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Vitamin B12 and folic acid in advanced oesophageal and gastric cancer714Cancer Chemotherapy and Pharmacology (2018) 82:39%u2013486]. Homocysteine To determine the bound platinum n at %u221220%u00a0%u00b0C until art was mixed with , and centrifuged. [20]. Free plasma and protein-bound ess atomic absorp667C > T MTHFR ctively, 37 and 20 e association with vement in the RR plemented arm to sample size of 82 If the true RR difld be %u226515%, there ty of selecting the s used to compare used to compare s. An intention to OS and TTP were s. The correlation atment groups was s <0.05 were conty to%u00a0cisplatinonditions CaCo-2 than WiDr cells 0.5%u00a0%u00b5M for WiDr, en cultured under s were two to five C2LFbliaccumulated more platinum than WiDr-LF cells (50 %u00b1 0.5 vs. 28 %u00b1 3%u00a0pmol/106 cells, respectively; p < 0.0001), while CaCo-2 cells (96 %u00b1 16%u00a0pmol/106 cells) accumulated more platinum than CaCo-2-LF/LV (58 %u00b1 8%u00a0 pmol/106 cells; p < 0.05) or CaCo-2-LF/FA (44 %u00b1 6%u00a0pmol/106 cells; p < 0.02). Co-incubation with gemcitabine resulted in a slight increase in cisplatin accumulation, especially under LF conditions (not shown). Overall, these data demonstrate that high folate conditions can increase sensitivity of adenocarcinoma cells to cisplatin, and that this is associated with higher intratlltiltiiditilfAB 01234567High folate Low folateLV FAIC50 (%u00b5M)CISPLATINGEM-CISWiDr024681012High folate Low folateIC50 (%u00b5m)CISPLATINGEM-CISCaCo-2Fig. 1 High folate conditions can increase sensitivity of adenocarcinoma cells to cisplatin. CaCo-2 and WiDr adenocarcinoma cell lines were treated with cisplatin and gemcitabine under high folate or low folate conditions. a CaCo-2 and sublines CaCo-2/LF/LV and CaCo-2/LF/FA; b WiDr. CaCo-2-LF sublines CaCo-2-LF/LV (IC505.6 %u00b1 0.5%u00a0%u00b5M; p < 0.01), CaCo-2-LF/FA (IC50 3.4 %u00b1 0.3%u00a0%u00b5M; p < 0.02), and WiDr/LF (IC50 10.1 %u00b1 0.1%u00a0 %u00b5M; p < 0.02) under low folate (LF) conditions were two to five fold less sensitive to cisplatin compared to culture under high folate conditions. LF low folate, FA folic acid reduced into the nM range, LV leucovorin reduced into the nM rangeFigure 1. High folate conditions can increase sensitivity of adenocarcinoma cells to cisplatin. CaC02 and WiDr adenocarcinoma cell lines were treated with cisplatin and gemcitabine under high folate or low folate conditions. (A) CaC02 and sublines CaCo2/LF/LV and CaCo2/LF/FA; (B) WiDr. CaCo2-LF sublines CaCo2-LF/LV (IC50 5.6 %u00b1 0.5 %u00b5M; p<0.01), CaCo2-LF/FA (IC50 3.4 %u00b1 0.3 %u00b5M; p<0.02), and WiDr/LF (IC50 10.1 %u00b1 0.1 %u00b5M; p<0.02) under low folate (LF) conditions were 2-5 fold less sensitive to cisplatin compared to culture under high folate conditions. Abbreviations: LF, low folate; FA, folic acid reduced into the nM range; LV, leucovorin reduced into the nM range.Patient characteristicsA total of 82 patients were randomly assigned to each treatment arm (41 patients in each arm). Baseline characteristics were generally well matched between the two treatment arms (Table 1). The mean age of patients was 61 years (range 35-83). The majority of patients were male, and most (72%) suffered from advanced esophageal cancer. In 85-90% of patients the ECOG performance score was 0-1. Less than 10% of the supplemented patients and none of the unsupplemented patients had undergone prior treatment for esophagogastric carcinoma (two patients received palliative radiotherapy of the primary tumor, one patient received