Cancer is known to be caused by a large group of various diseases, all involved in cellular malfunction. It dates back to about 1600 BC when it was first found in an Egyptian papyrus (Wu et al, 2006) and thought to be incurable till surgery and radiation became the means of treatment in the mid-1900s. After many years it was realised that using either or combination of treatment, metastatic cancer could not be controlled and in order to gain therapeutic effect, the therapy had to reach every organ of the body. Research in drug discovery and development now focuses on using chemotherapy especially those that are selectively toxic e.g. antimetabolites (Thurston, 2007). It is not fully understood why they are selectively toxic but they are more effective on tumour cells because they are able to divide faster that healthy cells. Selective toxicity was defined as materials that are able to damage some types of cells and not the others (Albert, 1951). Even though mortality rate has not improved much, characteristics and pathways of cells in different tumours have been identified so as to develop therapies for specific tumour. The therapies developed either target protein that cause or are involved in development of tumour directly or by targeting drugs to the tumour.
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Examples of new drugs that have resulted from advances in drug discovery are (Narang & Desai, 2009) :
Imatinib (Gleevec) inhibits binding of protein (BCR-ABL) which is found in CML tumour cells.
Gefitinib (Iressa1) inhibits epidermal growth factor receptorââ‚¬â„¢s. It is used to treat lung cancer.
Trastuzumab (Herceptin1) is another monoclonal antibody that binds the cell surface HER2/neu (erbB2) receptor and is used in treating erbB2+ breast cancer.
This report will focus on principles and challenges of selective toxicity of chemotherapy, how they work, the limitations of the current chemotherapy and ways to improve drugs.
MECHANISM OF ACTION
Chemotherapy drugs are able to move throughout the body to get to where they are intended by entering the bloodstream through an injection, a drip which are usually through a vein or as capsules and tablets. For chemotherapy to work it is important to understand cell cycle, this is because chemotherapy drugs work mainly on actively reproducing cells in the body where some drugs attack particular phases of the cell cycle like the S phase. In cancerous cells, the checkpoints are damaged causing the cancer cells to continue to grow out of control. Chemotherapy works by damaging the genes present inside the nucleus of cells. Some drugs work by damaging cells when they are beginning to divide or while copies are being made. Chemotherapy drugs cause the cancerous cells to think that their lifespan has finished which leads to apoptosis.
There are different classes of selective toxicity drugs which have different methods for killing cancerous cells, some of which are below(ACS, 2013):
Alkylating agents (e.g. busulfan) are selectively toxic to DNA, where they damage DNA so as to prevent cancer cells from reproducing. Active in all the phases of cell cycle and are used to treat a wide variety of cancer like leukaemia
Antimetabolites(5-fluorouracil), these agents alter DNA and RNA growth by replacing building blocks normally present in DNA and RNA. They work in the S phase and are used to treat breast cancer.
Anti-tumour antibiotics/Anthracyclines (Doxorubicin) are also important as they affect the enzymes that contribute to DNA replication.
Other cancer drugs- these are not classified as chemotherapy drugs and they are still new. There are different types, the active and passive where active stimulates the immune system to attack the disease and passive(monoclonal antibody, e.g. Rituximab which binds to particular substances) uses antibodies that were made synthetically. In 2010, the first vaccine for cancer called the Provenge for prostate cancer was approved by the FDA (ACS, 2013).
Below Figure 1 shows the new selectively toxic agents that target specific sites and how they influence those sites.
Figure : Shows new group of anti-cancer agents designed to target specific protein that contributes to growth of tumour (Wu et al, 2006).
Chemotherapy drugs that are selectively toxic have been the first choice of treatment for many cancers and there are over 100 drugs in the market today (ACS, 2013) used alone or with other treatments.
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It is also important to understand how these drugs work so doctors (oncologists) can predict which drugs can be combined with them and how often each drug can be administered to patients.
There are three key goals of these chemotherapy treatment (ACS, 2013):
The most important goal of chemotherapy is to cure cancer where the cancer/tumour is cleared from the system. There are no guarantees with this treatment as it might even take years for a patient to be cured of cancer.
In a situation where cure is not possible it is important to control the disease by shrinking cancer or stopping it from growing or spreading. This is also important as it gives the possibility of a longer life because it is controlled like a disease that is chronic like diabetes.
Last is palliation, which is important when cancer is at an advanced stage. Chemotherapy drugs in this case can be used to relieve symptoms or improve the patients quality of life.
Normal cells that divide rapidly are damaged by these chemotherapeutic agents because they cannot differentiate between cell reproducing normal tissues and cancer cells as they are not highly selective therefore causing the following side effects (Salmon & Sartorelli, 1998).
Bone marrow suppression because the bone marrow cells normally divide quickly
Alopecia because hair follicle cells are able to divide frequently as well
GI disturbances (Nausea and Vomiting) due to mucosal cells dividing rapidly
Some of these agents cause serious side effects which may lead to permanent damage to a vital organ (liver, lungs) in the body, cause infertility, heart problems or disrupt the central nervous system by causing damage. Another big problem is the development of resistance of chemotherapy drugs to treating different tumours which can occur before treatment with drug or over time after treatment. In some cases continuous/prolonged exposure to one chemotherapy drug can cause resistance to other compounds with similar structures (Akhdar, 2012). Resistance can also develop if the drug concentration in the patient is reduced due to diminished cellular diffusion or increased drug efflux.
Chemotherapy treatment is also expensive and might take a couple of years before the disease is eradicated. In some cases the treatment does not work or may not destroy the cancer completely. Lastly, it makes the immune system very weak.
Ways to Improve Drug
A way of improving drug or avoiding resistance is using a combination of variety of cytotoxic agents as it allows prompt attack of different biological targets therefore increasing the effect of the treatment (Thurston, 2007) or with other agents that act as sensitizers to these cytotoxic agents (Narang & Desai, 2009).
Another way is developing new formulations that can prevent the severe side effects associated with a particular drug e.g. Doxorubicin caused cardiotoxicity but with new formulations like the liposomal formulation there are decreased side effects that are manageable and due to the selectivity of the new drug it works better than the conventional anthracycline.
The use of adjuvants can minimize toxicity of anticancer drugs, therefore reducing the side effects of some of the drugs.
A better diet is also advised, especially with avoiding food that cause inactivation of the drugs. Vitamin C found in citrus fruits like oranges have been found to influence anticancer drugs and reduce toxicity to the body (Salmon & Sartorelli, 1998).
It can be concluded that there are three important factors to consider in selective toxicity of a drug, they are the tumour, drug and most especially the host. There have been a lot of improvement with using chemotherapy to manage cancer even though they cause severe side effects and resistance. Other challenges faced are the cost, time involved and the high mortality rate. This has brought about increase in effort of scientists to search for ways for the body to fight cancer tissue and find better cytotoxic agents to fight cancer cells.