Virus sebagai antikanser
Enhancement of Oncolytic Properties of
Recombinant Newcastle Disease Virus Through Antagonism of Cellular Innate
Immune Responses
(Citations:
9)
Dmitriy
Zamarin, Luis
Martínez-Sobrido, Kaitlyn
Kelly, Mena
Mansour, Gang
Sheng, Adam
Vigil, Adolfo
García-Sastre, Peter
Palese, Yuman
Fong
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.
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.
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.
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.
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.
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?
.
No comments:
Post a Comment
Note: only a member of this blog may post a comment.