Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracilmetabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT-PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35-fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells. [Cancer Res 2007;67(16):7917-22]

In experimental and clinical studies, conflicting results regarding the effect of oral anticoagulant therapy on bone metabolism have been reported. To measure a possible influence of long-term anticoagulant therapy with phenprocoumon on peripheral bone mass, measurements of peripheral bone mineral content (BMC) and serum osteocalcin levels were performed with single photon absorptiometry in a total of 78 patients on anticoagulant treatment. We studied 43 women (mean age 66 years +/- 2 SEM) and 35 men (mean age 65 years +/- 2 SEM) with a median duration of phenprocoumon therapy of 1 year (1-9 years). In all patients, the medical history gave no symptoms of metabolic bone disease, or diseases or medications causing osteoporosis. Both in the male and female groups, mean peripheral BMC was significantly decreased (male: P less than 0.01, female: P less than 0.003) when compared with corresponding controls. Serum OC-levels measured in 16 patients were also significantly lower than those of the controls (P less than 0.02). Our data of decreased BMC and low serum OC-levels indicate reduced bone mass in patients on long-term anticoagulant therapy with phenprocoumon. This may imply an influence of anticoagulants on bone metabolism resulting in decreased bone formation.

With advancing age both sexes have an increased incidence of osteoporotic fractures, although fractures are more common in women than in men. Whereas in women several potential risk factors have been identified, less is known about osteoporosis in men. A total of 27 Austrian men (mean age: 65 +/- 2 years) with atraumatic spine fractures were studied. In all patients, medical history gave no evidence of disease or medications causing osteoporosis. Peripheral bone mass was determined by single-photonabsorptiometry on the distal non-dominant forearm; lumbal bone density was measured by quantitative computed tomography. Serum levels of calcium, phosphate, alkaline phosphatase, osteocalcin, testosterone, estrogen, parathyroid hormone and 25-hydroxy-vitamin D as well as 2-h-urinary-OH proline and calcium excretion were measured. All data were compared with those of an age and sex matched control group consisting of 19 healthy males. A significant difference in mean peripheral and axial bone mass (SPA: P less than 0.004; QCT: P less than 0.0001) was observed between osteoporotic men and controls. When compared to controls, serum levels of alkaline phosphatase (P less than 0.012), urinary OH proline (P less than 0.05) and urinary calcium excretion (P less than 0.003) were significantly higher in the osteoporotic males. Additionally, there was a significant positive correlation between serum alkaline phosphatase and urinary OH proline excretion (r = 0.32; P less than 0.04) in the osteoporotics. All other biochemical parameters showed no significant differences. Our results may lead to the assumption that osteopenia in men is related to increased bone turnover.

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