研究人員鑒定出一系列能保護細(xì)胞免受常用化療藥物阿霉素（doxorubicin）傷害的基因,。
美國喬治亞醫(yī)學(xué)院癌癥中心的研
究人員Hernan Flores-Rozas博士指出，他們發(fā)現(xiàn)了一系列對細(xì)胞在接觸到阿霉素時得以存活至關(guān)重要的基因,。當(dāng)你開始失活這些基因時,，細(xì)胞變得非常敏感并且不再生長,。因此，研究人員現(xiàn)在已經(jīng)知道通過失活哪些基因能夠使其對這種藥物變得非常敏感,。
阿霉素廣泛用于治療從乳腺癌到前列腺和卵巢癌的一系列實體腫瘤,。一個稍加修飾的版本——柔毛霉素（doxorubicin）是一種強大的抗白血病和淋巴瘤藥物，常常用于治療兒童患者,。
但不幸的是,，在癌癥治療結(jié)束時，許多使用這種藥物的患者又會出現(xiàn)心臟問題,。武漢大學(xué)在該研究中心的交換博士生夏玲（女,，Ling Xia，音譯）解釋說,，心肌細(xì)胞會發(fā)生細(xì)胞凋亡,。而這種凋亡過程的結(jié)果就是出現(xiàn)心肌癥，即心臟不能再向著身體各個方向泵血。這種損傷甚至在治療后數(shù)年才發(fā)生,，目前還沒有辦法來預(yù)防或治療,，除了進行心臟移植。
他們的研究的長期目標(biāo)是通過找到關(guān)閉癌細(xì)胞中這些基因的方法來預(yù)防并改善癌癥治療效果,。這項研究的結(jié)果發(fā)表在12月1日的Cancer Research上,，文章的第一作者是夏玲。
夏玲博士與Hernan Flores-Rozas在實驗室
他們在相對簡單的酵母細(xì)胞中進行了研究,。酵母只有6000個基因,，是人類細(xì)胞研究的好模型，因為它們包含了相同的基礎(chǔ)細(xì)胞功能如復(fù)制,、DNA修復(fù),、信號途徑和細(xì)胞死亡。
他們發(fā)現(xiàn)71個基因能為細(xì)胞提供針對阿霉素的不同程度的保護作用,。細(xì)胞沒有一個特殊的機制來保護阿霉素的毒害,，一些基因的保護作用強于另外一些基因。誕生在缺少一些基因時,，細(xì)胞會因接觸這種藥物而發(fā)生死亡。
研究人員指出,，這些新確定的保護性基因可能在細(xì)胞接觸到化療藥物之前已經(jīng)發(fā)生了一定程度的表達(dá),，然后在接觸這種藥物是進一步增加表達(dá)。MCG的研究人員推測,，這些基因可能還可對其他脅迫如病毒感染等提供保護,。目前，他們正在分析這些基因的功能和在癌癥,、心臟細(xì)胞中的表達(dá)情況,。
原始出處:
Cancer Research 67, 11411-11418, December 1, 2007. doi: 10.1158/0008-5472.CAN-07-2399
Experimental Therapeutics, Molecular Targets, and Chemical Biology
Identification of Genes Required for Protection from Doxorubicin by a Genome-Wide Screen in Saccharomyces cerevisiae
Ling Xia1, Lahcen Jaafar1, Anil Cashikar2 and Hernan Flores-Rozas1,3
1 Institute of Molecular Medicine and Genetics, 2 Center for Molecular Chaperone/Radiobiology and Cancer Virology Group, and 3 Department of Medicine, Medical College of Georgia, Augusta, Georgia
Requests for reprints: Hernan Flores-Rozas, Medical College of Georgia, 1120 15th Street, CB-2803, Augusta, GA 30912. Phone: 706-721-1371; Fax: 706-721-8752; E-mail: [email protected] .
Anthracyclines are chemotherapeutic agents commonly used to treat a broad range of malignancies. Although effective, these drugs present serious complications, most notably cardiotoxicity. To determine the mechanisms that mediate cytoprotection from doxorubicin, we have screened the collection of Saccharomyces cerevisiae haploid gene deletion mutants. We have identified 71 deletion strains that display varying degrees of hypersensitivity to doxorubicin at a concentration that does not significantly reduce the viability of wild-type cells. Complementation of the doxorubicin-sensitive phenotype of the deletion strains with the wild-type genes proves that the sensitivity of the strain to doxorubicin is due to the gene deletion. The genes that mediate cytoprotection from doxorubicin belong to multiple pathways including DNA repair, RNA metabolism, chromatin remodeling, amino acid metabolism, and heat shock response. In addition, proteins with mitochondrial, osmosensing, vacuolar, and ribosomal functions are also required for protection from doxorubicin. We tested the sensitivity of the deletion strains to other cytotoxic agents, which resulted in different drug-specific sensitive groups. Most of the identified genes have mammalian homologues that participate in conserved pathways. Our data may prove useful to develop strategies aimed at sensitizing tumor cells to doxorubicin as well as protecting cardiac cells from its cytotoxic effects. [Cancer Res 2007;67(23):11411–8]
