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【j进展】Gleevec抗药性有了”克星”

Gleevec抗药性有了”克星”

在BMS开发的一种实验药物已在临床试验中初露”头角”, 能使对经典治疗Gleevec无效的CML白血病的病人起到”扭转乾坤”的作用, 在全美46届血液病年会的报告中, UCLA的HHMI研究员和M.D. Anderson Cancer Center及BMS的研究人员首次报告了BMS-354825能够成功治疗处在早期CML同时对Gleevec产生抗药性并且加重病情的患者.

这一药物地发现其实是研究为何许多病人产生抗药性时”意外发现”的副产品.

请读下列连接 有趣的科学发现和探索的故事.

http://www.hhmi.org/news/sawyers4.html 谢谢楼主。但是打不开那个链接 New Drug Sidesteps Gleevec Resistance in Human Trials
An experimental drug under development by Bristol-Myers Squibb is showing early promise in reversing the signs and symptoms of patients whose chronic myeloid leukemia failed to respond to Gleevec, which is considered the standard of treatment for the disorder.

In a study to be presented today at the 46th Annual Meeting of the American Society of Hematology in San Diego, Howard Hughes Medical Institute (HHMI) researchers at the University of California, Los Angeles, and colleagues at M.D. Anderson Cancer Center and Bristol-Myers Squibb in Princeton, NJ, report the first data from human clinical trials of the new compound, BMS-354825. Their studies indicate that the drug can successfully overcome Gleevec resistance in patients in the early stages of chronic myeloid leukemia. Patients enrolled in the study had experienced a worsening of the disease or intolerance when treated with Gleevec.

“The identification of this compound as a drug candidate is a direct byproduct of understanding why patients develop resistance to Gleevec.”
Charles L. Sawyers

Study leader, HHMI investigator Charles L. Sawyers, Neil P. Shah, and colleagues at UCLA's Jonsson Comprehensive Cancer Center, report that BMS-354825 successfully circumvented Gleevec (imatinib) resistance in 31 of the 36 patients treated with the drug during phase I clinical trials at UCLA and M.D. Anderson Cancer Center. Resistance to Gleevec develops when patients acquire mutations in an enzyme that is targeted by Gleevec. Phase I clinical trials evaluate drug safety and toxicity at different dose levels in a small number of volunteers.

“Our study examined patients in all phases of CML, including the chronic phase, the accelerated phase, and blast crisis. The patients responded quite well to this new compound, and we observed no side effects,” said Sawyers. “In fact, the results of this clinical trial match very closely with what we would have predicted the outcome to be based on our earlier studies of this drug in mice.”

The 36 patients treated by Sawyers and his colleagues were given BMS-354825 in doses ranging from 15 to 180 mg per day taken orally for five to seven days a week for a period of up to nine months. Dosing was fine-tuned for each patient based on detailed studies that examined how well the drug inhibited its target - a technique that was devised by Sawyers's group for use in earlier studies in mice. Another novel facet of the study, Sawyers said, is that each patient's resistance-enhancing mutation was sequenced by Bristol-Myers Squibb scientists. This provided a wealth of information about the type of mutation carried by each patient, and allowed the researchers to correlate how the drug responded to each type of mutation.

“The identification of this compound as a drug candidate is a direct byproduct of understanding why patients develop resistance to Gleevec,” said Sawyers. He notes that just as Gleevec was developed as a “molecularly targeted” inhibitor, the next generations of Gleevec, of which BMS-354825 is is one, are being refined and improved by structural biology studies that show how the drugs “fit” with their target, and how mutations alter the shape of that target.

In this case, the drug's target is the Abelson tyrosine kinase (ABL), an enzyme that becomes overactivated by a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid BCR-ABL enzyme that is always active. The hyperactive BCR-ABL, in turn, drives the overproliferation of white blood cells that is the hallmark of CML.

In studies published earlier this year in the journal Science, Sawyers and his colleagues demonstrated that BMS-354825 prolongs survival of mice with CML. In tests with cultured human bone marrow cells, the researchers showed that the drug inhibits the proliferation of bone marrow progenitor cells that are positive for BCR-ABL in patients who are resistant to Gleevec. “The bottom line is that our in vitro data indicate that this drug is active against all of the mutations except for one,” Sawyers said.

At the time Sawyers and his colleagues were writing their Science article, there were 17 reported Gleevec-resistance mutations. There are more known now. Each mutation hampers Gleevec's ability to bind to its target, the ABL kinase. In the case of both Gleevec and BMS-354825, there appears to be one particular mutation, known as T315I, which does not respond to either therapy. “That mutation will likely require a different drug, and researchers are working on that now,” said Sawyers.

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作者:admin@医学,生命科学    2011-07-21 18:16
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