Cancer is the general term used to describe a group of more than 200 diseases that can affect any part of the body. It is the major public health problem, with significant associated death and disability. Cancer begins in cells, the basic building blocks of the body. In a healthy body, cells will grow and divide to form new cells as the body needs them. Overtime, as cells get old they die and new cells take their place. This process is called the cell cycle. A key feature of cancer is that this process goes wrong: new cells form when the body does not need them and old cells do not die when they should. This leads to the formation of tumours. From the part of industry, oncology offers exciting oppurtunites in drug discovey and producing intelectual propery. As number of patients for cancer on the rise around the world, it is becoming a green pasture for development and discovery.
Virus as a causative agent
Viruses are responsible for diseases such as AIDS, polio, chicken pox, influenza, hepatitis, rabies, etc. Viruses can help to cause some cancers. But this does not mean that these cancers can be caught like an infection. What happens is that virus can cause genetic changes in cells that make them more likely to become cancerous. There are many cancers that are caused by viruses. Some of them are, cervical cancer, and other cancers of genital and anal area caused by human papilloma virus (HPV), primary liver cancer by hepatitis B and C viruses. T-cell leukaemia in adults by the human T-cell leukaemia virus. HPV also probably leads to oropharyngeal cancer and non melanoma skin cancers in some people.
Scientists have discovered how the notorious Epstein-Barr Virus (EBV) makes some people vulnerable to developing cancer. Around 90% of British adults are infected with EBV - but most come to no harm. However, in a small minority of cases the virus helps to trigger cancer. EBV has been linked to Hodgkin's disease, Burkitt's lymphoma, and nasopharyngeal cancer, as well as certain rare cancers in immunosupressed transplant patients.
Methods to treat cancer
Cancer can be treated in a number of ways, including surgery, radiation therapy, and systemic therapy. The doctor may use only one or combination of treatment methods depending on cancer to be treated. For example, if the cancerous mass is located remoetly the preferance is for the targetted drug delivery by monoclonal antibodies or by radiation may be the choice. If the cancerous mass is located in such a place that can be removed by surgery, then the preferance for surgery predominates. Surgery is the oldest treatment for cancer and is still a very important and often successful option for many cancer types. Radiation therapy is the practice of treating disease with ionising radiations. In two-thirds of patients given radio therapy, the treatment objective is curative, either alone or in combination with surgery or systemic therapy. Systemic therapy encompasses chemotherapy, hormonal therapy and targeted therapy. Chemotherapy is the general term for any treatment involving the use of chemical agents to kill cancer cells or stop them from growing. Chemotherapy also affects the fast growing cells in the body, including hair and blood cells leading to alopecia and hematological disorders. Hormonal therapy is used to treat certain cancers that depend on hormones to grow. The main hormone responsive cancers are breast, prostate and endometrial cancers and the main hormones involved are oestrogens, androgens and progesterones respectively. Targeted therapy is medication that blocks the growth and spread of cancer by interfering with specific molecules that are involved in carcinogenesis and tumour growth.
Therapeutic viruses
Though as we discussed that viruses as causative agents of cancer, they are now been exploited for the treatment of cancer. This is a novel approach in the treatment of cancer. Let us discus how they can be used effectively in the treatment of cancer.
Replication cycle of many viruses exploits the same cellular pathways that are altered in cancer cells. Viruses that invade cancer cells and lyse the tumour cells are called as oncolytic viruses. The poor immune responses of the cancer cell facilitate the attack and replication of oncolytic viruses in the cancer cells. Local replication of administered oncolytic viruses amplifies the input dose and creates a high concentration of therapeutic agent at the target site. The conventional chemotherapeutic agents extend their pathogenicity to normal cells also. By using the combination of both conventional drugs and oncolytic viruses, the local replication of oncolytic viruses amplifies the input dose of the therapeutic agent at the target site and limits it's toxicity to the normal tissue and even the drug resistance appears unlikely. So by arming the oncolytic viruses with therapeutic genes their antitumour activity could be increased.
Approaches to develop tumour-selective viruses
Inherent tumour-selectivity: Several RNA viruses are tumour tropic which means their ability to grow and invade the cancerous cells due to their weak antiviral response systems (e.g.: Newcastle disease virus and vesicular stomatitis virus).
These are sensitive to inhibition by interferon, thus normal cells are highly protective from these viruses while tumour cells are being invaded. Another RNA virus with inherent tumor selectivity is Reovirus, whose replication is restricted by activation of the double stranded RNA activated protein kinase (PKR). But increased levels of Ras activity (cell signalling pathway responsible for cell proliferation) are observed in many of the human tumours, counteract this inhibition by activating a phosphatase that antagonises the PKR effects, which enable virus replication.
Paro viruses lyse transformed fibroblasts but spare the normal cells. The mechanism of this process is yet to be elucidated.
Targeted deletion of viral genes
This involves the deletion of viral genes which are responsible for replication of viruses in normal cells. These genetically modified viruses include Herpes simplex virus (HSV), Adenovirus, Vaccinia virus, Poliovirus. Several viral gene products that interact with cellular components and there by influence the cell cycle and cell survival have been identified.
To target HSV replication to malignant cells, a variety of mutants have been designed with functional inactivation of the viral genes that encode for thymidine kinase, ribonucleotide reductase. But these are not expressed in quiescent cells, but upregulated during prereplication (G1) and replication(s) phases of cell cycle due to the generation of dNTPs.
Based on the attenuation approach, several oncolytic versions of vaccinia viruses that comprise mutations in the genes encoding thymidine kinase and/or vaccinia growth factor which render the viruses highly tumour selective, have been described.
Transcriptional targeting
This involves the engineering of tumour or cell type specific promoters and enhancers into virus to limit the expression of genes that are essential for viral replication in tumors.
Using prostate specific promoters, such as prostate specific antigen (PSA) promoter, the probasin promoter, adenoviruses that have restricted expression of E1A and E1B genes have been produced for prostate carcinoma.
Selective expression of E1A has been attempted in hepatocellular and breast carcinomas using alpha-fetoprotein promoter and mucin-1 promoter respectively. Calponin promoter has been used to generate HSV mutants that replicate selectively in malignant human soft tissue and bone tumours.
Cellular targeting
In this process uptake of replication competent viruses can be achieved by modifications of the viral coat. Theoretically this shows that more virulent forms can be used as they do not invade normal cells after modification. Fibre proteins of adenoviruses have been modified to redirect the natural vector tropism away from normal cells towards malignant cells.
Engineered HSV-1 vectors have been designed, they can only enter cells that express interlukin-13(IL-13) receptor alpha-2, such as brain tumours. In these mutants binding sites for sulphated proteoglycans in viral glycoproteins B and C have been ablated and IL-13 has been inserted.
(The authors are with Dept of Pharmacy Mangement, Manipal College of Pharmacuetical Sciences, Manipal University, Manipal 576104).