AIM： To clarify the relations between tumor differentiation phenotype and tumor invasion or genetic alterations in gastric differentiated-type tumors. METHODS： We examined the tumor differentiation phenotype, the pr...AIM： To clarify the relations between tumor differentiation phenotype and tumor invasion or genetic alterations in gastric differentiated-type tumors. METHODS： We examined the tumor differentiation phenotype, the presence of mutations in APC and p53, and the microsatellite instability （MSI） status in 48 gastric adenomas and 171 differentiated-type carcinomas, The tumor differentiation phenotype was determined by examining the expression of human gastric mucin （HGM）, NUC6, MUC2 and CD10, The tumors were then classified into gastric- （G-）, gastric and intestinal mixed （GI-）, or intestinal- （I-） phenotypes, according to the immunopositivity of the above markers, The presence of mutations in APC and p53 and the MSI status were also investigated in all the tumors, RESULTS： Gastric adenomas were significantly associated with CDIO expression, I-phenotype tumors and the presence of APC mutations, compared with carcinomas （66.7% vs 25.1%, P 〈 0.0001; 56.3% vs 14.6%, P 〈 0.0001; 39.6% vs 14.0%, P 〈 0.0001, respectively） and inversely associated with expressions of HGM and MUC6 and the presence of p53 mutations （10.4% vs 62.6%, P 〈 0.0001; 39.6% vs 64.3%, P = 0.003; 2.0% vs 26.3%, P = 0.001, respectively）. The frequency of APC mutations was significantly higher in HGM-negative tumors, MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors than in HGM-positive tumors, MUC6- positive tumors, CD10-negative tumors and G-phenotype tumors （32.7% vs 7.1%, P 〈 0.0001; 27.8% vs 14.0%, P = 0.0182; 37.3% vs 10.4%, P 〈 0.0001; and 38.5% vs 9.5%, P = 0.0017, respectively）. The frequency of MSI was significantly higher in MUC6-positive tumors, CD10- negative tumors and G-phenotype tumors than in MUC6- negative tumors, CD10-positive tumors and I-phenotype tumors （24.8% vs 6.7%, P = 0.0009; 22.2% vs 8.0%, P = 0.0143; and 28.6% vs 9.6%, P = 0.0353, respectively）. CONCLUSION： The tumor differentiation phenotype is closely related to tumor invasion and genetic alterations in gastric differentiated-type tumors.展开更多
Uncontrolled cell proliferation is the hall mark of many cancers, and is typically manifested by a deregulation of the cell-division cycle. CDKs play critical roles in regulating cell cycle, apop- tosis and cell diffe...Uncontrolled cell proliferation is the hall mark of many cancers, and is typically manifested by a deregulation of the cell-division cycle. CDKs play critical roles in regulating cell cycle, apop- tosis and cell differentiation. AG-024322 is a multitargeted CDK inhibitor that has been shown to induce cancer cell apoptosis and de- monstrate significant antitumor activity in hu-man tumor xenograft models. This compound is under clinical development as an intravenous anticancer agent. AG-024322 exhibited moder-ate to high systemic clearance across preclini-cal species. In vitro metabolism in human liver microsomes and hepatocytes demonstrates that glucuronidation and oxidation represent the major metabolic pathways of AG-024322. The experiments of chemical inhibition and micro-somes containing individual CYP or UGT iso-forms revealed that CYP3A and UGT1A1 appear to predominantly mediate AG-024322 oxidation and glucuronidation, respectively. Formation kinetics of the two pathways in human liver mi-crosomes suggested that the glucuronidation activity of AG-024322 was approximately 3-fold higher as compared to CYP-mediated oxidation, contributing approximately 37% and 13% of the total clearance, respectively, based on the pro-jected human clearance. UGT1A1 is a poly-morphic isoform involved in glucuronidation of bilirubin. It is of concern if glucuronidation via UGT1A1 plays a major role in the elimination of AG-024322 in humans as competitive inhibition of UGT1A1 has been associated with toxicity (Gilbert and Crigler-Najjar syndromes). There-fore, this information was used to influence the clinical study design to only include subjects having constitutive expression of UGT1A1 in the first human study, thereby decreasing the potential risk of toxicity to patients.展开更多
基金Supported by Grant-in-Aid for Scientific Research, Japan Society for the Promotion of Science, No. 17790928
文摘AIM： To clarify the relations between tumor differentiation phenotype and tumor invasion or genetic alterations in gastric differentiated-type tumors. METHODS： We examined the tumor differentiation phenotype, the presence of mutations in APC and p53, and the microsatellite instability （MSI） status in 48 gastric adenomas and 171 differentiated-type carcinomas, The tumor differentiation phenotype was determined by examining the expression of human gastric mucin （HGM）, NUC6, MUC2 and CD10, The tumors were then classified into gastric- （G-）, gastric and intestinal mixed （GI-）, or intestinal- （I-） phenotypes, according to the immunopositivity of the above markers, The presence of mutations in APC and p53 and the MSI status were also investigated in all the tumors, RESULTS： Gastric adenomas were significantly associated with CDIO expression, I-phenotype tumors and the presence of APC mutations, compared with carcinomas （66.7% vs 25.1%, P 〈 0.0001; 56.3% vs 14.6%, P 〈 0.0001; 39.6% vs 14.0%, P 〈 0.0001, respectively） and inversely associated with expressions of HGM and MUC6 and the presence of p53 mutations （10.4% vs 62.6%, P 〈 0.0001; 39.6% vs 64.3%, P = 0.003; 2.0% vs 26.3%, P = 0.001, respectively）. The frequency of APC mutations was significantly higher in HGM-negative tumors, MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors than in HGM-positive tumors, MUC6- positive tumors, CD10-negative tumors and G-phenotype tumors （32.7% vs 7.1%, P 〈 0.0001; 27.8% vs 14.0%, P = 0.0182; 37.3% vs 10.4%, P 〈 0.0001; and 38.5% vs 9.5%, P = 0.0017, respectively）. The frequency of MSI was significantly higher in MUC6-positive tumors, CD10- negative tumors and G-phenotype tumors than in MUC6- negative tumors, CD10-positive tumors and I-phenotype tumors （24.8% vs 6.7%, P = 0.0009; 22.2% vs 8.0%, P = 0.0143; and 28.6% vs 9.6%, P = 0.0353, respectively）. CONCLUSION： The tumor differentiation phenotype is closely related to tumor invasion and genetic alterations in gastric differentiated-type tumors.
文摘Uncontrolled cell proliferation is the hall mark of many cancers, and is typically manifested by a deregulation of the cell-division cycle. CDKs play critical roles in regulating cell cycle, apop- tosis and cell differentiation. AG-024322 is a multitargeted CDK inhibitor that has been shown to induce cancer cell apoptosis and de- monstrate significant antitumor activity in hu-man tumor xenograft models. This compound is under clinical development as an intravenous anticancer agent. AG-024322 exhibited moder-ate to high systemic clearance across preclini-cal species. In vitro metabolism in human liver microsomes and hepatocytes demonstrates that glucuronidation and oxidation represent the major metabolic pathways of AG-024322. The experiments of chemical inhibition and micro-somes containing individual CYP or UGT iso-forms revealed that CYP3A and UGT1A1 appear to predominantly mediate AG-024322 oxidation and glucuronidation, respectively. Formation kinetics of the two pathways in human liver mi-crosomes suggested that the glucuronidation activity of AG-024322 was approximately 3-fold higher as compared to CYP-mediated oxidation, contributing approximately 37% and 13% of the total clearance, respectively, based on the pro-jected human clearance. UGT1A1 is a poly-morphic isoform involved in glucuronidation of bilirubin. It is of concern if glucuronidation via UGT1A1 plays a major role in the elimination of AG-024322 in humans as competitive inhibition of UGT1A1 has been associated with toxicity (Gilbert and Crigler-Najjar syndromes). There-fore, this information was used to influence the clinical study design to only include subjects having constitutive expression of UGT1A1 in the first human study, thereby decreasing the potential risk of toxicity to patients.
