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BackgroundConsiderable variation in intravenous 5-fluorouracil (5-FU) metabolism can occur due to the wide range of dihydropyrimidine dehydrogenase (DPD) enzyme activity, which can affect both tolerability and efficacy. The oral fluoropyrimidine tegafur-uracil (UFT) is an effective, well-tolerated and convenient alternative to intravenous 5-FU. We undertook this study in patients with locally advanced rectal cancer to evaluate the efficacy and tolerability of UFT with leucovorin (LV) and preoperative radiotherapy and to evaluate the utility and limitations of multicenter staging using pre- and post-chemoradiotherapy ultrasound. We also performed a validated pretherapy assessment of DPD activity and assessed its potential influence on the tolerability of UFT treatment.MethodsThis phase II study assessed preoperative UFT with LV and radiotherapy in 85 patients with locally advanced T3 rectal cancer. Patients with potentially resectable tumors received UFT (300 mg/m/2/day), LV (75 mg/day), and pelvic radiotherapy (1.8 Gy/day, 45 Gy total) 5 days/week for 5 weeks then surgery 4-6 weeks later. The primary endpoints included tumor downstaging and the pathologic complete response (pCR) rate.ResultsMost adverse events were mild to moderate in nature. Preoperative grade 3/4 adverse events included diarrhea (n = 18, 21%) and nausea/vomiting (n = 5, 6%). Two patients heterozygous for dihydropyrimidine dehydrogenase gene (DPYD) experienced early grade 4 neutropenia (variant IVS14+1G > A) and diarrhea (variant 2846A > T). Pretreatment ultrasound TNM staging was compared with postchemoradiotherapy pathology TN staging and a significant shift towards earlier TNM stages was observed (p < 0.001). The overall downstaging rate was 42% for primary tumors and 44% for lymph nodes. The pCR rate was 8%. The sensitivity and specificity of ultrasound for staging was poor. Anal sphincter function was preserved in 55 patients (65%). Overall and recurrence-free survival at 3 years was 86.1% and 66.7%, respectively. Adjuvant chemotherapy was administered to 36 node-positive patients (mean duration 118 days).ConclusionPreoperative chemoradiotherapy using UFT with LV plus radiotherapy was well tolerated and effective and represents a convenient alternative to 5-FU-based chemoradiotherapy for the treatment of resectable rectal cancer. Pretreatment detection of DPD deficiency should be performed to avoid severe adverse events.

Histamine (1 mm) induced an accumulation of inositol monophosphate ([3H]‐IP1) in the U373 MG human astrocytoma cell line which increased with time in the presence of 30 mm Li+. After a 30 min incubation period with 1 mm histamine [3H]‐IP1 was the major product detected (84 ± 1 % of total [3H]‐IPx) and was present at a level 11 (±1) fold of basal accumulation. Concentration‐response curves for histamine‐induced [3H]‐IP1 accumulation in U373 MG cells (EC50 5.4 ± 0.5 μm) were shifted to the right in a parallel fashion by mepyramine (slope of a Schild plot 0.99 ± 0.08), yielding a Kd for mepyramine of 3.5 ± 0.3 nm, consistent with the involvement of histamine H1‐receptors. The temelastine‐sensitive binding of [3H]‐mepyramine to a membrane fraction from U373 MG cells was hyperbolic and had a mean Kd of 2.5 ± 1.0 nm. The maximum amount of temelastine‐sensitive binding was 86 ± 19 pmol g−1 membrane protein. Carbachol also induced [3H]‐IP1 accumulation in U373 MG cells, 2.8 (± 0.1) fold of basal with 1 mm carbachol, with an EC50 of 48 ± 8 μm. Pirenzepine shifted carbachol concentration‐response curves to the right (slope of Schild plot 0.89 ± 0.07) giving a Kd for pirenzepine of 0.10 ± 0.01 μm, suggesting that phosphoinositide hydrolysis in U373 MG cells is mediated by the M3‐, rather than the M1‐, muscarinic receptor subtype. [3H]‐IP1 accumulation induced by both 1 mm histamine and by 1 mm carbachol increased when the Ca2+ concentration of the medium was increased from ‘zero’ (no added Ca2+) to 0.3 mm. Histamine‐stimulated [3H]‐IP1 accumulation was further increased, although not so markedly, as the Ca2+ was raised to 4 mm. The same pattern was apparent with histamine‐induced accumulations of [3H]‐IP2 and [3H]‐IP3. In contrast, [3H]‐IPx accumulation in response to carbachol increased between 0.3 and 1.3 mm, but thereafter remained unchanged ([3H]‐IP1) or declined ([3H]‐IP2 and [3H]‐IP3). In HeLa cells, [3H]‐IP1 accumulations induced by 1 mm histamine and 1 mm carbachol showed the same pattern of Ca2+ dependence and were independent of extracellular Ca2+ above 0.3 mm (histamine) or 1.3 mm (carbachol). The response to carbachol appeared to be mediated by an M3‐muscarinic receptor (apparent Kd for pirenzepine 0.09 μm). In cross‐chopped slices of guinea‐pig cerebral cortex and guinea‐pig cerebellum, [3H]‐IP1 accumulation induced by 1 mm histamine in the presence of 10 mm Li+ increased as the extracellular Ca2+ was increased from 0.3 to 2.5 mm, but a further increase to 4 mm had no further effect. In contrast the response to histamine in rat cerebral cortex increased markedly between 1.3 and 4 mm Ca2+. Accumulations of [3H]‐IP1 induced by carbachol in guinea‐pig or rat cerebral cortical slices were not increased as extracellular Ca2+ was raised from 0.3 to 4 mm. Nimodipine (100 nm) and ω‐conotoxin (3 μm) had no significant effect on histamine‐induced [3H]‐IP1 accumulation in rat cerebral cortical slices or in U373 MG cells. We conclude that histamine‐induced [3H]‐IP1 accumulation in U373 MG cells does appear to have a compo...