PERSONALIZED MEDICINE IN CANCER THERAPY
		Case study
		Product:  gemcitabine
		Name:   Gemzar®
	ANN:		Gemcitabine HCL
	Side Effects:		The most frequent side effect is neutropenia; it was observed in 63% of patients, with moderate to severe decreases in 25% of patients. This effect on the blood was the most frequent reason for reducing or limiting the dose of Gemzar®.   Common adverse events in clinical trials included: — nausea and vomiting (69%) — fever (41%) — edema or fluid retention (up to 34%) — rash (30%) — flu-like symptoms (19%).   Hair loss, usually minimal, was reported in 15% of patients. This side effect was reversible, and none of the patients experienced complete hair loss as a result of Gemzar® treatment.   About 10% of all patients participating in Gemzar® clinical trials discontinued therapy due to side effects.
	PD:		Gemcitabine (2',2'-difluorodeoxycytidine) is an antimetabolite, antineoplastic, enzyme Inhibitor. Chemically it is a deoxycytidine analogue that is activated by deoxycytidine kinase (dCK) to its monophosphate and subsequently to its triphosphate dFdCTP, which is incorporated into both RNA and DNA, leading to DNA damage.
	Safety/Efficacy Pharmacogenomics:		Deoxycytidine kinase (dCK) is essential for the phosphorylation of gemcitabine; dCK expression as determined by competitive template reverse transcriptase PCR was significantly related with the dCK activity (r = 0.88; P = 0.025) and protein levels (p = 0.80; P = 0.052). The clear correlation between dCK levels and gemcitabine sensitivity in various murine tumors and human tumor xenografts may be a prognostic parameter when considering gemcitabine therapy.   Gemcitabine requires functional plasma membrane nucleoside transporter proteins to reach its intracellular targets and cause cytotoxicity. Nucleoside transporters vary widely in their affinity and capacity to transport gemcitabine. Variation in the tumor and tissue distribution of plasma membrane nucleoside transporter proteins may contribute to the solid tumor activities and schedule-dependent toxic effects of gemcitabine.   Multidrug resistance (MDR) is characterised by an overexpression of the membrane efflux pumps P-glycoprotein (P-gP) or multidrug resistance-associated protein (MRP). Tumoral cell lines transfected with the mdr1 gene was nine- to 72-fold more sensitive to gemcitabine than their parental cell lines. The doxorubicin-resistant cells 2R120 (MRP1) and 2R160 (P-gP) were nine- and 28-fold more sensitive to gemcitabine than their parental SW1573 cells, respectively (P<0.01).
	Conclusion:		Should deoxycytidine kinase (dCK) and multidrug resistance-associated protein (MRP) genotyping be used: (1)- as prognostic parameters when considering gemcitabine therapy? (2)- to identify cancer patients at risk of schedule-dependent toxic effects of gemcitabine?
	References:		Kroep JR, Loves WJ, van der Wilt CL, Alvarez E, Talianidis L, Boven E, Braakhuis BJ, van Groeningen CJ, Pinedo HM, Peters GJ. Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther. 2002 Apr; 1(6): 371-6   Mackey JR, Yao SY, Smith KM, Karpinski E, Baldwin SA, Cass CE, Young JD. Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J Natl Cancer Inst. 1999 Nov 3;91(21):1876-81   Bergman AM, Pinedo HM, Talianidis I, Veerman G, Loves WJ, van der Wilt CL, Peters GJ. Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines. Br J Cancer. 2003 Jun 16;88(12):1963-70   Rosell R, Felip E, Taron M, Majo J, Mendez P, Sanchez-Ronco M, Queralt C, Sanchez JJ, Maestre J. Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin Cancer Res. 2004 Jun 15;10(12 Pt 2):4215s-4219s.   Fukunaga AK, Marsh S, Murry DJ, Hurley TD, McLeod HL. Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway. Pharmacogenomics J. 2004;4(5):307-14.