Checkpoint Signaling, Base Excision Repair, and PARP Promote Survival of Colon Cancer Cells Treated with 5-Fluorodeoxyuridine but Not 5-Fluorouracil

The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor

Neurocognitive Effects in Welders Exposed to Aluminium: An Application of the NPC Test and NPC Ranking Methods

Aluminium exposure, Dependent rankings, Neurocognitive effects, Nonparametric combination, Permutation tests,

Statistical means to enhance the comparability of data within a pooled analysis of individual data in neurobehavioral toxicology

19reservedmixedMeyer-Baron M; Schäper M; Knapp G; Lucchini R; Albini E; Bast-Pettersen R; He S; Yuan H; Niu Q; Wang XL; Yang YJ; Iregren A; Sjögren B; Blond M; Laursen P; Netterstrom B; Mergler D; Bowler R; van Thriel CMeyer Baron, M; Schäper, M; Knapp, G; Lucchini, Roberto; Albini, Elisa; Bast Pettersen, R; He, S; Yuan, H; Niu, Q; Wang, Xl; Yang, Yj; Iregren, A; Sjögren, B; Blond, M; Laursen, P; Netterstrom, B; Mergler, D; Bowler, R; van Thriel, C

The neurobehavioral impact of manganese-Results and challenges obtained by a meta-analysis of individual participant data.

Results from a meta-analysis of aggregated data provoked a new analysis using individual data on the neuropsychological performance of occupationally exposed workers. Data from eight studies examining 579 exposed and 433 reference participants were included, 28 performance variables analyzed. The performance scores were adjusted for well-known individual-level covariates; possible, but unknown study-level covariates were attenuated by means of a z-normalization. Associations between performance and exposure were estimated by ANOVAs and ANCOVAs, the latter representing multi-level models. Four cognitive and motor performance variables each indicated significantly lower performances of exposed individuals when confounding was considered; slowed motor performances and deficits in attention and short-term memory were found. Performance on a single test was significantly related to the biomarker manganese in blood. The outcomes on susceptibility were weak. The slowing of responses was the most distinct feature of performances of exposed workers. It remains unclear, whether this result is related to the employed tests or provides important information about early stages of the neurotoxic impairment. More specific cognitive tests need to be employed to answer this question. The lack of dose-response relationships was related to features of the biomarker: it does not reflect the Mn in brain responsible for changes in performances