Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy.

BACKGROUND: For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R) and Transketolase-like-1 (TKTL1) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab. METHODS: Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR. RESULTS: Significantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers. CONCLUSION: High TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.

Population thiamine status and varying cancer rates between western, Asian and African countries.

The role of food supplements in the form of vitamins has not been extensively investigated in relation to varying cancer rates between populations of different geographical regions. New data indicate that thiamine (vitamin B1), a common food supplement in Western food products, is directly involved in nucleic acid ribose synthesis of tumor cells in its biologically activated form through the non-oxidative transketolase catalyzed pentose cycle reaction. Whether thiamine plays a role in increased cancer rates in the Western World by enhancing tumor cell proliferation, while increased consumption of thiaminase rich food limiting thiamine availability protects against common malignancies in Asia and Africa has not been evaluated. In the Western World, thiamine is a popular vitamin supplement in the form of tablets and it is also added to basic food items such as milled flour, cereals, peanut butter, refreshment drinks and pastas. On the contrary, thiaminase, the natural thiamine-degrading enzyme, is abundantly present in raw and fermented fish, certain vegetables and roasted insects consumed primarily in Africa and Asia. Excess thiamine supplementation in common food products may contribute to the increased cancer rates of the Western World.

Diuretic use: a risk for subclinical thiamine deficiency in elderly patients.

Long term diuretic therapy represents one central pharmacologic therapy of heart insufficiency and hypertension. Diuretics lead not only to an increased urinary excretion of electrolytes but also of water soluble vitamins. In this prospective study we evaluated the effect of hospitalization on the overall biochemical vitamin status in subjects older than 50 years (n=149, mean +/- SD age 70 +/- 10 years). Vitamin nutriture and other parameters were assessed at admission and discharge (duration of the hospitalization 19 +/- 1 day). Only vitamin B1 nutriture worsened during the hospitalization and in a multivariate procedure the only significant predictor of the change in the vitamin B1 nutriture was the use of diuretics during the hospitalization (F=4.06, p < 0.001). The changes in the ETK (erythrocyte transketolase activity in whole blood) and a-ETK (ETK activity coefficient) during the hospital stay correlated with the cumulative dosage of furosemide adjusted for the duration of the therapy (r = 0.36, p < 0.001 and r = - 0.28, p > 0.03). Our data suggest that hospitalized elderly are at increased risk for vitamin B1 deficiency especially when on a diuretic treatment. It is possible that a low dose thiamine supplementation my help to prevent the development of a subclinical wet-beriberi in older subjects on diuretics.

Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study.

PURPOSE: To test the hypothesis that long-term furosemide therapy in patients with congestive heart failure (CHF) is associated with clinically significant thiamine deficiency via urinary loss. DESIGN: (1) Biochemical evaluation of thiamine status in hospitalized patients with CHF treated with long-term furosemide and in age-matched control patients. (2) Uncontrolled trial of the effect of intravenous thiamine on cardiac performance in a subset of six patients with CHF. SETTING: General medical ward of a teaching community hospital. PATIENTS: Twenty-three patients with chronic CHF receiving furosemide, and 16 age-matched control patients without heart failure and not taking diuretics. Daily furosemide doses were 80 to 240 mg, and duration of furosemide therapy was 3 to 14 months. Patients with identifiable causes of inadequate thiamine intake, absorption, or utilization or increased metabolic requirements were excluded. INTERVENTION: A 7-day course of intravenous thiamine, 100 mg twice daily, in six consenting patients with CHF. RESULTS: A high thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in 21 of 23 furosemide-treated patients and in two of 16 controls (p less than 0.001). The mean (+/- SE) TPPE (normal: 0% to 15%) in furosemide-treated and control patients was 27.7 +/- 2.5% and 7.1 +/- 1.6%, respectively (p less than 0.001). Despite the high TPPE, the mean (+/- SE) urinary thiamine excretion in the furosemide-treated patients (n = 18) was inappropriately high (defined as greater than 130 micrograms/g creatinine), 410 +/- 95 micrograms/g creatinine, even in comparison with that in the controls (n = 14): 236 +/- 69 micrograms/g creatinine. In six patients treated with intravenous thiamine, the elevated TPPE decreased to normal, from a mean (+/- SE) of 27.0 +/- 3.8% to 4.5 +/- 1.3% (p less than 0.001), indicating normal thiamine utilization capacity. Left ventricular ejection fraction increased in four of five of these patients studied by echocardiography. CONCLUSIONS: These preliminary findings suggest that long-term furosemide therapy may be associated with clinically significant thiamine deficiency due to urinary loss and contribute to impaired cardiac performance in patients with CHF. This deficit may be prevented or corrected by appropriate thiamine supplements.

Sugar metabolism in transketolase mutants of Escherichia coli.

This paper continues the description of transketolase mutants of Escherichia coli; they are absolutely unable to grow on pentoses, but slightly "leaky" with respect to their aromatic requirement (B. L. Josephson and D. G. Fraenkel, 1969). Several experiments have explored the degree of leakiness and shown it to be low. There is little conversion of radioactive xylose to carbon dioxide. The labeling of ribose in cells grown on [1-(14)C]glucose and [2-(14)C]glucose accords with its origin being chiefly by the oxidative pathway. A mutant lacking both transketolase and gluconate-6-phosphate dehydrogenase has been constructed; it requires supplementation with pentose. Pentoses are inhibitory to growth of transketolase mutants, but high levels of pentose phosphates do not accumulate in this situation. Several experimental results are suggestive of regulation of metabolic flow in the oxidative branch of the hexose monophosphate shunt.