Chemotherapy - how does it work?

Updated: Mar 17

Chemotherapy is useful poison

Chemotherapy is harsh and if you have heard several times that chemotherapy is poison and is very harmful, you have heard it right. Something as aggressive as cancer cells, that can replace the normal functioning cells of human organs just by dividing uncontrollably, need a super strong poison to stop them from dividing and taking over entire organs. When cancer spreads, it spreads to organs, which then stop functioning properly and the patients die from multiple organ failure.

With the application of chemotherapy, of course, a lot of normal non-cancerous cells are going to die because of the toxic nature of the drugs, which you may want to think of as co-lateral casualty. That is why most of the time the outcome of chemotherapy is severe weight loss. But the good thing is, those tissues with non-cancerous cells can grow back eventually after processing all the chemotherapeutic damages. But nonetheless, chemotherapy has prolonged the lifespan of millions of cancer patients and there is no doubt about it.

Chemotherapy kills the monster that cancer is

Cancer is a biological accident. In this accident, a normal functional gene gets broken by a mutation in the DNA, which results into a mutated protein. Normally, humans will gather mutations throughout their lives, but not all mutations will translate into a mutated protein.

Proteins have important functions in the cell, such as controlling the cell division. Mutations in the genes which control cell division lead to the loss of control over cell division. Then cells start to divide in an uncontrolled fashion, leading to a tumor formation.

Albeit some cancers are hereditary (such as germline BRCA mutations), where a mutation can be passed on from one generation to another. But most cancerous mutations are acquired from environmental factors in the patients lifetime. A lot of mutated cells can be identified by the body's immune system and removed from the body. The cancerous mutations, which evade the body's immune system can eventually lead to cancer.

The toxic nature of chemotherapy stops the monster that cancer is

Chemotherapeutic drugs are molecules approved by the United States FDA to be used in human body to treat cancer by stopping these cancer cells from uncontrolled division.

Chemotherapeutic drugs usually damage the DNA in the cells or stabilizes the microtubules that are required for cell division. It can also be a drug used for targeted therapy, where mutated kinase proteins are targeted.

Platinum drugs (cisplatin, carboplatin and oxaliplatin) are the most used chemotherapeutic drugs and can induce DNA intra-strand (mostly) and inter-strand (less than 5%) crosslinks. These crosslinks are lethal, if not repaired properly and in a timely fashion they can induce cell death. Especially the inter-strand crosslinks are more lethal and need to be processed by the cells. If they are not removed, the two strands of the DNA cannot separate, which poses a problem with DNA replication. Unless the DNA replicates, the cell cannot divide. Hence, the uncontrolled cell division of the cancer cells can be stopped. In this process the normal cells also get damaged.

The cancer cells do not have a functional DNA repair system and cannot repair these chemotherapy induced damages, eventually resulting in cell death through a process called apoptosis. However, the normal cells also die from these chemotherapy-induced damages but some of the chemotherapeutic damages can be repaired. Although chemotherapy is toxic for the body, the benefit outweighs the risk.

Other than the platinum drugs, there are other type of damage inducing chemotherapeutic drugs. The DNA double-strand break inducing drugs, such as doxorubicin, Zeocin etc. induce the lethal DNA double strand breaks. The taxol drugs used for chemotherapy, such as docetaxel and paclitaxel, cause cell cycle arrest by stabilizing the tubules that eventually pull the duplicated chromosomes from the mother cell to the daughter cells. Chemotherapeutic drugs also antibody-drug conjugates, that can deliver the chemotherapeutic drug selectively to the cancer cells. In addition, there are tyrosine kinase inhibitors for specific cancers.

Radiation therapy also uses the same process of damaging the DNA through high doses of radiation, mostly creating DNA double strand breaks. So almost all the chemotherapeutic drugs as well as the radiation treatment are cytotoxic in nature but they have the power to stop the indiscriminate spread of the cancer cells.

The toxic nature of chemotherapy is what makes it work. Majority of the normal human cells do not grow uncontrollably due to proper control of cell division through a well regulated process. There are cell cycle checkpoints that make sure cells are not aberrantly dividing.

The very few cells that continually divide, such as hair follicles, the cells in the lining of the gastroesophageal lining, white blood cells etc. suffer from the chemotherapy. As a result of chemotherapy, patients often experience loss of hair, nausea vomiting and diarrhea, compromised immune system etc. Sometimes, processing of these chemotherapeutic lesions in normal human cells may result in a mutation, which may cause secondary cancer later in the future. Regardless of the painful side effects, millions of patients throughout the world have experienced increased lifespan and remission as a direct result of chemotherapy. It is worth mentioning that patient care has improved a lot in the past several decades. In the past 25 years the mortality rate from cancer has reduced by 25%. Cancer is not an immediate death sentence anymore.

Chemotherapy is not effective equally for later stages of chemoresistant and recurrent cancers

Although the cancer cells respond to the chemotherapeutic drugs in the beginning, they eventually develop resistance to chemotherapeutic drugs. Additionally, when there is recurrence, the same chemotherapeutic drug or combination cannot be used anymore. Because now, the cancer cells know how to bypass the damage. Chemoresistant cancer cells can bypass the damage, can pump out the chemotherapeutic drugs efficiently from the cells or they develop high damage tolerance and keep dividing. The cancer genome is very heterogenous and it keeps mutating. Therefore, as time progresses, they acquire capabilities they did not have before. That is why when the cancer comes back a second line of drug needs to be used to achieve clinical benefit. Eventually the second line of drug will also fail and third line of drugs need to be used.

#chemotherapy #cancer

Author: Anirban Mukherjee, PhD

Founder, Cancer Therapies 4 U

Cancer Scientist at the University of Texas at Austin

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