[show abstract][hide abstract] ABSTRACT: Many physiological, biochemical and behavioral processes are under circadian regulation, which is generated by an in- ternal 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.
[show abstract][hide abstract] ABSTRACT: 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 im- portant 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).
[show abstract][hide abstract] ABSTRACT: Recent studies implicate circadian genes in the regulation of cell cycle, apoptosis, and cell proliferation at a molecular level. These genesey affect cancer incidence, prognosis, and chemosensitivity. In this study, we measured the expression levels of clock genes and correlated their expression levels with clinicopathological parameters in epithelial ovarian cancer.
The expression levels of core clock genes, per1, per2, per3, cry1, cry2, Bmal1, clock, and CKIepsilon were quantified by real-time quantitative Reverse transcription-polymerase chain reaction in 83 ovarian cancer tissues and 11 normal ovarian tissues.
The expression levels of per1, per2, cry2, clock, CKIepsilon in ovarian cancers were significantly lower than those in normal ovaries. In contrast, cry1 expression was highest among the eight examined clock genes, followed by per3 and Bmal1. Cry1 expression was much higher in cancer than that in normal ovaries. Localized circadian gene expression was determined in cancer cells by in situ hybridization analysis. Cry1 expression was significantly reduced in mucinous and grade 3 tumors. Bmal1 expression was also significantly reduced in mucinous adenocarcinomas as compared to other histologies. In a multivariate analysis, the combination of low cry1 expression and low Bmal1 expression was an independent prognostic factor, as well as stage and histological subtype.
The antiphase expression of cry1 and Bmal1 may be preserved in ovarian cancers. The combination of cry1 and Bmal1 expression might become a possible prognostic marker in epithelial ovarian cancer.
[show abstract][hide abstract] ABSTRACT: Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC) to generate phosphatidic acid (PA) and choline. PA acts as a second messenger in cell proliferation; therefore PLD is believed to play an important role in carcinogenesis. PLD activity has been reported to be elevated in human breast, gastric, renal cell and colorectal carcinomas, compared with adjacent non-neoplastic tissues. The activity of PLD was also correlated with nuclear grade in breast cancer, tumor size in gastric carcinoma, and nodal involvement and deeper invasion in colorectal carcinoma. However, the number of cases in each study was small. The aim of this study was to investigate the expression level of PLD2 and its association with clinicopathological features in human colorectal carcinoma. Ninety-seven colorectal carcinomas were obtained from surgery. Expression level of PLD2 was assessed by real-time PCR. The prognostic relevance of PLD2 expression level in patients with colorectal carcinoma was also analyzed by the survival analysis of mortality follow-up data covering the period 2000-2004. PLD expression level was varied from tumor to tumor. Expression level of PLD was significantly correlated with tumor size (P<0.05); it was independent of lymph node metastasis, extent of invasion, pathological classification, distant metastasis and Dukes' stage. PLD expression level was also significantly correlated with survival of patients with colorectal carcinoma (P<0.05). These findings suggested that PLD2 plays an important role in progression of colorectal carcinoma and that PLD2 could be a target for therapy in colorectal carcinoma.
[show abstract][hide abstract] ABSTRACT: Many physiological, biochemical, and behavioral processes are under circadian regulation, which is generated by an internal time-keeping mechanism referred to as biological clock. The regulators of circadian rhythm in human plasma have not been completely elucidated. Here we demonstrated that the isolated protein from human plasma, which down-regulated expression level of cry1 in Jurkat cells, was apoprotein H (ApoH). Further, mRNA expression level of ApoH indicated circadian rhythm in Jurkat cells. The concentration of ApoH was subject to circadian rhythm in human plasma. These experimental results suggested that ApoH may be one of the members of the regulator of circadian rhythm and that ApoH expression level was also dependent on circadian rhythm in Jurkat cells and in human plasma.
Biochemical and Biophysical Research Communications 09/2007; 360(2):418-22. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space.
To identify the responsible gene that causes pulmonary alveolar microlithiasis.
By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis.
We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function.
Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.
American Journal of Respiratory and Critical Care Medicine 03/2007; 175(3):263-8. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: A 71-year-old woman was seen at our hospital because of abdominal fullness and dyspnea. Examinations revealed a tumor in the pelvis with fluid collection and dissemination was seen in the abdomen and chest. Moreover, hyaluronate in ascites rose to 20,000 mg/dl. Finally, by cytology of ascites using immunohistochemistry, the patient was diagnosed as malignant peritoneal mesothelioma with disseminations in the abdomen and chest. After intraperitoneal administration of 25 mg of cisplatin (CDDP), we started carboplatin (CBDCA) plus paclitaxel (PTX) combination chemotherapy (each treatment course consisted of 100 mg of PTX and 400 mg of CBDCA on day 1 and PTX 100 mg on day 8 and day 15 by intravenous administration followed by 2 drug-free weeks). After the sixth course, a complete remission was observed. Malignant mesothelioma is known to have a poor prognosis. However, we successfully treated malignant peritoneal mesothelioma with CBDCA and PTX combined chemotherapy. Our case suggests that we could improve the prognosis of malignant mesothelioma by aggressive chemotherapy.
Gan to kagaku ryoho. Cancer & chemotherapy 08/2006; 33(7):1001-4.
[show abstract][hide abstract] ABSTRACT: The authors identified a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), who completely fulfilled the clinical criteria with low thymidine phosphorylase (TP) activity. However, the same homozygotic S471L TP gene mutation was also found in her unaffected mother, but with normal TP activity. To elucidate the pathogenesis of MNGIE, we performed the analysis below.
We analyzed the TP gene mutation in the proband and 145 unrelated individuals by direct sequence and restriction fragment length polymorphism (RFLP). TP activity was determined by the spectrophotometric method for each TP S471L genotype.
Among 145 normal persons, the S471L homozygote mutants were identified in 2.76% and their enzyme activity was normal.
TP gene mutation is not a primary cause of MNGIE, but with a mitochondrial deletion mutation, a single nucleotide polymorphism (SNP) of the TP gene may be crucial in the pathogenesis of MNGIE.
Internal Medicine 02/2006; 45(7):443-6. · 0.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed in endometrial carcinoma. Our goal was to investigate if ATP7B is expressed in endometrial carcinoma and whether its expression correlates with prognosis.
We performed immunohistochemical analysis of ATP7B using a monoclonal antibody against ATP7B in 51 endometrial endometrioid adenocarcinomas. 27 of 51 patients were treated with cisplatin-based chemotherapy after surgery.
Cytoplasmic staining of tumor cells was observed in 37.3% (19/51 cases) of the analyzed carcinomas and no staining was observed in adjacent non-neoplastic cells. ATP7B positivity in the degree of differentiation of G2 and G3 carcinoma was significantly higher than that of G1 carcinoma (P = 0.019). The patients with ATP7B-positive tumors had a worse prognosis than that with ATP7B-negative tumors in overall survival and disease-free survival, respectively (P < 0.01).
These findings suggest that overexpression of ATP7B expression in endometrial carcinoma is correlated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. ATP7B expression could be considered as a prognostic factor in patients with endometrial carcinoma.
[show abstract][hide abstract] ABSTRACT: Despite the significance of tumor angiogenesis and the extensive knowledge on the molecular basis of blood vessel formation in carcinoma of colorectum, no data exist in hyperplastic polyp. This prompted us to examine angiogenesis in hyperplastic polyp. Eleven small hyperplastic polyps, 13 large hyperplastic polyps and their adjacent normal mucosas were included in this study. Angiogenesis was assessed by immunohistochemistry using monoclonal antibody against CD34. Angiogenic factor, thymidine phosphorylase was also examined by immunohistochemistry. Intra-tumoral microvessel density (IMD) in large hyperplastic polyp was significantly higher than that in small hyperplastic polyp (P<0.01) and that in normal mucosa (P<0.01). DAD in small hyperplastic polyp was also significantly higher than that in normal mucosa (P<0.01). Expression of dThdPase was almost observed in stromal cells in normal, small and large hyperplastic polyp. In addition, the proportion of the stromal cells expressing dThdPase in large hyperplastic polyp was significantly higher than that in small hyperplastic polyp and normal tissue (P<0.01, respectively). The proportion of the stromal cells expressing dThdPase in small hyperplastic polyp was significantly higher than that in normal tissue (P<0.01). The present study provides that angiogenesis may have an important role(s) in the development of hyperplastic polyp and dThdPase in stromal cells may support angiogenesis in hyperplastic polyp. Anti-angiogenic therapy might be available for suppression of hyperplastic polyp.
Cancer letters 03/2005; 218(2):223-8. · 4.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Translational research (TR) involves both the development of novel diagnostics and novel therapeutics. These two major developmental areas are often associated with each other and these associations often bring new paradigms in the management of cancer patients. For example, the development of trastuzumab-based treatments has been conducted in harmony with the development of new methodologies to assess the expression of the Her-2 gene or protein, and from this, a therapeutic modality was established for breast cancer patients as a novel and individualized treatment system. TR covers a broad spectrum, from diagnosis to treatment, and it seems to act as a catalyst for developing novel paradigms. Therefore, it is crucial to conduct TR in clinical trials, in particular, prospective clinical trials. In this regard, TR can accelerate the development of new methodologies and increase trial efficiency. In this review, we describe the importance of TR, particularly that related to novel therapeutics.
Breast Cancer 02/2005; 12(2):86-90. · 1.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Thymidine phosphorylase (TP), an enzyme involved in pyrimidine metabolism, is identical with an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF). TP is overexpressed in various tumors and plays an important role in angiogenesis, tumor growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP. A novel, specific TP inhibitor, TPI, inhibits angiogenesis induced by overexpression of TP in KB/TP cells (human KB epidermoid carcinoma cells transfected with TP cDNA), as well as the growth and metastasis of KB/TP cells in vivo. 2-deoxy-D-ribose, the degradation product of thymidine generated by TP activity, has both angiogenic and chemotactic activity. Both 2-deoxy-D-ribose and TP inhibit a hypoxia-induced apoptotic pathway. These findings suggest that 2-deoxy-D-ribose is a downstream mediator of TP function. 2-deoxy-L-ribose, a stereoisomer of 2-deoxy-D-ribose, inhibits the promotion of angiogenesis, tumor growth and metastasis by TP. Although the mechanism of the action of 2-deoxy-D-ribose is still unknown, 2-deoxy-L-ribose may inhibit the physiological activities of 2-deoxy-D-ribose, and consequently those of TP. Inhibition of TP activity and function appears to be a promising approach for the chemotherapy of various tumors.
Cancer Science 12/2004; 95(11):851-7. · 3.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: A major obstacle in the treatment of ovarian carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Cu-transporting ATPase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed. Our goal was to investigate ATP7B expression in ovarian carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment.
We retrospectively examined the expression of ATP7B and p53 in primary ovarian carcinoma and its association with chemotherapeutic effect. Tissues were surgically removed from 104 ovarian carcinomas patients who received cisplatin-based chemotherapy. We performed immunohistochemical analysis of ATP7B and p53 using a monoclonal antibody against ATP7B and DO7 antibody against p53 protein in 104 ovarian carcinomas and adjacent nonneoplastic tissues. The significance of ATP7B and p53 in the prognosis of patients with ovarian carcinomas was also examined in the survival analysis of mortality follow-up data covering the period between 1988 and 2001. Furthermore, mutation analysis at the six Cu-binding domain and ATP-binding domain, which may be important for cisplatin transport, were performed using single-strand conformational polymorphism after reverse transcriptase-PCR.
A variable degree of cytoplasmic staining of ATP7B in tumor cells was observed in 34.6% (36 of 104 cases) of the analyzed carcinomas. ATP7B expression was not observed in adjacent nonneoplastic tissues. ATP7B positivity in poorly/moderately differentiated carcinoma was significantly higher than that in low malignant potential tumor/well-differentiated carcinoma (P = 0.0276). Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.025). The multivariate Cox regression analysis revealed that ATP7B expression (hazard ratio, 1.8; 95% confidence interval, 1.0-3.2, P = 0.048), as well as International Federation of Gynecologists and Obstetricians stage (hazard ratio, 2.0; 95% confidence interval, 1.1-3.6, P = 0.018), was prognostic for poor disease outcome after adjustment for p53 expression, grade, and residual tumor. p53 expression was detected in 31.5% (26/104 cases). No mutation was observed on the six Cu-binding domain or ATP-binding domain in human ovarian carcinomas expressing ATP7B gene.
This study demonstrates that overexpression of ATP7B in ovarian carcinoma is correlated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, ATP7B expression may be considered as a predictive marker of chemoresistance for cisplatin-based chemotherapy in patients with ovarian carcinoma. We further predict that drugs targeting ATP7B might be useful in combination with cisplatin-based regimen for the improvement of patients with ovarian carcinoma.
Clinical Cancer Research 05/2004; 10(8):2804-11. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ovarian tumours of low malignant potential (LMP) are intermediate between adenomas and ovarian carcinomas. These tumours are often associated with a significantly better prognosis than ovarian carcinomas. However, a subset of these tumours can progress and become lethal. In order to seek sensitive diagnostic tools for monitoring patients after surgical operation, we performed a genome-wide scan for loss of heterozygosity (LOH) in 41 mucinous LMPs using 91 polymorphic microsatellite markers at an average interval of 50 cM across all of the human chromosomes and 25 LOH markers reportedly associated with ovarian carcinoma. In addition, we assessed whether clinicopathological parameters, microvessel density, Ki-67 labeling index, apoptotic index or p53 overexpression would be useful for predicting the postoperative outcome of LMP patients. Of the 116 markers examined, 19q12 and Xq11-12 showed significant correlation between postoperative progression-free survival time and LOH status (P<0.05). Patients with a high Ki-67 labeling index had a significantly poorer progression-free survival time than those with lower levels (P=0.042). Other clinicopathological factors and immunohistochemical analysis had no correlation with progression-free survival time in this series of patients. When the combination of LOH at 19q12 and/or Xq11-12 was assessed using Cox's regression analysis, patients with tumours that showed LOH at these positions were at greatest risk of progression (P=0.0073). These findings suggest that the identification of LOH at 19q12 and/or Xq11-12 in former mucinous LMP sites should alert the clinician to the presence of a potentially aggressive lesion in the coelomic epithelium, even if a distinction between second primary tumours or recurrence could not be determined.
British Journal of Cancer 03/2004; 90(6):1204-10. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: The international guidelines for the evaluation of microsatellite instability (MSI) in colorectal cancer were defined in 1997 by the National Cancer Institute (NCI). Here, the relationship between MSI, cancer-associated genes and their clinicopathological variables were revaluated using these guidelines.
Mutations of K-ras at exon 1 and p53 at exons 5, 6, 7 and 8 were analyzed in 43 cases of sporadic colorectal carcinoma. MSI was analyzed using the 5 markers recommended by the NCI reference panel.
The proportion of p53 mutations in the MSI-H cases (0 out of 5; 0%) was lower than that of non-MSI-H cases (23 out of 38; 60.5%) (p=0.0117). The proportion of p53 mutations in microsatellite stable (MSS) cases (21 out of 34; 61.8%) was higher than that of non-MSS cases (2 out of 9; 22.2%) (p=0.0366). The proportion of K-ras mutations in MSI-H tumors (1 out of 5; 20.0%) was less frequent than in non-MSI-H tumors (19 out of 38; 50.0%) (p=0.2115).
p53 mutations in MSI-H tumors were much less common than in non-MSI-H tumors. This result suggested that alterations of the p53 gene are not closely associated with carcinogenesis in MSI-H carcinomas.
Anticancer research 01/2004; 24(3b):2047-52. · 1.71 Impact Factor