International Biopharmaceutical Association Publication
CANCER-FROM MOLECULAR BIOLOGY TO
DRUG DEVELOPMENT
Sonal Gupta
sg52003@gmail.com
Abstract: Cancer is a condition in which control of cell
division is lost and cells start to divide uncontrollably. These cells attain the ability to detach from
their organ of origin and invade other tissues, a process called
metastasis. Metastasis is the process
which differentiates malignant tumors from benign tumors. Finding a cure for cancer with minimal
side-effects has been a huge challenge for scientists all over the world. The biggest hurdle in finding a cure for
cancer is the nature of disease which involves multiple levels of
complexity. The complex nature of
disease begins with its causative agents.
Unlike other diseases, a single agent could not be linked with the
cancer. Factors leading to cancer may be
as diverse like high-energy radiations, certain chemicals, biological agents
like certain bacteria and virus, genetics makeup of the individual and even
life-style. But one common theme among
all of these agents is their ability to alter genetic material of the
cell. There are more than 130 genes,
mutation in which may lead to cancer. While most diseases affect a single
organ-system of the body, cancer is not limited to only one organ-system. Despite the complex nature of the disease, currently
available treatments may significantly better the condition of the
patient. Present treatments include
chemotherapy, surgery, biological therapy and radiation therapy etc. These treatments are not very specific to
cancer cells and affect normal cells too causing significant side-effects. But enormous research is being done for the
cancer treatment and the results are very promising. Better understanding of
the molecular biology of cancer cells and advancement of techniques like
micro-array, led to the discovery of more specific treatments which exclusively
affect cancer cells without any serious harm to normal cells. These new approaches include targeted therapies,
gene therapy, angiogenesis inhibitors and cancer vaccines. Some of these new treatments have already
been approved by FDA while many are in pre-clinical or in clinical phase.
Cancer: Introduction
Cancer is one of the
most dreaded diseases and numbers of its victims are next only to the cardiovascular
disease. Approximately 1500 people die each day in the
Scientific term for cancer is malignancy. It is the condition in which control of cell-cycle is lost and cells start to divide uncontrollably. These deadly cells may detach from their organ of origin and may spread to other organs too. This process of invading other organs is called metastasis and it is the most problematic quality of malignant cells while looking for a cure for malignancy. Metastasis is the process which differentiates malignant tumors/malignancy from benign tumors, which are self-limited and do not invade other tissues and for most part are harmless.
Though cancer may attack any organ of the body at any age including fetus its risk increases with the age. Organs which are more commonly affected by malignancy are liver, breast, colon, lining of stomach, kidney, cervix, prostate and bladder etc.
Causes of Cancer:
Invention of a cure for cancer has proved difficult because there is no single cause for cancer. The risk-factors for cancer are as diverse as physical inactivity to hereditary. The agents which are known to stimulate the process of cancer are called carcinogens. Here is a list of certain risk-factor which increases the chance that a person will develop cancer:
Apart from UV radiations, other ionizing radiations like radon gas and X-ray may also increase chances of getting cancer. Radon is a radioactive gas that forms in soil and rocks and people working in mines may be exposed to that. It increases chances of getting lung cancer. Medical procedure like X-ray and radiation therapy are also a source of ionizing radiation but the chances of getting cancer are much lower in these type of radiations and benefits always significantly overweigh the small risk.
Molecular biology of Cancer:
Though a single agent could not be linked to all types of cancer but all of these agents cause some sort of changes in genetic makeup. There are two important classes of genes which are critical in the development or suppression of cancer; these genes are called proto-oncogenes and tumor suppressor genes. In an easy sense proto-oncogenes can be compared to gas-pedal of the car which causes cells to divide while tumor-suppressor genes can be compared to the break pedal of the car which controls when to stop the cell division. In almost all types of cancers, a series of independent mutations are accumulated in a step-wise progression in several proto-oncogenes and tumor suppressor genes; this assembly of independent mutations is responsible for the transition from normal cell to cancerous cell. This explains the reason why cancer is more prevalent in older people because cells in their body have had more time to accumulate mutations which are responsible for causing cancer. Because of their critical role in the development of cancer, proto-oncogenes and suppressor genes will be discussed at a length here:
Oncogenes: In normal cells proto-oncogenes genes code for the proteins that control cell division and regulate how often a cell divides and the degree to which it specializes. Mutation in a proto-oncogene may cause it to become an oncogene (gene responsible for causing cancer). More than hundred oncogenes have been recognized by now. Unlike proto-oncogenes, oncogenes are permanently activated, as a result of which control of cell-cycle is lost and cell divides too quickly.
Growth of a normal cell starts with a growth factor, which binds to a growth factor receptor located on the cell surface. The signal from the receptor to the nucleus is sent via a signal transducer. As a response to this signal a transcription factor is produced this initiates the cell to divide. If any abnormality is detected during the cell division, cell is made to commit suicide by programmed death cell regulators.
On the basis of their action on the cell cycle, oncogenes have been divided into five different classes: growth factors, growth factor receptors, signal transducer, transcription factors and cell death regulators. As oncogenes are permanently activated, cells divide continuously and even in the presence of any abnormality cells do not die as cell death regulators do not turn off.
Tumor suppressor genes: These are genes which code for the proteins which make cell to slow down its division, repair DNA and tell cells when to die. About thirty tumor suppressor genes have been discovered by now. The main functional abnormality caused by the mutations in oncogenes and suppressor genes differs in their state of activation. Mutations in oncogenes leading to the cancer make them permanently on while in tumor suppressor genes theses mutations cause them to permanently turn off.
On the basis of their function tumor suppressor genes have been divided into three classes: genes controlling cell-division, genes that repair DNA and cell suicide genes. As mutations in these genes make them permanently inactive cell-division continues uncontrollably, DNA does not get repaired in case of any damage and cells containing any abnormality do not undergo the process of cell death or apoptosis.
Apart from mutations in proto-oncogenes and suppressor genes, other changes like structural changes in genetic material and epigenetic changes may also lead to cancer. Structural changes are chromosomal level changes in which a portion of the chromosome may undergo processes like duplication, translocation, inversion, gene-amplification and anupleoidy. While epigenetic changes do not actually change the nucleotide sequence, the expression of the gene is altered by the addition of the methyl group in the nucleotide or by the addition of acetyl group on the histone protein making the expression of gene less and more active respectively.
Problems in finding a cure for Cancer:
Cancer is a behemoth of a challenge for the scientists all over the world. More than 1.7 million papers have been published on cancer research but still no satisfactory cure without tons of side-effects could be found for all types of cancer, though a lot has been understood about the mechanism and biology of cancer. And it helped for the development of various lines of treatments which can be used individually or in combination for the treatment of cancer.
Basic problems in finding a cure for cancer are multifold because of the complexity of cancer at all levels. Unlike most other diseases the causative agent of cancer is not known. A single agent could not be linked even to one type of cancer. The other problem is the diversity of changes in genetic material which may lead to cancer. There are about hundred oncogenes and about thirty suppressor genes in a cell. Even a single nucleotide change in these genes may be a stimulant towards the cancer. Normally cancer develops following a series of changes in the genes, so there are numerous possible combinations in which these changes may occur leading to cancer. Another hurdle in finding a cure to cancer is the ability of cancerous cells to metastasize. These cells may degrade binding proteins and invade other tissues and cause cancer to spread from one organ to other. By the time cancer is diagnosed in the primary organ it has already spread to the secondary organs making condition even more complicated.
Treatment of Cancer:
Present approaches
Though a definite cure could not be found for cancer, there are methods of treatment which increase life expectancy as well as provide better quality of life. The benefit depends on the stage of the cancer and the organ involved.
Here is a list of types of treatment available for cancer:
1. Surgery: This is the first line of treatment for many solid tumors. If diagnosed at an early stage, surgery alone may be sufficient to cure the cancer by removing all cancerous cells. Depending on the size, location and type of cancer surgery is often used in combination with radiation or chemotherapy.
2. Radiation therapy: This therapy utilizes high energy radiations like x-rays to kill cancerous cells or shrink tumors. Radiation therapy destroys cells in the area under treatment by damaging their genetic material. Although radiation therapy damages both normal and cancerous cells, most normal cells are able to recover from the radiations. This therapy is often used in combination with surgery or chemotherapy.
3. Chemotherapy: Chemotherapy is a type of treatment that uses drugs to kill quickly dividing cancer cells. But at the same time it also kills quickly dividing normal cells like those present in the lining of mouth and intestine and those that cause hair to grow. Damage to healthy cells is responsible for the side effects of chemotherapy. Depending on the type of cancer and how advanced it is chemotherapy may cure, control or ease cancer symptoms.
4. Biological therapy or Biological Response Modifier (BRM) therapy: BRMs are the compounds which are used to treat cancer by augmenting body’s immune system. These compounds target immune system cells and cause increased production of cytokines and immunoglobulin. These compounds too have side effects when used in high doses required for cancer treatment and their effectiveness depends on the type of cancer.
5. Hormone therapy: Although abnormal, cancer cells retain their ability to respond to hormonal signals. The idea behind this therapy is to starve cancer cells of these hormone signals which otherwise stimulate these cells to divide. Cutting off the hormonal supply has side effects on normal cells too. Not all cancers respond to hormone therapy. Some types of breast cancer, uterine cancer and prostate cancer are sensitive to hormone therapy.
6. Antibody therapy: Monoclonal antibodies can be used to inhibit the growth of cancer cells by different approaches. These antibodies perform their action either by stimulating cancer cell killing or blocking a growth receptor. These antibodies may also be tagged with toxins which would eventually kill cancer cell.
7. Alternative approaches: These approaches include ancient knowledge of Indian Yoga, Ayurveda and Chinese feng-shui etc. Though modern science does not give an explanation for their mode of action, but some people claim to get benefit from these approaches.
Future Drug development in Cancer Treatment:
Immuno-modulation: Introduction of genes which enhance the immune response of the body.
Targeting genetic lesions in tumor cells: Introduction of genes which code for the reverse sequence of faulty genes in tumors. mRNA of the faulty gene and the gene introduced in gene therapy will form Watson-Crick base pair. These double stranded mRNA can not be translated and will block the expression of specific genes responsible for the disease.
Suicide genes: These genes are transferred into cancer cells and then a pro-drug (inactive form of a drug) is given to the patients. This drug is converted into its active form only in the cells containing the transferred gene. And these cells die because of the active form of the drug.
These are the most popular strategies with the gene therapy for the treatment of cancer, but other strategies are also in the pre-clinical or clinical phases.
References:
www.krctraining.com
http://www.medschool.lsuhsc.edu/
http://patient.cancerconsultants.com
http://www.ias.ac.in/currsci/sep102001/555.pdf