Onyx-15
Encyclopedia
Onyx-015 is an experimental oncolytic virus
created by genetically engineering
an adenovirus. It has been trialed as a possible treatment for cancer. The E1B-55kDa
gene has been deleted allowing the virus to selectively replicate in and lyse
p53
-deficient cancer cells.
s when mutations in genes
involved in cell cycle
control and apoptosis
accumulate over time. Most tumours studied, have defects in the p53
tumor suppressor
pathway. p53 is a transcription factor
that plays a role in apoptosis
, cell cycle and DNA repair
. It blocks cell progression in response to cellular stress or DNA damage. Many viruses replicate by altering the cell cycle and exploiting the same pathways
that are altered in cancer cells. E1B proteins
produced by adenoviruses protect the infected cell by binding to and degrading the p53 transcription factors, preventing it from targeting the cell for apoptosis. This allows the virus to replicate, package its genome, lyse
the cell and spread to new cells.
This gave rise to the idea that an altered adenovirus could be used to target and eliminate cancer cells. Onyx-015 is a adenovirus that was developed in 1987 with the function of the E1B gene knocked out
, meaning cells infected
with Onyx-015 are incapable of blocking p53's function. If Onyx-015 infects a normal cell, with a functioning p53 gene, it will be prevented from multiplying by the action of the p53 transcription factor. However if Onyx-015 infects a p53 deficient cell it should be able to survive and replicate, resulting in selective destruction of cancer cells.
and 5-fluorouracil to combat head and neck tumours. Onyx-015 has been extensively tested in clinical trials, with the data indicating that it is safe and selective for cancer. However, limited therapeutic effect
has been demonstrated following injection and systemic spread of the virus was not detected. Further development of Onyx-015 was abandoned in the early 2000s, the rights being sold to the Chinese company, Shanghai Sunway Biotech. On November 17, 2005, the Chinese State Food and Drug Administration approved H101, an oncolytic adenovirus similar to Onyx-015 (E1B-55K/E3B-deleted), for use in combination with chemotherapy for the treatment of late-stage refractory nasopharyngeal cancer.
Oncolytic virus
An oncolytic virus is a virus that preferentially infects and lyses cancer cells; these have obvious functions for cancer therapy, both by direct destruction of the tumour cells, and, if modified, as vectors enabling genes expressing anticancer proteins to be delivered specifically to the tumor...
created by genetically engineering
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
an adenovirus. It has been trialed as a possible treatment for cancer. The E1B-55kDa
Adenovirus E1B protein
Adenovirus E1B protein usually refers to one of two proteins transcribed from the E1B gene of the adenovirus: a 55kDa protein and a 19kDa protein. Primarily, the two work to delay cell lysis during viral replication. Afterwards, they help induce cell death and control the export of viral transcripts...
gene has been deleted allowing the virus to selectively replicate in and lyse
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
-deficient cancer cells.
Background
Tumours form in cellCell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s when mutations in genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
involved in cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
control and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
accumulate over time. Most tumours studied, have defects in the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
pathway. p53 is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
that plays a role in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, cell cycle and DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
. It blocks cell progression in response to cellular stress or DNA damage. Many viruses replicate by altering the cell cycle and exploiting the same pathways
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
that are altered in cancer cells. E1B proteins
Adenovirus E1B protein
Adenovirus E1B protein usually refers to one of two proteins transcribed from the E1B gene of the adenovirus: a 55kDa protein and a 19kDa protein. Primarily, the two work to delay cell lysis during viral replication. Afterwards, they help induce cell death and control the export of viral transcripts...
produced by adenoviruses protect the infected cell by binding to and degrading the p53 transcription factors, preventing it from targeting the cell for apoptosis. This allows the virus to replicate, package its genome, lyse
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
the cell and spread to new cells.
This gave rise to the idea that an altered adenovirus could be used to target and eliminate cancer cells. Onyx-015 is a adenovirus that was developed in 1987 with the function of the E1B gene knocked out
Knocked Out
"Knocked Out" is the first song Paula Abdul Recorded and the first single, released in 1988 from the album Forever Your Girl. It was written by Babyface, L.A. Reid and Daryl Simmons and produced in early 1988 by the former two.-Song information:...
, meaning cells infected
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
with Onyx-015 are incapable of blocking p53's function. If Onyx-015 infects a normal cell, with a functioning p53 gene, it will be prevented from multiplying by the action of the p53 transcription factor. However if Onyx-015 infects a p53 deficient cell it should be able to survive and replicate, resulting in selective destruction of cancer cells.
Trials
The patent for ONYX-015 was held by ONYX Pharmaceuticals and it was used in combination with the standard chemotherapeutic agents cisplatinCisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
and 5-fluorouracil to combat head and neck tumours. Onyx-015 has been extensively tested in clinical trials, with the data indicating that it is safe and selective for cancer. However, limited therapeutic effect
Therapeutic effect
A therapeutic effect is a consequence of a medical treatment of any kind, the results of which are judged to be desirable and beneficial. This is true whether the result was expected, unexpected, or even an unintended consequence of the treatment...
has been demonstrated following injection and systemic spread of the virus was not detected. Further development of Onyx-015 was abandoned in the early 2000s, the rights being sold to the Chinese company, Shanghai Sunway Biotech. On November 17, 2005, the Chinese State Food and Drug Administration approved H101, an oncolytic adenovirus similar to Onyx-015 (E1B-55K/E3B-deleted), for use in combination with chemotherapy for the treatment of late-stage refractory nasopharyngeal cancer.