-nan

doi:10.1080/02841860600902197

Cited by 14 publications

(9 citation statements)

References 13 publications

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“…Consistent with the results of our study, clinical data from Wong et al (2006) support a lack of CYP3A5 contribution to clearance of vinorelbine. In contrast, CYP3A5*1 genotype has even been shown to be moderately associated with better overall median survival rates in patients with NSCLC (Pan et al, 2007). In the study of P450 genotypes and clinical outcomes in patients with NSCLC, they found that patients with at least one CYP3A5*1 allele had slower rates of tumor growth and a higher associated median survival rate than did patients without a CYP3A5*1 allele.…”

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confidence: 96%

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

et al. 2013

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Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b 5 (CYP3A4+b 5 ) and CYP3A5 +b 5 , the Michaelis-Menten constants for vinorelbine were 2.6 and 3.6 mM, respectively, but the V max of 1.4 pmol/min/pmol was common to both enzymes. In HLMs, the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity, and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b 5 and CYP3A5+b 5 as determined by NMR and mass spectrometry analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b 5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.

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confidence: 96%

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

et al. 2013

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“…For example, patient genotype for various drug metabolism pathways could alter both drug efficacy and drug toxicity. We will not discuss these further in this paper, but several examples of these have been described in lung cancer patients39–41. However, we will discuss in later sections how host genotype for specific resistance factors impacts therapy outcome, and examples are presented in Table 2.…”

Section: 0 Backgroundmentioning

confidence: 99%

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Stewart

2010

Critical Reviews in Oncology/Hematology

161

157

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While chemotherapy provides useful palliation, advanced lung cancer remains incurable since those tumors that are initially sensitive to therapy rapidly develop acquired resistance. Resistance may arise from impaired drug delivery, extracellular factors, decreased drug uptake into tumor cells, increased drug efflux, drug inactivation by detoxifying factors, decreased drug activation or binding to target, altered target, increased damage repair, tolerance of damage, decreased proapoptotic factors, increased antiapoptotic factors, or altered cell cycling or transcription factors. Factors for which there is now substantial clinical evidence of a link to small cell lung cancer (SCLC) resistance to chemotherapy include MRP (for platinum-based combination chemotherapy) and MDR1/P-gp (for non-platinum agents). SPECT MIBI and Tc-TF scanning appears to predict chemotherapy benefit in SCLC. In non-small cell lung cancer (NSCLC), the strongest clinical evidence is for taxane resistance with elevated expression or mutation of class III β-tubulin (and possibly α tubulin), platinum resistance and expression of ERCC1 or BCRP, gemcitabine resistance and RRM1 expression, and resistance to several agents and COX-2 expression (although COX-2 inhibitors have had minimal impact on drug efficacy clinically). Tumors expressing high BRCA1 may have increased resistance to platinums but increased sensitivity to taxanes. Limited early clinical data suggest that chemotherapy resistance in NSCLC may also be increased with decreased expression of cyclin B1 or of Eg5, or with increased expression of ICAM, matrilysin, osteopontin, DDH, survivin, PCDGF, caveolin-1, p21WAF1/CIP1, or 14-3-3sigma, and that IGF-1R inhibitors may increase efficacy of chemotherapy, particularly in squamous cell carcinomas. Equivocal data (with some positive studies but other negative studies) suggest that NSCLC tumors with some EGFR mutations may have increased sensitivity to chemotherapy, while K-ras mutations and expression of GST-pi, RB or p27kip1 may possibly confer resistance. While limited clinical data suggest that p53 mutations are associated with resistance to platinum-based therapies in NSCLC, data on p53 IHC positivity are equivocal. To date, resistance-modulating strategies have generally not proven clinically useful in lung cancer, although small randomized trials suggest a modest benefit of verapamil and related agents in NSCLC.

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“…Metagenes MAGEA9B and MAGEA10 have been involved in congenital dyskeratosis,33 and NLRP2 may be involved in another type of familial imprinting disorder 34 . CYP3A5 , located in the second top metagene, contains one of the most commonly detected polymorphisms that influences the efficacy of vinorelbine-based therapies to treat NSCLC 35.…”

Section: Resultsmentioning

confidence: 99%

Metagenes Associated with Survival in Non-Small Cell Lung Cancer

et al. 2011

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NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%–55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies.A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two-sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR.Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified.Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients.

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CYP450 polymorphisms predict clinic outcomes to vinorelbine-based chemotherapy in patients with non-small-cell lung cancer

Abstract: (2007) CYP450 polymorphisms predict clinic outcomes to vinorelbine-based chemotherapy in patients with non-small-cell lung cancer, Acta Oncologica, 46:3, 361-366,

Cited by 14 publications

References 13 publications

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Metagenes Associated with Survival in Non-Small Cell Lung Cancer

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