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Many behavioral processes are under circadian regulation in almost all organisms from bacteria to mammals. Although substantial evidences support the idea that circadian clock could modulate the efficacy of anticancer therapy, the mechanism(s) has not been clear. Here we demonstrated that expression of topoisomerase I (top1) mRNA and its promoter activity underwent circadian oscillation after serum-rich medium treatment in HCT 116 cells. Moreover, the formation of cleavage complex composed of top1 and top1 poison, camptothecin (CPT), detected by nicking assay was also oscillated. Colony formation assay indicated that cytotoxicity of 8h-CPT treatment was significantly higher at 4-h after serum-shock than at 20-h (p = 0.0289). In addition, dexamethasone treatment also induced circadian rhythm of top1 in HCT 116 cells. These results raise the possibility that the circadian rhythm of top1, which would be induced by some types of drugs such as dexamethasone, could be considered for chemotherapy in clinic.

Many physiological, biochemical and behavioral processes are under circadian regulation, which is generated by an internal time-keeping mechanism referred to as biological clock in almost all organisms from bacteria to mammals. Although the substantial evidences that the circadian clock could modulate the morbidity and efficacy of anticancer therapy have been proposed, underlying mechanisms for chronotherapy has been only poorly elucidated, and it has not been popular in clinic. The aim of this study was to determine the relationship between the expression of P-glycoprotein (P-gp)/MDR1, which is one of the important molecules in anti-cancer drug resistance, and circadian rhythm in KB-C2 cells. The present study demonstrated that both MDR1 expression level and its promoter activity oscillated after treatment with high concentration of fetal bovine serum. Moreover, cytotoxic effect of taxol were dependent on the fluctuated levels of MDR1. These results suggest that the circadian rhythm of MDR1 may have an influential effect on cytotoxicity of anti-cancer drug and could be available for chemotherapy in clinic.

It has been suggested that inflammatory components, including interleukin (IL)-6 and transforming growth factor (TGF)-β, play an important role in the formation of cancer cachexia. Cyclooxygenase (COX)-2 has been reported to suppress tumor progression and to inhibit production of these inflammatory mediators, and, thus, may not only be effective in preventing cachexia, but also beneficial for survival. Etodolac, one of the selective COX-2 inhibitors, was administered to mice bearing cachexigenic clones of colon 26, together with either one of two doses (5 and 10 mg/kg/day) of 5-fluorouracil. Serum concentrations of IL-6 were measured in each treatment group. In the groups treated with 5-fluorouracil alone, survival and tumor growth were significantly improved with 10 mg/kg/day. In the group with etodolac alone, survival improved, however, tumor growth was enhanced. Combination of 5-fluorouracil (5 mg/kg/day) and etodolac improved survival, and the enhancement of tumor growth seen in the etodolac only group, disappeared. By combining 5-fluorouracil (10 mg/kg/day) with etodolac, positive effects on survival and tumor growth were obtained. Serum concentrations of IL-6 were elevated in tumor-bearing mice and were significantly suppressed by treatment with etodolac. In the group with combined treatment, the suppressive effect on IL-6 was synergistic. Our findings suggest that the potential use of COX-2 inhibitors in combination with chemotherapy might be therapeutically advantageous especially in patients with terminal stages of cancer.

Purpose: The cyclooxygenases (COX) catalyze the formation of prostaglandins, affecting cell proliferation and altering the response of the immune system in malignant cells. The inducible forms of COX-1 and COX-2, have been shown to be important in carcinogenesis. Peroxisome-proliferator activated receptor gamma (PPARgamma) belongs to a family of nuclear receptors and acts as receptor for peroxisome-proliferators, steroids, retinoic acids, and polyunsaturated fatty acids. The aim of this study is to investigate the clinicopathological significance of the expressions of COX-1, COX-2 and PPARgamma genes in 90 colorectal carcinomas.Experimental Design: The expressions of COX-1, COX-2 and PPARgamma genes were examined in surgical specimens of colorectal carcinoma and corresponding normal tissues from 90 patients using modified Real Time PCR.Result: There was increase in the expression of PPARgamma in colorectal carcinomas compared to paired normal tissue (p = 0.03). Greater COX-2 expression was correlated with lymph node metastasis (p = 0.02) and venous invasion (p = 0.01).

Chronotherapy is one of the most active treatment schedule, based on the adjustment of drug delivery to the 24-hour rhythms generated by circadian rhythm. The aim of this study is to confirm that the efficacy of 5-fluorouracil (5-FU) is dependent on circadian rhythm, using Walker-256 xenografted rat. The present study demonstrated that tumor developed more rapidly at night rather than at day. Moreover, the administration of 5-FU at night was more effective rather than that at day. Furthermore, the microvessel count by immunohistochemical staining of endothelial cells revearled that tumors treated with 5-FU at night contained significantly less microvessels than those at day. In conclusion, our present data suggested that chronotherapy would contribute to the improvement of chemotherapy in patients with some population of malignancy through the control of angiogenesis.