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Wednesday, 2 January 2019

Virus sebagai antikanser





Virus sebagai antikanser


Enhancement of Oncolytic Properties of Recombinant Newcastle Disease Virus Through Antagonism of Cellular Innate Immune Responses   (Citations: 9)




Newcastle disease virus (NDV) has been previously shown to possess oncolytic activity, causing specific lysis of cancerous but not normal cells. Here we show that despite these findings, the oncolytic efficiency of naturally occurring NDV strains can still be relatively low, as many tumors exhibit strong innate immune responses that suppress viral replication and spread. To overcome this problem, we generated a recombinant fusogenic NDV expressing influenza NS1 protein, a protein exhibiting interferon (IFN)-antagonist and antiapoptotic functions in human and mouse cells. Interestingly, the resultant virus was dramatically enhanced in its ability to form syncytia, lyse a variety of human and mouse tumor cell lines, and suppressed the induction of the cellular IFN responses. Using the aggressive syngeneic murine melanoma model, we show that the NDV-NS1 virus is more effective than virus not expressing NS1 in clearing the established footpad tumors and results in higher overall long-term animal survival. In addition, mice treated with NDV-NS1 exhibited no signs of toxicity to the virus and developed tumor-specific cytotoxic T lymphocyte (CTL) responses. These findings demonstrate that modulation of innate immune responses by NDV results in enhancement of its oncolytic properties and warrant further investigation of this strategy in design of oncolytic NDV vectors against human tumors.


Journal: Molecular Therapy - MOL THER , vol. 17, no. 4, pp. 697-706, 2009


Newcastle disease virus (NDV) is a negative-sense RNA virus that has been shown to possess oncolytic activity. NDV's selective replication in tumor cells has been previously suggested to be due to the lack of a proper antiviral response in these cells. Here we demonstrate that NDV possesses oncolytic activity in tumor cells capable of a robust type I interferon (IFN) response, suggesting that another mechanism underlies NDV's tumor specificity. We show that the oncolytic selectivity of NDV for tumor cells is dependent upon tumor cell resistance to apoptosis. Utilizing the human non-small-cell lung cancer cell line A549 overexpressing the antiapoptotic protein Bcl-xL, we show significant enhancement of oncolytic activity and NDV replication. Interestingly, while the Bcl-xL-overexpressing cells were resistant to apoptotic stimuli induced by chemotherapeutic agents and early viral replication, during the subsequent viral cycles, we observed a paradoxical increase in apoptosis in response to NDV. The increased oncolytic activity seen was secondary to enhanced viral replication and syncytium formation. The induction of a type I IFN response was enhanced in Bcl-xL cells. Overall, these findings propose a new mechanism for cancer cell specificity for NDV, making it an attractive anticancer agent for chemoresistant tumors with enhanced antiapoptotic activity.
Mansour, Mena; Palese, Peter; Zamarin, Dmitriy


Purpose Malignant pleural mesothelioma (MPM) is a highly aggressive tumor. Alternative treatment strategies such as oncolytic viral therapy may offer promising treatment options in the future. In this study, the oncolytic efficacy and induction of tumor remission by a genetically-engineered Newcastle disease virus (NDV(F3aa)-GFP) in MPM is tested and monitored by bioluminescent tumor imaging. Experimental Design The efficacy of NDV(F3aa)-GFP was tested against several mesothelioma cell lines in vitro. Firefly luciferase transduced MSTO-211H* orthotopic pleural mesothelioma tumor-bearing animals were treated with either single or multiple doses of NDV(F3aa)-GFP at different time points (days 1 and 10) after tumor implantation. Tumor burden was assessed by bioluminescence imaging. Results Mesothelioma cell lines exhibited dose-dependent susceptibility to NDV lysis in the following order of sensitivity: MSTO-211H>MSTO-211H*>H-2452>VAMT>JMN. In vivo studies with MSTO-211H* cells showed complete response to viral therapy in 65% of the animals within 14 days after treatment initiation. Long term survival in all of these animals was > 50 days after tumor installation (control animals <23 days). Multiple compared with single treatment showed a significantly better response (p=0.005). Conclusions NDV appears to be an efficient viral oncolytic agent in therapy of MPM in an orthotopic pleural mesothelioma tumor model.
Silberhumer, Gerd R.; Brader, Peter; Wong, Joyce; Serganova, Inna S.; Gonen, Mithat; Gonzalez, Segundo Jaime; Blasberg, Ronald; Zamarin, Dmitriy; Fong, Yuman




Abstract Virotherapy of cancer exploits the potential of naturally occurring and engineered oncolytic viruses to selectively replicate in and cause cytotoxicity to tumor cells without affecting healthy normal cells. The tumor selectivity of Newcastle disease virus (NDV), a member of the family Paramyxoviridae, depends on the differential type I interferon (IFN) response. Further understanding of the key mechanisms and immune effector molecules involved will aid in augmenting the oncolytic properties of NDV. Here we report on the infection kinetics and innate immune responses to a recombinant LaSota strain of NDV (rLaSota eGFP) in human tumor and normal cells. We observed varying replicative fit and cytotoxicity of rLaSota eGFP depending on the tumor cell type, with severely restricted replication in normal cells. The absence of retinoic acid-inducible gene I (RIG-I), a cytosolic RNA sensor, determined sensitivity to NDV. Productive NDV infection with a moderate IFN-? induction in human multiple myeloma cells suggested a role for IFN-independent mechanisms or lack of type I IFN reinforcement by RIG-I. Proinflammatory cytokines and chemokines were altered differentially in infected normal and tumor cells. Our results suggest that tumor selectivity is dependent on variations in the cellular antiviral response to infection with NDV and RIG-I expression.
Biswas, Moanaro; Kumar, Sandeep R.P.; Allen, Adria; Yong, Wang; Nimmanapalli, Ramadevi; Samal, Siba K.


Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and intrinsically oncolytic because of its potent ability to induce apoptosis. Several studies have demonstrated that NDV is selectively cytotoxic to tumor cells but not normal cells due to defects in the interferon (IFN) antiviral responses of tumor cells. Many naturally occurring strains of NDV have an intact IFN-antagonistic function and can still replicate in normal human cells. To avoid potential toxicity issues with NDV, especially in cancer patients with immunosuppression, safe NDV-oncolytic vectors are needed. We compared the cell killing abilities of (i) a recombinant NDV (rNDV) strain, Beaudette C, containing an IFN-antagonistic, wild-type V protein (rBC), (ii) an isogenic recombinant virus with a mutant V protein (rBC-Edit virus) that induces increased IFN in infected cells and whose replication is restricted in normal human cells, and (iii) a recombinant LaSota virus with a virulent F protein cleavage site that is as interferon sensitive as rBC-Edit virus (LaSota V.F. virus). Our results indicated that the tumor-selective replication of rNDV is determined by the differential regulation of IFN-? and downstream antiviral genes induced by IFN-?, especially through the IRF-7 pathway. In a nude mouse model of human fibrosarcoma, we show that the IFN-sensitive NDV variants are as effective as IFN-resistant rBC virus in clearing the tumor burden. In addition, mice treated with rNDV exhibited no signs of toxicity to the viruses. These findings indicate that augmentation of innate immune responses by NDV results in selective oncolysis and offer a novel and safe virotherapy platform.
Elankumaran, Subbiah; Chavan, Vrushali; Qiao, Dan; Shobana, Raghunath; Moorkanat, Gopakumar; Biswas, Moanaro; Samal, Siba K.


Oncolytic viruses have been extensively evaluated for anticancer therapy because this virus preferentially infects cancer cells without interfering with normal cells. Newcastle Disease Virus (NDV) is an avian virus and one of the intensively studied oncolytic viruses affecting many types of cancer including glioma. Nevertheless, the capability of NDV infection on heterogeneous glioma tissue in a cerebrospinal fluid atmosphere has never been reported. Recently, Rac1 is reported to be required for efficient NDV replication in human cancer cells and established a link between tumourigenesis and sensitivity to NDV. Rac1 is a member of the Rho GTPases involved in the regulation of the cell migration and cell-cycle progression. Rac1 knockdown leads to significant inhibition of viral replication. In this work, we demonstrated that NDV treatment led to significant reduction of tumour tissue viability of freshly isolated heterogeneous human brain tumour slice, known as an ex vivo glioma acute slice (EGAS). Analysis of gene expression indicated that reduced tissue viability was associated with downregulation of Rac1. However, the viability reduction was not persistent. We conclude that NDV treatment induced EGAS viability suppression, but subsequent downregulation of Rac1 gene may reduce the NDV replication and lead to regrowth of EGAS tissue.

Mustafa, Zulkifli; Shamsuddin, Hilda Shazana; Ideris, Aini; Ibrahim, Rohaya; Jaafar, Hasnan; Ali, Abdul Manaf; Abdullah, Jafri Malin



Cisplatin (DDP) is widely used in lung cancer chemotherapy. However, cisplatin resistance represents a major obstacle in effective clinical treatment. This study aims to investigate whether Newcastle disease virus (NDV) exhibits an oncolytic effect on cisplatin-resistant A549 lung cancer cells. We found that NDV induced A549/DDP cell apoptosis via the caspase pathway, particularly involving caspase-9, while the mitogen-activated protein kinase (MAPK) and Akt pathways also contributed to apoptotic induction. Furthermore, NDV displayed oncolytic effects in a mouse A549/DDP lung cancer model. Collectively, our data indicate that NDV could overcome the cisplatin resistance in lung cancer cells in vitro and in vivo. PMID:22095029

Meng, Songshu; Zhou, Zhizhi; Chen, Fei; Kong, Xiangang; Liu, Huairan; Jiang, Ke; Liu, Wenbo; Hu, Maozhi; Zhang, Xiaorong; Ding, Chan; Wu, Yantao
2011-11-15



Newcastle disease viruses (NDV) are endemic in many countries around the world and have caused outbreaks in most countries since it was identified in 1926. Many countries vaccinate poultry to prevent economic losses from sickness and death. The majority of vaccines administered are formulated from N...



Newcastle disease virus (NDV) is one of the most economically important avian virus which affects the poultry industry worldwide. Although NDV is being very actively studied in Malaysia, there are still no studies on its potential as an anticancer agent, a new approach to treating cancer known as virotherapy. Currently, a collaborative research is being undertaken between Universiti Putra Malaysia (UPM), Universiti Sains Malaysia (USM) and Majlis Kanser Nasional (MAKNA) in characterising various local NDV isolates as anticancer agent. This paper describes an overview of the research that have been carried out worldwide in the use of NDV for cancer treatment and also some of our findings in characterising local NDVs with oncolytic properties.
Omar, Abdul Rahman; Ideris, Aini; Ali, Abdul Manaf; Othman, Fauziah; Yusoff, Khatijah; Abdullah, Jafri Malin; Wali, Haryati Shila Mohamad; Zawawi, Madihah; Meyyappan, Narayani
2003-01-01




Newcastle disease virus (NDV) is an avian virus that causes deadly infection to over 250 species of birds, including domestic and wild-type, thus resulting in substantial losses to the poultry industry worldwide. Many reports have demonstrated the oncolytic effect of NDV towards human tumor cells. The interesting aspect of NDV is its ability to selectively replicate in cancer cells. Some of the studies have undergone human clinical trials, and favorable results were obtained. Therefore, NDV strains can be the potential therapeutic agent in cancer therapy. However, investigation on the therapeutic perspectives of NDV, especially human immunological effects, is still ongoing. This paper provides an overview of the current studies on the cytotoxic and anticancer effect of NDV via direct oncolysis effects or immune stimulation. Safety of NDV strains applied for cancer immunotherapy is also discussed in this paper.

Lam, Han Yuen; Yeap, Swee Keong; Rasoli, Mehdi; Omar, Abdul Rahman; Yusoff, Khatijah; Suraini, Abd Aziz; Banu Alitheen, Noorjahan
2011-01-01


P/S : Daripada citation abstrak ini jelas sekali Allah tidak zalim tetapi Allah lebih pengasih dari segala yang pengasih. Yang zalim itu sebenarnya adalah manusia sendiri kerana mereka sanggup menyembunyikan kaedah rawatan yang baik, kurang kesan sampingan, mudah, murah dengan kualiti hidup lebih baik daripada rawatan konvensional kimoterapi dan radioterapi sedangkan pesakit kanser menderita hidup mereka.

Manusia yang sihat sebaliknya sibuk mempromosikan kaedah rawatan yang tidak menyembuhkan tetapi melambatkan kematian manakala pesakit menderita dengan kesan kimoterapi dan radioterapi yang dasyat. Tidak ada doktor yang akan berani memberi jaminan bahawasanya kimoterapi dan radioterapi boleh menyembuhkan pesakit kanser kerana kesan sampingan kimoterapi dan radioterapi itu sendiri boleh melemahkan tubuh manusia dan susceptible pula untuk mendapat kanser jenis lain pula kerana system immunity badan telah dilemahkan oleh kimo/ radioterapi.

Saya pernah berpengalaman berjumpa dengan doktor registrar (si penyibuk) yang dengan zalimnya mempromosikan kaedah pembedahan radikal kepada saya atau anda bagi mengisi log book mereka sebelum mereka boleh bergelar pakar bedah! Keesokkan harinya selepas lulus ujian peperiksaan pakar ( tetapi belum register dalam NSR sebab masih terlalu baru lulus ), anda boleh lihat muka mereka berada di pusat rawatan swasta bagi mengaut wang dari para pesakit kanser yang kaya raya!!! Siapakah yang memantau aktiviti kurang sihat ini???  Justeru, jangan cari doktor registrar tetapi carilah doktor yang benar benar telah berpengalaman yakni beliau sudah berada dalam tempoh lama dalam kepakaran beliau dan telah diiktiraf sebagai pakar oleh National Specialist Registry (NSR).

Sehingga waktu artikel ini ditulis, rawatan kimoterapi dan radioterapi memberikan jangkahayat maksimum 5 tahun sahaja iaitu:

Tempoh anda masih hidup (Tahun)
Peratus kejayaan rawatan dikatakan:
1
20% berjaya
2
40% berjaya
3
60% berjaya
4
80% berjaya
5
100% telah berjaya dirawat atau dikatakan telah sembuh walaupun anda menderita kesan sampingan kimo / radioterapi!
6 atau lebih
Bonus


Rawatan kimo / radioterapi tidak sesekali akan berani menjanjikan kesembuhan 100% dari kanser. Mungkin akan ada recurrence. Justeru, kaedah rawatan sebenar pesakit kanser terletak di tangan anda sendiri. Anak anak atau pasangan yang masih sihat berperanan besar dalam mencari kaedah rawatan / pemakanan / cara hidup dsbnya yang terbaik untuk anda.  Buatlah kajian menyeluruh, cari pendapat kedua atau ketiga, cari pakar yang terbaik antara yang terbaik dan anda berubat dengan mereka. Yang terbaik selalunya datang dari alam semulajadi.

Malang sekali manusia telah berleluasa menerangkan hutan, menggondol atau meratakan bukit dan gunung, membuang sampah, mencemari sungai dan tasik, membenarkan kilang yang mengeluarkan sisa pencemaran berleluasa sehingga pupus ribuan macam spesis tumbuhan dan haiwan yang bermanfaat kepada manusia…

Bukankah antara sebab manusia itu diciptakan untuk menjadi rahmat kepada sekalian alam?




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