Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?

Ueno, Hideki; Kiyosawa, Kendo; Kaniwa, Nahoko

doi:10.1038/sj.bjc.6603860

Cited by 133 publications

(122 citation statements)

References 30 publications

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“…19). dFdC-treated patients with tumors expressing low levels of DCK have shorter survival rates compared with those with tumors expressing high levels of this enzyme (20,21). Previous studies show a good correlation among measurements of tumor DCK mRNA (22), protein (23), and enzymatic activity (15), and responses to dFdC and ara-C.…”

mentioning

confidence: 89%

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Laing

Walter²,

Campbell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Gemcitabine (2 ,2 -difluorodeoxycytidine, dFdC) and cytosine arabinoside (cytarabine, ara-C) represent a class of nucleoside analogs used in cancer chemotherapy. Administered as prodrugs, dFdC and ara-C are transported across cell membranes and are converted to cytotoxic derivatives through consecutive phosphorylation steps catalyzed by endogenous nucleoside kinases. Deoxycytidine kinase (DCK) controls the rate-limiting step in the activation cascade of dFdC and ara-C. DCK activity varies significantly among individuals and across different tumor types and is a critical determinant of tumor responses to these prodrugs. Current assays to measure DCK expression and activity require biopsy samples and are prone to sampling errors. Noninvasive methods that can detect DCK activity in tumor lesions throughout the body could circumvent these limitations. Here, we demonstrate an approach to detecting DCK activity in vivo by using positron emission tomography (PET) and 18

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mentioning

confidence: 89%

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Laing

Walter²,

Campbell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…A major impediment related to gemcitabine efficacy is its rapid inactivation, since upon administration more than 90% of gemcitabine is converted to its inactive metabolite, 2, 2'-difluorodeoxyuridine (dFdU) and its monophosphate derivative (dFdUMP). 28,29 …”

Section: Introductionmentioning

confidence: 99%

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Καράμπελας

Argyros

Sayyad³

et al. 2014

Bioconjugate Chem.

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Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing HormoneReceptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG, showed a significant advantage in tumor growth inhibition when compared to gemcitabine. 3 IntroductionDespite advancements in methods for early cancer detection and improved insights into the molecular mechanisms and treatment options, advanced prostate cancer (CaP) remains a major health problem for the aging man. 1,2 Hormonal therapy is usually the first line of defense for CaP treatment by using drugs that lead to chemical castration, suppression of testosterone and dihydrotestosterone (DHT) biosynthesis. 3,4 The hormonal ablation approach has been achieved successfully using agonist (through desensitization) or antagonist analogue drugs, of the native Gonadotropin Releasing Hormone (GnRH). These drugs exert their effects primarily on the pituitary gland through the GnRH-R by lowering gonadotropins and downstream gonadal sex steroids. Nevertheless, in many cases after treatment, following initial tumor regression, CaP progresses to an androgen-independent state with poor prognosis, which presents a major challenge for the physician and the patient. 3,[5][6][7][8][9][10] Research on the GnRH-R has shown that its expression is not confined solely to the pituitary but that is also present in several other tissues such as prostate, breast 11-13 and the GnRH-R level of expression along with cell context is critical for cell responses to either agonist or antagonist drugs of the receptor. 14 It is also well established that GnRH-R gene expression is upregulated in patients with androgenindependent CaP, making the GnRH-R an attractive target for the design of novel and specific therapeutics. 15 A modern approach to improve conventional chemotherapy is by direct targeting of chemotherapeutic agents to cancer cells in order to enhance the tumoricidal effect and reduce peripheral toxicity of a specific drug. Linking chemo...

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“…There were substantial interpatient variations at the four studied dose levels, reflecting the wide variation in pharmacokinetics and pharmacodynamics of the drug (25)(26)(27)(28). Indeed gene polymorphisms were reported for several enzymes involved in dFdC metabolism, including deoxycytidine kinase and cytidine deaminase (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Difluorodeoxyuridine plasma concentrations after low-dose gemcitabine during chemoradiation in head and neck cancer patients

Specenier

Guetens

Dyck

et al. 2010

Cancer Chemother Pharmacol

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Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?

Cited by 133 publications

References 30 publications

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Difluorodeoxyuridine plasma concentrations after low-dose gemcitabine during chemoradiation in head and neck cancer patients

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