Background:We studied the correlations between CHFR(checkpoint with FHA and RING finger)gene methylation and responses to microtubule inhibitors(MI)in gastric cancer.Methods:We examined 9 gastric cancer cell lines and...Background:We studied the correlations between CHFR(checkpoint with FHA and RING finger)gene methylation and responses to microtubule inhibitors(MI)in gastric cancer.Methods:We examined 9 gastric cancer cell lines and 46 gastric cancer specimens from patients who underwent surgical resection.Promoter methylation was determined by methylation-specific polymerase chain reaction(MSP).CHFR mRNA expression was estimated by quantitative reverse transcription-PCR.The MI-induced growth inhibition was assayed by a standard MTT method.Results:CHFR expression was silenced by aberrant promoter methylation in 3 of 9 gastric cancer cell lines.The level of CHFR mRNA expression was closely correlated with IC50 in the MI-treated cells(R = MI 0.889,P= 0.005).In 46 patients with gastric cancers,24(52%)presented aberrant CHFR methylation.Among them,12 patients had received treatment with MI because of advanced-stage tumor or tumor recurrence after surgery.The responders to the MI treatment were 29%in patients with CHFR methylation and 20%in those without the methylation.However,6(86%)of 7 patients with methylated CHFR tumor showed some regression or no progression,whereas 4(80%)of 5 patients with unmethylated CHFR tumor manifested progressive deterioration.Conclusions:These observations indicated that CHFR methylation may be a clinically useful approach to predict the responsiveness of gastric cancers to treatment with MI.展开更多
Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carr...Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis （CoMFA） for training set with significant statistical quality （R2=0.898） and predictive ability （q2=0.654） was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2（pred） reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows： the substituents R3-R5 （on the phenyl ring） with higher electronegativity, the substituent R6 with higher eleetropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.展开更多
文摘Background:We studied the correlations between CHFR(checkpoint with FHA and RING finger)gene methylation and responses to microtubule inhibitors(MI)in gastric cancer.Methods:We examined 9 gastric cancer cell lines and 46 gastric cancer specimens from patients who underwent surgical resection.Promoter methylation was determined by methylation-specific polymerase chain reaction(MSP).CHFR mRNA expression was estimated by quantitative reverse transcription-PCR.The MI-induced growth inhibition was assayed by a standard MTT method.Results:CHFR expression was silenced by aberrant promoter methylation in 3 of 9 gastric cancer cell lines.The level of CHFR mRNA expression was closely correlated with IC50 in the MI-treated cells(R = MI 0.889,P= 0.005).In 46 patients with gastric cancers,24(52%)presented aberrant CHFR methylation.Among them,12 patients had received treatment with MI because of advanced-stage tumor or tumor recurrence after surgery.The responders to the MI treatment were 29%in patients with CHFR methylation and 20%in those without the methylation.However,6(86%)of 7 patients with methylated CHFR tumor showed some regression or no progression,whereas 4(80%)of 5 patients with unmethylated CHFR tumor manifested progressive deterioration.Conclusions:These observations indicated that CHFR methylation may be a clinically useful approach to predict the responsiveness of gastric cancers to treatment with MI.
基金This work was supported by the National Natural Science Foundation of China （No.20673148）. We heartily thank the Molecular Discovery Ltd. for giving us the Dock 6.0 program as a freeware and the College of Life Sciences, Sun Yat-Sen University for the SYBYL 6.9 computation environment support.
文摘Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis （CoMFA） for training set with significant statistical quality （R2=0.898） and predictive ability （q2=0.654） was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2（pred） reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows： the substituents R3-R5 （on the phenyl ring） with higher electronegativity, the substituent R6 with higher eleetropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.
