Abstract
Abstract Defining the parameters contributing to variability in clinical toxicity is necessary to optimise cancer treatment. Some variability is accounted for by variations in 5FU pharmacokinetics, differences in co-morbidity (liver & renal), pre-disposing factors (gender & age). But a considerable amount remains unexplained. This study aims to identify various factors contributing to such toxicity in colorectal cancer patients receiving 5FU. The variables chosen for study include those that control 5FU metabolism including measures of dihydropyrimidine dehydrogenase (DPD) activity which is critical for 5FU catabolism, together with polymorphic analysis of thymidylate synthase (TS), methyltetrahydrofolate reductase (MTHFR) and methionine synthase (MS) activity. The addition of pharmacodymamics and the ability of end-organs to respond to drug treatment further refined the predictive model, particularly the ability to identify those patients most likely to experience severe myelosuppression in response to chemotherapy. In this regard, the replicative capacity of bone marrow progenitors was determined by measuring telomere length (TL) in peripheral blood mononuclear cells (PBMNC). Clinical toxicity was determined in 42 colorectal patients receiving 5FU. Toxicity (≥ grade 2) included neutropenia (n=25), leukopenia (n=14), mucositis (n=19) and diarrhea (n=5). While the severity of toxicity significantly correlated with the magnitude of the insult, ie 5FU dose, the analysis also showed that toxicity significantly correlated with TL, with short telomeres predicting for higher toxicity. Univariate analysis showed TL significantly correlated with leukopenia (r=-0.461, P=0.009), neutropenia (r=-0.413, P=0.021) and mucositis (r=-0.341, P=0.048). Multivariate analysis further confirmed the significant role of TL in these clinical toxicities. Collectively, these results support the link between TL and progenitor replicative capacity. In conclusion, PBMNC TL may be exploited to tailor chemotherapy schedules for colorectal cancer patients receiving 5FU. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2621.
Published Version
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