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).
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.
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.
Angiogenesis is essential for tumor growth and metastasis, therefore, inhibition of angiogenesis has emerged as a new therapy to treat cancers. Although vascular endothelial cell growth factor (VEGF) induces tumor growth and metastasis by its angiogenic property, the mechanism(s) of circadian rhythm in angiogenesis has not been fully analyzed. Here we revealed that VEGF mRNA expression level, protein expression level and its promoter activity belonged to circadian rhythm in human colon carcinoma cell line, HCT116 cells. HIF (hypoxia inducible factor)-1α also underwent circadian oscillation at levels of mRNA and promoter activity. Co-transfection of Bmal1 and Clock enhanced HIF-1α luciferase activity, but not VEGF luciferase activity, indicating that VEGF is not a direct target of Bmal1/Clock. However, inhibition of HIF-1α by chrysin resulted in disappearance of VEGF circadian oscillation, suggesting that HIF-1α is involved in the regulation of the VEGF expression. Moreover, circadian oscillation of VEGF and HIF-1α was induced by 100 nM of dexamethasone. These results suggest the link between the circadian oscillation between VEGF and HIF-1α, raising a possible strategy for chronotherapy in clinic.
Xeroderma Pigmentosum Group G (XPG) is one of the proteins involved in nucleotide excision repair, and is related to Xeroderma pigmentosum, a rare hereditary disease characterized by hypersensitivity to ultraviolet light, high incidence of actinic carcinomas and neurological abnormalities. The aim of this study was to investigate the expression of XPG in sporadic human breast carcinoma and to determine whether it's expression was predictive for response to tamoxifenbased chemotherapy and survival in the patients with breast carcinoma. We investigated the expression levels of mRNA and protein of XPG in 43 sporadic human breast carcinomas by real time PCR and immunohistochemical analysis. All the patients were primarily treated with reductive surgery and doxorubicin and tamoxifen-based regimen. XPG expression was observed in 35 of 43 cases (81.4%). The proportion of the cases with high expression level of XPG was 48.8% (21/43 cases). Interestingly, the cases showing the expression of mRNA without detectable levels of protein were observed in 5 of 43 cases (11.6%). The sequence analysis showed one mutation such as deletion at codon117 that leads to a following stop codon. Moreover, patients with high expression levels significantly had a poorer overall survival than those with low expression level (P = 0.048). These results suggest that XPG may be the useful molecular marker to choose the anticancer drugs for tamoxifen-based chemotherapy in human sporadic breast carcinoma.
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.