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【Cancer research】法尼基转移酶抑制剂 (FTIs)
The K-ras protooncogene is activated (mutated) in the majority of pancreatic cancers. The key enzyme catalyzing the synthesis of ras-protein is the farnesyl transferase, and theoretically, inhibition of this enzyme may have a clinical relevance.
A number of oral, small-molecule FTIs have been synthesized and tested in clinical trials. These agents are cytotoxic against a variety of solid and hematologic tumor types. However, their precise mechanism of action remains questionable since Ras may also be prenylated by other enzymes such as genarylgenaryl transferase . In addition, targeting of other farnesylated proteins such as RhoB may be partly responsible for the antitumor activity of FTIs. Two phase II studies of tipifarnib in patients with advanced pancreatic cancer have shown disappointing results . Tipifarnib was administered orally at the dose and schedule of 300 mg bid for 21 days of a 28-day cycle . Fatigue and nausea/vomiting were the most frequent toxicities; myelosuppression and elevation of transaminases, alkaline phosphatase, and bilirubin were also common. In one of the trials, 20 patients received only 33 cycles of therapy . No objective response was reported. In the other trial, a preliminary analysis of 47 patients showed a median OS of only 2.7 months . The median TTF was approximately 5 weeks in both trials. The authors concluded that tipifarnib, given at this dose and schedule, is inactive in this disease.
In a phase III trial, 688 patients were randomised to treatment with gemcitabine plus tipifarnib or gemcitabine plus placebo. OS (193 days versus 182 days) and 6-month and 1-year survbival rates were not significantly different between the two arms. Myelosuppression, diarrhea, and hypokaliemia were slightly more frequent among patients randomised to tipifarnib.
The lack of clinically significant activity of tipifarnib in advanced pancreatic cancer remains unexplained. One pharmacodynamic hypothesis is that farnesyltransferase inhibition is not sufficient alone to abrogate Ras function. In addition, Ras may still undergo posttranslational prenylation by other enzymes, such as genarylgenaryl transferase. In preclinical models, tumor cell lines with wild-type ras or mutated N-ras or H-ras are more sensitive to tipifarnib than those with K-ras mutations, which are more frequent in pancreatic cancer; in addition, one study demonstrated that tipifarnib has a predominantly cytostatic effect on CAPAN-2 pancreatic cancer cell lines. It is also conceivable that tipifarnib produces insufficient inhibition of protein farnesylation at clinically tolerable concentrations . Finally, the heterogeneity of pancreatic tumors and their dependence on multiple pathways for survival may explain the apparent failure of FTIs in advanced disease. 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领 Farnesyl transferase inhibitors (FTIs) 法尼基转移酶抑制剂（抑制剂）
The K-ras protooncogene is activated (mutated) in the majority of pancreatic cancers.
在大多数胰腺癌中K - ras基因原癌基因被激活（突变）
The key enzyme catalyzing the synthesis of ras-protein is the farnesyl transferase, and theoretically, inhibition of this enzyme may have a clinical relevance.催化合成ras蛋白的关键酶是法尼基转移，从理论上讲，抑制这种酶可能有临床意义
A number of oral, small-molecule FTIs have been synthesized and tested in clinical trials. 一些口服的，小分子抑制剂已合成并在临床试验测试。
These agents are cytotoxic against a variety of solid and hematologic tumor types.
这些制剂是对各种固体和血液类型肿瘤有细胞毒性However, their precise mechanism of action remains questionable since Ras may also be prenylated by other enzymes such as genarylgenaryl transferase然而，其确切的作用机制仍值得怀疑，因为Ras也可被其他酶异戊烯基化，如genarylgenaryl转移酶。
. In addition, targeting of other farnesylated proteins such as RhoB may be partly responsible for the antitumor activity of FTIs. 此外，针对其他法尼基蛋白质，如RhoB，可能是具有抗肿瘤活性的抑制剂
Two phase II studies of tipifarnib in patients with advanced pancreatic cancer have shown disappointing results . Tipifarnib was administered orally at the dose and schedule of 300 mg bid for 21 days of a 28-day cycle . 两个第二阶段研究tipifarnib治疗晚期胰腺癌显示的结果令人失望。在这个方案中 Tipifarnib口服的剂量300毫克一日两次，28天为一个周期
Fatigue and nausea/vomiting were the most frequent toxicities疲劳和恶心/呕吐是最常见的副作用
; myelosuppression and elevation of transaminases, alkaline phosphatase, and bilirubin were also common骨髓抑制和转氨酶，碱性磷酸酶，胆红素升高也是很常见的。
. In one of the trials, 20 patients received only 33 cycles of therapy . 在一个试验中， 20例，接受了33个疗程的治疗
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作者:admin@医学,生命科学 2011-02-19 05:11
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