The Genotoxicity of Chemotherapy

By: Risa Harris  |  December 5, 2022

By Risa Harris 

Chemotherapy is a technique used by healthcare providers to fight cancer. Although it is common knowledge that this treatment has various negative side effects, the genotoxic risks of chemotherapy are less widely known. Chemotherapy may cause mutations in cells other than the already cancerous ones, making it important to identify alternative cancer-fighting methods. 

Cancer is the by-product of certain cells growing at an uncontrollable rate. Normally, human cells grow and multiply to form new cells in a process known as mitosis. When cells grow old or become damaged, they die or commit apoptosis, allowing new cells to take their place. During mitosis, some cells accumulate damage, which is normally remedied at various checkpoints in the cell cycle. However, sometimes these checkpoints do not perform properly, allowing these damaged cells to multiply. These damaged cells turn into tumors which can become cancerous. These malignant tumors spread into nearby tissues and can travel to distant places in the body to form new tumors. Cancer cells divide at a high rate, grow in the absence of stimulus, and evade the immune system, which normally eliminates damaged cells. They can even instruct blood vessels to grow towards the tumors which provides them with a supply of oxygen and nutrients.

One integral development in the fight against cancer has been chemotherapy, which uses chemicals and cytotoxic agents to kill cells with a high turnover rate. One specific type of chemotherapeutic drug is Chlorambucil, which is an alkylating agent. This class of chemotherapy drugs prevents cells from making more copies of itself by damaging its DNA. When a cell attempts to copy its DNA, Chlorambucil sticks to one of the two strands of double-sided DNA and prevents them from separating. The cell cannot divide properly, which can lead to cell death if it is not repaired. “Normal” cells have mechanisms in place to repair this damage, but cancer cells absorb a very high concentration of alkylating agents since they multiply at such a rapid rate, leaving them with less time to repair the damage. This method is, therefore, effective at killing cancer cells. 

Chemotherapy is designed to be genotoxic to cancer cells, meaning that it causes damage to the DNA in cells. However, chemotherapy is also genotoxic to “normal” cells. This is the reason cancer patients can experience various side effects ranging from nausea and hair loss to the development of secondary cancer. Tragically, it is possible that the medium used to fight one’s cancer can actually cause the development of a new cancer a few years down the line. Chemotherapeutics are unfortunately not yet specific enough to distinguish between a cancer cell and other cells that enter the cell cycle more frequently, and therefore they can cause significant unintended damage. The genotoxicity posed by chemotherapy is a major concern because it induces DNA damage and instability in the patient’s genome. Chemotherapy-related genetic instability is presumed to cause secondary tumors, especially acute myeloid leukemia or myelodysplasia, affecting 2-15% of patients receiving chemotherapy.

Researchers at Rouen University Hospital conducted a study on mice that were exposed to genotoxic chemotherapies to determine if the exposure would increase the risk of developing tumors. 208 mice were exposed to either genotoxic chemotherapy or non-genotoxic chemotherapy. The researchers used various genotoxicity assays, which are tests done to assess the possibility of mutations that could occur through the use of this drug. After examining the results, the researchers saw that exposure to topoisomerase inhibitors (a common genotoxic chemotherapeutic) had drastically increased the risk of tumor development in the mice, while the non-genotoxic chemotherapy (docetaxel, a mitotic spindle poison) had little to no impact on the development of tumors. This strongly supports the contribution of genotoxic chemotherapeutic drugs towards MPC (Mesangiogenic progenitor cell, present in bone marrow) development.

Another genotoxic risk that chemotherapy can induce is infertility. Spermatozoa, or male sex cells, are highly vulnerable to oxidative stress which can induce damage to the sperm DNA, RNA transcripts, and telomeres. This could contribute to, and even cause, male infertility as well as childhood cancers in children fathered by men with defective sperm cells. Morris conducted an experiment to test the DNA damage on men who had received chemotherapy, using Comet and Chromatin structure assays (SCSA). This genotoxic assay can detect if a sperm sample has a high degree of DNA damage, such as fragmentation in the sperm chromosome. They discovered that these patients had actually accrued increased and persistent DNA damage in sperm, which rendered some men infertile or as suffering from other fertility issues.

Thankfully, scientists have been able to develop alternative chemical compounds which have an antitumor effect while limiting the harmful genotoxic effects. A study conducted in 2017 found that Pilosocereus gounelli, an extract taken from a cactus, has possible chemopreventive effects against cyclophosphamide induced DNA damage from chemotherapy. The researchers performed micronucleus tests to assess the genotoxic damage. A micronucleus test screens for any chemicals that could cause spindle formation and micronuclei, or clumps of chromatin which is formed in the event that chromosomes fragment due to DNA damage. The detection of these clumps indicate that there was significant DNA damage. Then, the cyclophosphamide drug was administered while the P. gounelli stem extract was administered to counteract the cyclophosphamide genotoxicity. It was found that P. gounelli plays an integral role in inhibiting the cyclophosphamide-induced genotoxic damage

An additional study found that Curcumin, the active compound from the plant Curcuma longa L., has anticancer activities and can protect normal cells from chemotherapy-induced damages. Curcumin could initiate cells’ DNA repair pathways and repair the potentially-cancerous damage. An additional method theorized to limit the genotoxic effects of chemotherapy would be to use anti-telomere (telomerase inhibitors) molecules when administering chemotherapy. The level of chromosome instability caused by chemotherapy is very high, and therefore scientists have proposed to use the telomere functional parameters as a marker of chemotherapy sensitivity and toxicity, therefore, using anti-telomerase molecules could increase its sensitivity to chemotherapy.

The genotoxic risks that chemotherapy treatment can induce are significant and can even be fatal. There are studies that have developed alternative solutions that are less genotoxic, but there is still a long way to go. Chemotherapy, for now, is a trade-off where healthcare providers must weigh the risks and benefits of treatment by these means. The goal is to kill the highest percentage of cancerous cells while saving the highest percentage of “normal” ones. Hopefully, in the future, this tradeoff will become less risky.