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【bio-news】研究显示分子如何抑制肺癌细胞生长
03/12/07 -- By mapping the interlocking structures of small molecules and mutated protein "receptors" in non-small cell lung cancer (NSCLC) cells, scientists at Dana-Farber Cancer Institute and their colleagues have energized efforts to design molecules that mesh with these receptors, potentially interfering with cancer cell growth and survival.
In a study published in the March issue of Cancer Cell, researchers led by Michael Eck, MD, PhD, of Dana-Farber used X-ray crystallography to determine the structure of two mutated forms of the epidermal growth factor receptor (EGFR) in lung cancer cells. EGFR, a protein known as a tyrosine kinase, plays a key role in relaying growth signals within cells. When mutated, it can become overactive, leading to excessive cell division and cancer.
"It turns out that in some cases, the very mutation that causes the cancer in the first place is also the cancer's Achilles heel," said Eck, the paper's senior author. "We now see that inhibitors such as gefitinib actually bind more tightly to some of the cancer-causing mutants, even though they were originally developed to block the normal receptor."
Cai-Hong Yun, PhD, of Dana-Farber is the paper's first author.
Mutations in the EGFR kinase domain occur in approximately 16 percent of NSCLCs, but at much higher frequencies in selected populations, including nonsmokers, women, and East Asian patients. Laboratory and clinical studies have shown that tyrosine kinase inhibitors are more effective against some EGFR mutations than others, although the molecular reasons for this are unclear. By developing a better understanding of the effect of the mutations on inhibitor binding at a structural level, it may be possible to develop more effective therapies.
In the current study, Eck and his colleagues analyzed the three-dimensional structures of the normal and mutated versions of EGFR bound to several different types of inhibitor molecules. They found that two inhibitors - the drug gefitinib (marketed as Iressa(R), and a compound called AEE788 - bind especially tightly to one of the mutated forms, meaning these inhibitors are potentially more effective at blocking the growth of cancer cells containing that mutation. In the case of gefitinib, it bound 20 times more tightly to the L858R mutant than to the normal, mutation-free EGFR.
The research team concluded that the particular EGFR mutation within tumor cells determines which inhibitor molecules are likely to be able to slow or stop the growth of those cells.
"Although structural divergence in the EGFR mutants may complicate efforts to treat the disease, it may also present an advantage in that it introduces the possibility of developing inhibitors that target specific mutations, which should lead to more effective treatments," said Eck, who also an associate professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. "These targeted therapies likely would be less toxic as they, in theory, would not affect the normal functioning EGFR proteins."
Source: Dana-Farber Cancer Institute
http://www.bio.com/newsfeatures/newsfeatures_research.jhtml?cid=27000005 Study Reveals How Some Molecules Inhibit Growth of Lung Cancer Cells
03/12/07 -- By mapping the interlocking structures of small molecules and mutated protein "receptors" in non-small cell lung cancer (NSCLC) cells, scientists at Dana-Farber Cancer Institute and their colleagues have energized efforts to design molecules that mesh with these receptors, potentially interfering with cancer cell growth and survival.
研究发现一些分子抑制肺癌细胞生长的机制
03/12/07—通过对非小细胞型肺癌(NSCLC)细胞中小分子的连锁结构和突变蛋白“受体”的基因定位，Dana-Farber癌症研究所的科学家和他们的同事努力去设计可以获取这些受体（可能妨碍癌细胞的生长与存活）的分子。
In a study published in the March issue of Cancer Cell, researchers led by Michael Eck, MD, PhD, of Dana-Farber used X-ray crystallography to determine the structure of two mutated forms of the epidermal growth factor receptor (EGFR) in lung cancer cells. EGFR, a protein known as a tyrosine kinase, plays a key role in relaying growth signals within cells. When mutated, it can become overactive, leading to excessive cell division and cancer.
3月份出版的《肿瘤细胞》上有一项研究，由Dana-Farbe的Michael Eck博士带领研究人员利用X(射)线衍射晶体分析法确定了肺癌细胞中表皮生长因子受体(EGFR)的两种突变形式。EGFR是一种已知的酪氨酸激酶蛋白，对细胞内生长信号的转导起关键作用。当EGFR发生突变时，它会变得活动过度，导致细胞过度分裂和癌症。
"It turns out that in some cases, the very mutation that causes the cancer in the first place is also the cancer's Achilles heel," said Eck, the paper's senior author. "We now see that inhibitors such as gefitinib actually bind more tightly to some of the cancer-causing mutants, even though they were originally developed to block the normal receptor." Cai-Hong Yun, PhD, of Dana-Farber is the paper's first author.
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作者:admin@医学,生命科学 2011-04-06 14:04
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