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Articles: R. Stephanie Huang and Mark J. Ratain Pharmacogenetics and pharmacogenomics of anticancer agents CA Cancer J Clin 2009; 59: 42-55 [Abstract] [Full text] [PDF]

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For individualization of cancer therapy there is still a long way to go

Dr. Jinrong Zhao, Dr. Zhen Yan   (29 December 2009)

eLetter for Pharmacogenetics and Pharmacogenomics of Anticancer Agents

Bangle Zhang, Wei He, PhD; Xiaoli Sun, PhD   (17 June 2009)

For individualization of cancer therapy there is still a long way to go 29 December 2009
Dr. Jinrong Zhao School of Pharmacy, Fourth Military Medical University, Dr. Zhen Yan Send comment to journal: Re: For individualization of cancer therapy there is still a long way to go zhaojrr{at}fmmu.edu.cn Dr. Jinrong Zhao, et al.	Dear Editor, In the paper titled “Pharmacogenetics and Pharmacogenomics of Anticancer Agents”, the authors point out that extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside [1]. Indeed, for many diseases identifying host genetic variations that contribute to drug efficacy and/or the risk of toxicity will provide a means with which to tailor therapy. But for individualization of cancer therapy, especially for those with low 5-year-survival rates, I think there is still a long way to go. The reasons are as follows. Firstly, at present to find effective drug targets is still the major task for cancer therapy. The 5-year-survival rates of some cancers, for example lung cancer, are below 15%, which means most of the existing anticancer agents are not successful for these cancers, and more effort should be put on finding better therapy targets and developing more effective anticancer agents, but not identifying and validating PGx markers, which has in fact limited value and causes extra cost in this situation. Secondly, existing anticancer agents can not discriminate tumor and nontumor cells, which is the major reason of toxicity to patients receiving anticancer agents. So the fundamental way to avoid or decrease the toxicity of anticancer agents is to try to develop target-specific anticancer agents, but not to find and measure toxicity-associated PGx markers. In summary, at present for cancer therapy, more effort should be put on developing effective anticancer agents with target specificity. Here what PGx can really help is to find new drug targets and select special groups for clinical trials, thus accelerating and simplifying the process of drug development. Sincerely yours, Dr. Jinrong Zhao Dr. Zhen Yan School of Pharmacy Fourth Military Medical University 17 Changle West Road Xi’an, Shaanxi, China Correspondence: Dr. Jinrong Zhao, E-mail: zhaojrr@fmmu.edu.cn; or Dr. Zhen Yan, E-mail: yanzhen@fmmu.edu.cn. References 1. Huang RS, Ratain MJ. Pharmacogenetics and pharmacogenomics of anticancer agents. CA Cancer J Clin. 2009;59:42-55.
eLetter for Pharmacogenetics and Pharmacogenomics of Anticancer Agents 17 June 2009
Bangle Zhang, PhD Department of Pharmaceutics and Pharmacology, Fourth Military Medical University, Wei He, PhD; Xiaoli Sun, PhD Send comment to journal: Re: eLetter for Pharmacogenetics and Pharmacogenomics of Anticancer Agents blezhang{at}fmmu.edu.cn Bangle Zhang, et al.	Dear Editor, We have much appreciated the review entitled “Pharmacogenetics and Pharmacogenomics of Anticancer Agents” by Huang and Ratain recently published in the journal [1]. The authors have proposed an excellent five-stage architecture for PGx research, which is laconic and useful to discover and validate genetic variants that contribute to the efficacy and toxicity associated with anticancer therapy. This paper focuses mainly on the general genetics approach to screen and identify genetic variants. In fact, PGx studies of anticancer agents are quite complicated. In the process to find genetic markers associated with drugs, accumulating initial clinical drug information, determining the imbalance of genetic variants in tumor and non-tumor tissues, excluding non-genetic factors and analyzing the correlation of genetic variants with drug response are also required, especially in the case of multiple genetic variants involved or the variation induced only after anticancer drug treatment. In addition, micro RNA polymorphism can affect the response and toxicity and plays a critical role in human phenotypic diversity [2-4]. Although the knowledge of PGx was far less for individualized anticancer therapy, many clinicians have recognized the importance of PGx and begun to use pharmacogenetics information to guide therapy in recent years. Based on PGx evidence, genetic variants could explain variations including both pharmacokinetics (metabolism enzyme and transport carrier concerned) and pharmacodynamics (drug target concerned). This review provides several classic PGx examples of anticancer drugs, but most genetic markers were connected with pharmacokinetics (enzyme variation involved in drug metabolism or prodrug activation), such as CYP2D6, TPMTs, and UGT1A1 genotyping. As continuing education for prescribers, other anticancer drugs in current clinical practice and all-around PGx information should be mentioned, for example, drug target variation (paclitaxel associated with variations in tubulin isotype expression) [5-6] and drug transporter variation (doxorubicin in MDR polymorphism) [7-9]. With best regards, Bangle Zhang, PhD Wei He, PhD Xiaoli Sun, PhD Correspondence: Bangle Zhang, PhD, Department of Pharmaceutics and Pharmacology, Fourth Military Medical University, 17 Changle West Road, Xian, Shaanxi, P. R. China; E-mail: blezhang@fmmu.edu.cn or Wei He, PhD, Xiaoli Sun, PhD, Department of Medicinal Chemistry, Fourth Military Medical University, 17 Changle West Road, Xian, Shaanxi, P. R. China; E-mail: heweichem@gmail.com. Financial Disclosures: Dr Zhang reported having received research funding and support from the National Natural Science Foundation of China (No.30700887 and 20702063). References 1. Huang RS, Ratain MJ. Pharmacogenetics and pharmacogenomics of anticancer agents. CA Cancer J Clin. 2009;59:42-55. 2. Bertino JR, Banerjee D, Mishra PJ. Pharmacogenomics of micro RNA: a miRSNP towards individualized therapy. Pharmacogenomics 2007;8:1625-1627. 3. Chen K, Song F, Calin GA, Wei Q, Hao X, Zhang W. Polymorphisms in microRNA targets: a gold mine for molecular epidemiology. Carcinogenesis. 2008;29:1306-1311. 4. Johnson AD, Zhang Y, Papp AC, et al. Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic expression imbalance in human target tissues. Pharmacogenet Genomics. 2008;18:781-191. 5. Bhattacharya R, Cabral F. Molecular basis for class V beta- tubulin effects on microtubule assembly and Paclitaxel resistance. J Biol Chem. 2009;284:13023-13032. 6. Freedman H, Huzil JT, Luchko T, Luduena RF, Tuszynski JA. Identification and characterization of an intermediate Taxol binding site within microtubule nanopores and a mechanism for tubulin isotype binding selectivity. J Chem Inf Model. 2009;49:424-436. 7. Huang Y, Penchala S, Pham AN, Wang J. Genetic variations and gene expression of transporters in drug disposition and response. Expert Opin Drug Metab Toxicol. 2008;4:237-254. 8. Nakamura Y. Pharmacogenomics and drug toxicity. N Engl J Med. 2008;359:856-858. 9. Yin JY, Huang Q, Yang Y, et al. Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population. Pharmacogenet Genomics. 2009;19:206-216.