IJC：安定类药物可有效杀死癌细胞

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澳大利亚的研究人员经实验证明，治疗精神疾病的安定类药物可有效杀死癌细胞，从而降低癌症发病率。这一发现将推动关于使用安定类药物治疗癌症的相关研究。该研究成果发表在近期的《国际癌症杂志》网络版上。
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% h* f& O& w& X+ u) J: B流行病学研究显示，精神分裂症患者患上癌症的几率较其他人低。除去遗传因素和其他一些降低患癌症几率的可能性外，研究人员一直认为，是安定类药物发挥着一定的作用。  x: ?7 C' ^( `/ U. v; j3 n0 x/ r; i

2 B2 d- i; {" S  L8 Z澳大利亚新南威尔士大学和昆士兰大学的研究人员最近测试了6种安定类药物对癌细胞的作用，匹莫齐特（pimozide，一种镇静剂）是这6种药物中药性最强的一种。体外实验表明，匹莫齐特可杀死肺癌、乳腺癌和脑癌肿瘤细胞。6 `4 O9 `  [) |  U

' O5 w' Z9 s* y$ c癌细胞的快速分裂需要胆固醇和脂质，研究人员怀疑是匹莫齐特阻断了癌细胞中胆固醇和脂质的合成或运动，导致癌细胞死亡。为了测试匹莫齐特是否会打乱胆固醇的体内平衡，研究人员将其与美伐他汀（一种抑制细胞胆固醇的药物）结合使用。结果发现，对癌细胞来说，这种药物组合比单独使用匹莫齐特更为致命。
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使用高剂量的安定类药物会有副作用，如颤抖、肌肉痉挛、口齿不清等。但研究人员认为，在其他治疗手段都失效的情况下，患者是能够忍受这些副作用的。而且这种药物也只是短期使用。如果与降脂类药物如美伐他汀结合使用，其副作用将会降低。
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研究人员还测试了第二代精神病药物奥拉扎平（olazapine）的效果，发现它也能够杀死肿瘤细胞，但副作用较轻。这种药物会在病人肺部聚集，表明它可能对肺癌最有疗效。+ x9 G- ]# u! Z

; c7 Z8 _# w0 R/ R/ V& ?9 e7 L目前，研究人员正在测试这些药物对脑癌肿瘤细胞和具有抗药性的癌症细胞的作用。脑癌非常难治疗，很难进行病况的预后诊断，一般被诊断出患有恶性胶质瘤的病人活不到一年。而对于有抗药性的癌症肿瘤，目前的化疗方法则根本无能为力。报道称，对脑癌肿瘤的测试结果令人鼓舞，与目前广泛应用的化疗药物相比，安定类药物能更有效地杀死恶性胶质瘤细胞，其效果要好50倍。; {* j7 Y# x) m2 f
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报道还称，一种被称为SERMs的药物也有很好的研究前景，该种药物在结构上与安定类药物相似，但副作用要小得多。（生物谷Bioon.com）
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" }/ l7 A+ ^5 A1 S; N( |生物谷推荐原始出处：1 j2 ?3 Q' o9 P  {( j

! ?! o1 P& n. qInternational Journal of Cancer 6 Aug 2009' c7 ~* _4 `/ d" i1 k' u

( ?6 W: B4 W3 ?6 CCytotoxic effects of antipsychotic drugs implicate cholesterol homeostasis as a novel chemotherapeutic target
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Erik D. Wiklund 1 a, Vibeke S. Catts 2, Stanley V. Catts 3, Teng Fong Ng 4, Noel Whitaker 4, Andrew J. Brown 4, Louise H. Lutze-Mann 4 *
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1School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052
; R# `1 f2 q. Z' ^* O$ u2Discipline of Psychiatry, University of Queensland, St Lucia QLD 4072
$ f: K4 Z, d# Y3Discipline of Psychiatry, University of Queensland, St Lucia QLD 4072 and Mental Health Centre, Royal Brisbane and Women's Hospital, Herston QLD 4029
2 Q) R2 b$ m; B; {# `- X4School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052( V% J$ l$ K) `

! J( s; g6 ~6 O5 `9 G, \0 G& q! HThe reported reduction in cancer risk in those suffering from schizophrenia may be because antipsychotic medications have anti-neoplastic effects. In this study, six antipsychotic agents with a range of structural and pharmacological properties (reserpine, chlorpromazine, haloperidol, pimozide, risperidone and olanzapine), were screened for their effect on the viability of cell lines derived from lymphoblastoma, neuroblastoma, non-small cell lung cancer and breast adenocarcinoma. We aimed to determine if antipsychotic drugs in general possess cancer-specific cytotoxic potential, and whether it can be attributed to a common mode of action. With the exception of risperidone, all drugs tested displayed selective inhibition of the viability of cancer cell lines compared to normal cells. Using Affymetrix expression microarrays and quantitative real time PCR (qRT-PCR), we found that for the antipsychotic drugs, olanzapine and pimozide, cytotoxicity appeared to be mediated via effects on cholesterol homeostasis. The role of cholesterol metabolism in the selective cytotoxicity of these drugs was supported by demonstration of their increased lethality when co-administered with a cholesterol synthesis inhibitor, mevastatin. Also, pimozide and olanzapine showed accelerating cytotoxic effects from 12 to 48 hours in time course studies, mirroring the time-dependent onset of cytotoxicity induced by the amphiphile, U18666A. Based on these results, we concluded that the class II cationic amphiphilic properties of antipsychotic drugs contribute to their cytotoxic effects by acting on cholesterol homeostasis and altering the biophysical properties of cellular membranes, and that drugs affecting membrane-related cholesterol pathways warrant further investigation as potential augmentors of standard cancer chemotherapy.