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Drug Resistance

How it Occurs

Resistance to chemotherapy is, in many ways, similar to the drug resistance that develops in bacterial infections. It is the innate (or acquired) ability of cancer cells to evade the effects of chemotherapeutics, making it an important problem in cancer therapy and management, as well as affecting a vast majority of patients. Besides, there is no cancer treatment that is effective against widespread disease.

It is important to comprehend that in the process of evolving into a malignant cell, changes take place at the molecular level to immortalize the cancer. To achieve this power of survival and endless growth, the developing cancer commandeers many cellular processes which may ultimately be responsible for drug resistance. It could arise due to host- or tumour-related factors and it is responsible for therapeutic failure-and eventually, death.

Most of the drugs administered do not act to produce their anti-cancer effect just like that. They require activation in the body to achieve potency. Therefore, many host-related factors alter the effectiveness of the drugs by preventing them from reaching their target, rendering them unable to achieve their intended goal. These factors may impact the absorption, distribution, metabolism, or excretion of the drug. They include long-standing toxicity of the drug on the liver and/or the kidneys. The liver is responsible for metabolizing most of the drugs administered and often suffers the brunt of the toxicity, while the kidneys excrete the drug and its breakdown products, which may interfere with its normal functioning.

Failure of the drug's effects can also occur after the drug has reached the tumour. This is referred to as local resistance, and it occurs because the tumour is highly heterogeneous. Heterogeneity implies that one population of cancer cells may be sensitive to the drug, while others may be innately drug-resistant. Chemotherapy kills the sensitive cells, leaving behind a high proportion of drug-resistant cells. These resistant cells have a propensity to grow unhindered while the patient is still on a particular treatment. As time passes, the cancer continues to grow and further treatment with a particular drug is completely ineffective.

In fact, drug resistance is complicated and has many factors. Programmed cell death is promoted by p53—the protector of the genome in response to chemotherapy. But p53 is mutated in about 50 per cent of the cancers, hence this gene is rendered non-functioning and allows drug resistance. Another factor includes the receptors on the cell surface and the transporter substance within the tumour, which control the entry of the drugs into the malignant cell. Enhanced transporter substances within the tumour cells are associated with poor prognosis due to rapid drug efflux. Inhibitors of these transporter substances are being used in treatment, along with chemotherapy, to reduce drug efflux and increase the concentration of the chemotherapeutic drug within the tumour cells.

It has also been seen that over time, elevation of certain enzymes within cancer cells enhances the detoxification of the anti-cancer drug. This results in reduced damage to the malignant cell, circumventing the effect of the drug. One of the responses to chemotherapy is DNA damage, but there are inherent mechanisms within cells which repair the damaged DNA. Cells with damaged DNA are removed by the body. When this mechanism comes into play, it also results in resistance. Inhibitors of the repair pathway, taken along with chemotherapy, increase the efficacy heterogeneous due to 'aberrant DNA repair mechanisms and of the treatment. It can be said that malignant cells are cell death dysregulation pathways'14

Malignant tumours also have stem cells which can be remissions, both at the local site of the cancer and in the area of metastasis. It is these cells that may be responsible drug-resistant. These cancer mother' cells persist during for relapse at either of these sites. As medical understanding of the molecular mechanisms of drug resistance improves, new solutions are being found. However, a lot more research is needed to unravel the entire picture, and drug resistance remains a challenge.

Fighting Drug Resistance

A drug combination is generally used during chemotherapy to reduce the chances of toxicity and the risk of developing resistance early. When a single chemotherapeutic agent is given, it has to be administered in higher doses and therefore, it is more likely to have many side-effects. The other rationale behind giving a cocktail of drugs is that when several agents are administered, they are likely to target different populations of the cancer cells, thereby reducing the total population of tumour cells that are differently mutated. Resistance to one drug is unlikely to result in resistance to the other.