O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been...O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.展开更多
目的:探讨重组人血管内皮抑制素(recombinant human endostatin,rh-endostatin)联合达卡巴嗪(Dacarbazine)能否增强抗黑素瘤作用,并初步分析其作用机制。方法:分别采用MTT法和FCM法检测重组人血管内皮抑制素单药及其联合达卡巴嗪对黑素...目的:探讨重组人血管内皮抑制素(recombinant human endostatin,rh-endostatin)联合达卡巴嗪(Dacarbazine)能否增强抗黑素瘤作用,并初步分析其作用机制。方法:分别采用MTT法和FCM法检测重组人血管内皮抑制素单药及其联合达卡巴嗪对黑素瘤B16F10细胞增殖和凋亡的影响;Western印迹法检测重组人血管内皮抑制素对黑素瘤细胞中细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)磷酸化的影响;建立C57BL/6黑素瘤荷瘤小鼠模型,研究重组人血管内皮抑制素联合达卡巴嗪能否增强体内抗黑素瘤的作用。结果:重组人血管内皮抑制素、达卡巴嗪以及两药联合处理对黑素瘤B16F10细胞增殖的抑制率分别为(9.67±2.89)%、(22.67±3.06)%和(30.33±1.16)%,差异有统计学意义(P<0.05);重组人血管内皮抑制素组黑素瘤细胞的ERK分子磷酸化水平明显降低。接种肿瘤18d时,重组人血管内皮抑制素组、达卡巴嗪组和两药联合组荷瘤小鼠的肿瘤体积分别为(6.45±1.24)cm3、(8.94±2.04)cm3和(4.56±0.98)cm3,两药联合组的肿瘤体积明显低于达卡巴嗪单药组(P<0.05)。结论:重组人血管内皮抑制素联合达卡巴嗪体外可增强抗黑素瘤B16F10细胞增殖的作用,体内可增强达卡巴嗪对荷瘤小鼠黑素瘤生长的抑制作用,并提高荷瘤小鼠的存活率。推测抑制黑素瘤细胞中ERK分子酪氨酸磷酸化可能是重组人血管内皮抑制素发挥其抗黑素瘤作用的机制之一。展开更多
Objective： To investigate fotemustine plus dacarbazine （DTIC） with dendritic cell （DC） vaccines on patients with advanced acral lentiginous melanoma （ALM）. Fotemustine is a cytotoxic alkylating agent with a rem...Objective： To investigate fotemustine plus dacarbazine （DTIC） with dendritic cell （DC） vaccines on patients with advanced acral lentiginous melanoma （ALM）. Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with （DTIC）. DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods： This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m^2, dr, 12, DTIC 400 mg/d d2-6, DC vaccines subcutaneously dT, 9, 13 repeated every 28 days. Ten HLA-A02＋24＋ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 （Mart-i） and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival （PFS）. Secondary end-points were overall survival （OS）, overall response rate （ORR） and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors （RECIST）. Results： The 15 men and 13 women had a median age of 51 years. 16 patients had stage Mlc disease and 11/16 had liver metastasis. Patients received an average of 3.82±1.25 cycles. Follow-up for the 18 surviving patients ranged from 7-41 months with a median of 12 months. Median PFS was 8.5 months （95% CI： 7.86-15.21） with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months （95% CI： 10.33-18.24）. ORR （CR＋PR） was 35.7% including 3 complete response （CR） and 7 partial response （PR）. Six patients had disease stable. A total of 19 Grade Ⅲ/Ⅳ toxicities were observed including thrombocytopenia （n=8）, neutropenia （n=5）, fatigue （n=6） and hypersensitivity reaction （n=1）. One patient died of Grade IV thrombocytopenia. Conclusion： Fotemustine and dacarbazine plus DC vaccines are safe 展开更多
文摘O6-methylguanine DNA methyltransferase(MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.
文摘目的:探讨重组人血管内皮抑制素(recombinant human endostatin,rh-endostatin)联合达卡巴嗪(Dacarbazine)能否增强抗黑素瘤作用,并初步分析其作用机制。方法:分别采用MTT法和FCM法检测重组人血管内皮抑制素单药及其联合达卡巴嗪对黑素瘤B16F10细胞增殖和凋亡的影响;Western印迹法检测重组人血管内皮抑制素对黑素瘤细胞中细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)磷酸化的影响;建立C57BL/6黑素瘤荷瘤小鼠模型,研究重组人血管内皮抑制素联合达卡巴嗪能否增强体内抗黑素瘤的作用。结果:重组人血管内皮抑制素、达卡巴嗪以及两药联合处理对黑素瘤B16F10细胞增殖的抑制率分别为(9.67±2.89)%、(22.67±3.06)%和(30.33±1.16)%,差异有统计学意义(P<0.05);重组人血管内皮抑制素组黑素瘤细胞的ERK分子磷酸化水平明显降低。接种肿瘤18d时,重组人血管内皮抑制素组、达卡巴嗪组和两药联合组荷瘤小鼠的肿瘤体积分别为(6.45±1.24)cm3、(8.94±2.04)cm3和(4.56±0.98)cm3,两药联合组的肿瘤体积明显低于达卡巴嗪单药组(P<0.05)。结论:重组人血管内皮抑制素联合达卡巴嗪体外可增强抗黑素瘤B16F10细胞增殖的作用,体内可增强达卡巴嗪对荷瘤小鼠黑素瘤生长的抑制作用,并提高荷瘤小鼠的存活率。推测抑制黑素瘤细胞中ERK分子酪氨酸磷酸化可能是重组人血管内皮抑制素发挥其抗黑素瘤作用的机制之一。
文摘Objective： To investigate fotemustine plus dacarbazine （DTIC） with dendritic cell （DC） vaccines on patients with advanced acral lentiginous melanoma （ALM）. Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with （DTIC）. DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods： This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m^2, dr, 12, DTIC 400 mg/d d2-6, DC vaccines subcutaneously dT, 9, 13 repeated every 28 days. Ten HLA-A02＋24＋ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 （Mart-i） and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival （PFS）. Secondary end-points were overall survival （OS）, overall response rate （ORR） and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors （RECIST）. Results： The 15 men and 13 women had a median age of 51 years. 16 patients had stage Mlc disease and 11/16 had liver metastasis. Patients received an average of 3.82±1.25 cycles. Follow-up for the 18 surviving patients ranged from 7-41 months with a median of 12 months. Median PFS was 8.5 months （95% CI： 7.86-15.21） with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months （95% CI： 10.33-18.24）. ORR （CR＋PR） was 35.7% including 3 complete response （CR） and 7 partial response （PR）. Six patients had disease stable. A total of 19 Grade Ⅲ/Ⅳ toxicities were observed including thrombocytopenia （n=8）, neutropenia （n=5）, fatigue （n=6） and hypersensitivity reaction （n=1）. One patient died of Grade IV thrombocytopenia. Conclusion： Fotemustine and dacarbazine plus DC vaccines are safe
