The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5 0 UTR and 3 0 UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR ¼ 7.32; Po0.0001); (b) high-5FU clearance predicted poorer DFS (HR ¼ 1.96; P ¼ 0.041) and OS (HR ¼ 3.37; P ¼ 0.011); (c) advanced age was associated with shorter DFS (HR ¼ 3.34; P ¼ 0.0008) and OS (HR ¼ 2.66; P ¼ 0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3 -4 toxicity (P ¼ 0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.
Within the fascinating world of chemokines, C and CX3C chemokines have long been regarded as two minor components, even though they present unique features and show less redundancy than the other chemokine families. Nevertheless, the body of data on their expression and role in various inflammatory disorders has grown in the past few years. The C chemokine family is represented by two chemokines, XCL1/lymphotactin-alpha and XCL2/lymphotactin-beta, whereas the CX3C chemokine family contains only one member, called CX3CL1/ fractalkine. In this review, we present an overview on the structure, expression and signaling properties of these chemokines and their respective receptors and examine how they contribute to inflammation and the regulation of leukocyte trafficking, as well as their potential role in the pathophysiology of human inflammatory diseases. Taken together, these data expand the biological importance of C and CX3C chemokines from that of simple immune modulators to a much broader biological role, even though their precise commitment within the framework of immune responses has still to be determined.
A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.
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