生物谷報(bào)道,，HIV藥物對(duì)癌細(xì)胞有抑制作用,，抗HIV藥物可以阻礙腫瘤的生長(zhǎng)速度。被用于治療其他疾病的藥物現(xiàn)在可以用來殺死癌細(xì)胞,。研究者發(fā)現(xiàn)一種通常用于抗HIV病毒的藥物可以阻礙癌細(xì)胞的生長(zhǎng)速度,。這個(gè)發(fā)現(xiàn)增加了現(xiàn)有藥物用于治療另一種疾病的希望,。研究成果發(fā)表在臨床腫瘤研究期刊上。

根據(jù)新的研究,，抗HIV藥物那非那韋第一次試驗(yàn)性地用于多種癌癥患者上,。腫瘤科學(xué)家認(rèn)為這些抗HIV藥物的新藥可以拯救生命，并且減少了15年等待新抗癌藥物進(jìn)入到臨床和節(jié)省了十億用于研發(fā)的開支,。  位于馬里蘭州的Bethesda美國(guó)癌癥研究所的Phillip Dennis和他的合作者在注意到抗HIV藥物對(duì)癌細(xì)胞和HIV病毒有相似的毒性作用后,，開始檢測(cè)抗HIV藥物。對(duì)抗癌藥物新的搜尋方法導(dǎo)致了先前的止痛藥和早孕反應(yīng)療法被列為治療癌癥的方法,。Dennis的隊(duì)伍往含有多種癌細(xì)胞的培養(yǎng)基中加入了六種已證實(shí)的抗HIV藥物,。其中的三種可以顯著阻礙癌細(xì)胞的生長(zhǎng)速度，加快癌細(xì)胞死忙,。療效最好的那非那韋,，不僅可以阻礙細(xì)胞中的蛋白降解酶的活動(dòng)，而且可以阻礙被注入癌細(xì)胞的小鼠腫瘤的生長(zhǎng),?？茖W(xué)家認(rèn)為像HIV之類的病毒保護(hù)它們免于人體免疫系統(tǒng)的攻擊的方法是分解寄主細(xì)胞的垃圾處理部位－蛋白酶體。這樣,，在免疫細(xì)胞可以抗擊病毒之前,，防護(hù)免疫蛋白就被破壞了。變異的癌癥細(xì)胞也可以激活蛋白酶體,，像那非那韋之類阻斷蛋白分解的藥物,，理論上可以治療癌癥。
   那非那韋只是臨床試驗(yàn)的第一步,，它使我們了解癌癥病人的耐藥量和藥物是如何影響體內(nèi)堅(jiān)硬的腫瘤,。在藥物之間改變其原有用途的想法正在發(fā)展，例如已試驗(yàn)的抗HIV藥物用來對(duì)抗SARS病毒,，抗瘧藥氯喹作為可行的抗癌療法,。

原文出處：

Clinical Cancer Research    Sep 1, 2007; 13 (17)

Phillip Dennis et al.

Nelfinavir, a lead HIV protease inhibitor, is a broad spectrum, anti-cancer agent that induces ER stress, autophagy and apoptosis in vitro and in vivo

作者簡(jiǎn)介：

Phillip A. Dennis, M.D., Ph.D.

Medical Oncology Branch and Affiliates

Head, Signal Transduction Section

Senior Investigator

Dr. Dennis received his B.A. in 1984 as an Echols Scholar from the University of Virginia, and his Ph.D. and M.D. degrees in 1991 and 1992, respectively, from the New York University School of Medicine as part of the Medical Scientist Training Program. He completed his Internal Medicine training on the Osler Medical Service at Johns Hopkins Hospital. Following his residency, he completed a fellowship in Medical Oncology at the Johns Hopkins Oncology Center and then joined the laboratory of Dr. Michael Kastan as a postdoctoral fellow. Dr. Dennis joined the NCI in 1999 as a tenure track investigator. In 2005, he became Clinical Director at NCI/Navy Medical Oncology, and in 2006 became a Senior Investigator in the Medical Oncology Branch. Dr. Dennis is a recipient of the Alton Ochsner Award Relating Tobacco and Health and an NIH Merit Award, and is an elected member of the American Society for Clinical Investigation.

Research

Activation of the PI3K/Akt pathway and the biology of lung cancer

Lung cancer kills more Americans than any other cancer, and ~90,000,000 Americans are at permanent increased risk to develop lung cancer. To address this health problem, our group studies the role of signal transduction pathways that promote the formation, maintenance, and therapeutic resistance of lung cancer. We have focused on one pathway, the Akt/mTOR pathway. Our research can broadly divided into two areas, to understand the mechanisms of activation and consequences of activation of the Akt/mTOR pathway in lung cancer, and to develop approaches to inhibit the pathway. Several studies from our group have validated the Akt/mTOR pathway as a target for prevention of lung cancer. We showed that two tobacco components, nicotine and the tobacco-specific carcinogen, NNK, rapidly activate the pathway in normal human lung epithelial cells. Activation occurred within minutes at concentrations that are achievable in smokers, and could be inhibited with pathway inhibitors or nicotinic antagonists. Because activation of Akt caused a partially transformed phenotype through inhibition of apoptosis and decreased reliance on extracellular growth factors, we have hypothesized that Akt activation serves as a biochemical gatekeeper for tobacco-related carcinogenesis. In support of this hypothesis, we showed that activation of Akt and mTOR increased with phenotypic progression of tobacco-induced lung lesions in a mouse model of lung cancer. Most recently, we showed that rapamycin, an mTOR inhibitor that is FDA-approved for other indications, inhibited the number of tobacco carcinogen-induced lung lesions by 90%, as well as tumor size. Together, these studies have expanded the concept of how tobacco causes lung cancer, and have raised awareness of pathway activation as a biomarker for prevention studies. Importantly, they provide a strong rationale to use mTOR inhibitors in human lung cancer prevention trials.

Other studies from our group have validated inhibition of the Akt pathway as a target for treatment of lung cancer. We first identified constitutive activation of Akt in 16/17 NSCLC cell lines, and showed that pathway activation promoted cellular survival under conditions of serum deprivation or administration of chemotherapy or radiation therapy. Using a set of 252 lung cancer specimens with surrounding normal tissues and clinical outcomes, we have shown that Akt activation is specific for lung cancers and not surrounding lung tissue, and confers a poor prognosis especially for those with early stage disease. This is potentially important because most patients diagnosed with lung cancer through screening will have early stage disease. Determining which subset of patients will benefit most from more intensive observation and/or therapy could be of great clinical benefit. Our studies suggest that Akt activation could be one factor to distinguish patients that are at increased risk to relapse or recur.

Despite the strong rationale to target Akt, no Akt inhibitors are clinically approved. We have led a large collaborative effort in academia, industry and the Developmental Therapeutics Program at NCI, to develop lipid-based inhibitors of Akt called phosphatidylinositol ether lipid analogues (or PIAs). PIAs were synthesized using molecular modeling of Akt, and members of our group and our colleagues at Georgetown University are co-inventors of PIAs. Unlike most pharmaceutical efforts to develop Akt inhibitors that have focused on the ATP binding domain, the PIAs that we are developing target the pleckstrin homology (PH) domain. We identified 5 active PIAs that inhibit Akt within minutes and selectively kill cancer cells with high levels of Akt activation. More recently, we have identified molecular correlates of response to PIAs, as well as other biological effects of PIAs that contribute to their toxicity, and could be used as biomarkers for administration of PIAs. We are continuing to investigate mechanisms of action of PIAs and other lipid-based Akt inhibitors, and we are comparing the biologic activities of lipid-based inhibitors to small molecule inhibitors that target the ATP binding region of Akt. Other efforts to develop pathway inhibitors include the use of bioinformatics to perform virtual screening of large chemical libraries, and the screening of drugs that are FDA-approved for other indications for inhibition of Akt and induction of apoptosis in Akt-dependent cancer cells.

To complement our preclinical efforts to develop Akt inhibitors, we are implementing clinical trials that are testing inhibitors of the Akt/mTOR pathway in lung cancer patients. Examples of proposed trials include first-in-human (so called “Phase 0”) trials with PIAs, trials combining mTOR inhibitors with standard chemotherapies, and trials that will test “off the shelf” drugs for their ability to inhibit Akt in lung cancer patients. Together, these studies could increase therapeutic options for lung cancer patients and could shed insight into the clinical benefit achieved by inhibiting the Akt/mTOR pathway.

Our collaborators in this work are Stephen Hewitt, Curtis C. Harris, NCI; Abdel Elkahloun, NHGRI; and Alan Kozikowski, University of Illinois at Chicago.

背景知識(shí)：

#609423

HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO
HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, RESISTANCE TO, INCLUDED
Gene map locus 19q13.4, 19p13.3, 17q12, 17q11.2-q12, 17q11.2, 16p12.1-p11.2, 12q14, 10q11.1, 2q35