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Review
Genotoxic Effects of Chemotherapy 
By: Aviva Itskowitz

Abstract

Genotoxic substances are present everywhere and are unavoidable. This poses a large risk due to their ability to cause great damage to a person’s DNA. Unfortunately, this may lead to an increased risk of the development of cancer cells within an organism. If the cancer caused by these genotoxic chemicals is left untreated, it will largely decrease a person’s quality of life and will often lead to fatality. Although chemotherapy is a very strong and often successful form of cancer treatment, the drug poses many risks within the realm of genotoxicity. This study aimed to evaluate the risks posed to both patients and the healthcare providers in order to determine the overall value of this treatment. A major genotoxic risk that arises from the use of chemotherapeutics is the possibility of secondary cancers arising. For example, Myelodysplastic Syndromes and Acute Myeloid Leukemia are very common secondary cancers. It was found that there was a significant increase in DNA damage and numbers of abnormal cells after chemotherapy treatment. In addition, genetic lesions occurred, adding to the overall genetic instability and risk for future therapy-related malignancies. The study also explored the different routes in which chemotherapy proves toxic to a person’s DNA: directly and indirectly. After gaining a full understanding, multiple prevention ideas were explored. Treatment with DNA neutralizing agents and the relationship between nutrition and chemotherapy-induced toxicity were considered in this study. It was found that due to the fact that normal cells and cancerous cells react differently to fasting, intermittent fasting may have positive effects for cancer patients being treated with chemotherapy. Epigenetic reprogramming was explored to fully grasp the influence diet can have in chemotherapy treatment. The use of ketogenic diets (KD’s) in cancer treatment was also explored. The use of tyrosine kinase inhibitors (TKIs) combined with fasting was also explored to understand if it could enhance the efficacy of cancer treatment. Although many of these studies produced promising results, further research must be done to establish these results. 

Introduction

Over a lifetime, humans interact with many external chemicals present in the environment. Many of these chemicals cause significant damage to the DNA of these organisms by causing DNA mutations which lead to an increased risk of cancer.1 These mutations can be assessed using assays, or tests that measure the biochemical activity of a substance. The results of these assays indicate the overall impact that a genotoxic chemical has on a specimen. Given the level of exposure that humans have to genotoxic chemicals, it behooves scientists to acknowledge the devastating effects of these substances, attempts to regulate human exposure to them, and work to better understand their mechanisms of action to limit their impact. 

While damage to DNA is unwanted, the main treatment for cancer utilizes these effects of toxic substances in a positive manner. Chemotherapy is a drug treatment that is “administered to inhibit the growth of cancer cells, kill cancer cells, or block cancer cell proliferation”.2 These drugs achieve this goal by interfering with the RNA or DNA of the patients’ growing cancer cells. Chemotherapy treatments are costly, timely, often rigorous, and have many side effects. Despite these drawbacks, the survival rate of cancer patients around the world has greatly increased due to improvements in this method of treatment. Chemotherapy has either added years to cancer patients’ lives or eradicated their cancer completely, enabling the patient to thrive and live a “normal life”.3,4,5

At first glance, these chemicals would be great assets in treating terminal illnesses. However, while these drugs do interact favorably with cancer cells, they do have negative effects on healthy cells in patients’ bodies. Additionally, the long-term exposure of oncologists who deal with these substances daily can cause DNA damage to them as well, even though the drug is not being administered to them directly. Supported by research that has shown that chemotherapeutics have induced genotoxic effects on those healthcare providers administering the treatment to patients, it is essential for those administering to learn proper techniques to minimize danger to themselves and the patient.6 

Although there are over one-hundred types of chemotherapeutics, they can be divided into seven main categories of drugs: alkylating agents, nitrosoureas, anti-metabolites, plant alkaloids/natural products, antitumor antibiotics, hormonal agents, and biological response modifiers.6 Depending on the type and severity of the cancer, one or more of these categories of chemotherapy drugs will be administered to the patient. The more exposure the patient has to the drug, the more the health care providers will be exposed as well, thus increasing their overall genotoxic effects.

Mechanisms of Chemotherapeutic Genotoxic Effects in Cells

Chemotherapeutics may cause genotoxic effects through a few different mechanisms. According to a study performed in 2017, chemotherapy induced toxicity to healthy cells occurs in one of two ways: directly or indirectly. Direct toxicity means that the chemotherapy induces the same methods of damage to healthy cells as it does to the cancer cells. However, indirect damage occurs from the release of cell-free chromatin (cfCh) from the dying cancer cells, which then damages the healthy cells by triggering the DNA damage response or causing inflammation (Figure 1).7 

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Genotoxic Effects of Chemotherapy on Healthy Cells

A major genotoxic effect of chemotherapeutics is that they can cause a wide range of other cancers to arise in a patient. For example, cells within the bone marrow are vital in maintaining hematopoiesis after chemotherapy. However, it is known that these cells are damaged greatly by chemotherapeutic drugs and the mutations induce many types of bone marrow cancer. In 2017, a study was performed to determine the long-term effects of damage to these cells in patients specifically receiving the alkylating agent - cyclophosphamide - which can cause a reduction in healthy cells. Using the micronucleus and comet assays, it was determined that there was a significant increase in DNA damage and the numbers of abnormal cells increased. Genetic lesions also occurred, adding to the genetic instability and risk for future therapy-related malignancies.8

Myelodysplastic Syndromes and Acute Myeloid Leukemia are very common therapy-related malignancies. Over time, there has been a great increase in these malignancies since the high success rate of chemotherapeutic drugs has increased the drive to use the treatment and thus overall human exposure. “Therapy-related leukemias are a major problem in patients treated for Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, polycythemia, breast cancer, ovarian carcinoma, or testicular carcinoma”.9 Studies have found that the highest potential of developing a secondary leukemia comes from treatments using alkylating agents, nitrosoureas, and procarbazine. Despite the evident genotoxic risk, doctors often determine that the risk is worth it in order to treat the active cancer in patients.9 

Genotoxic Effects on Healthcare Providers Administering Chemotherapy

 

One study, performed in 2007, assessed the genotoxicity caused to the nurses and doctors administering chemotherapy drugs. It was reported that “occupational exposure to anti-cancer drugs can represent a potential health risk to humans.” Both the comet assay and micronucleus assay test were used in this study. They found both an increase in DNA damage in lymphocytes and an increase of micronuclei found in the nurses being exposed to the drugs.10 As indicated by the results of this study, more stringent safety precautions are necessary to maintain the safety of those administering and handling these powerful drugs.

Prevention of the Genotoxic Effects of Chemotherapeutics

There have been many research initiatives focused on preventing healthy cell damage that occurs from chemotherapy treatment. The first study that was looked at was based on the hypothesis that DNAse is an enzyme that breaks down the hydrogen bonds that hold the two DNA strands together (Figure 2). The study suggests that “treatment with DNAse or other DNA neutralizing agent can prevent chemotherapy-induced toxicity in healthy cells”.12 The powerful enzymes have the ability to break these necessary bonds within the cancer cells. The “results suggest that toxicity of chemotherapy is caused to a large extent by cfCh released from dying cells and can be prevented by concurrent treatment with cfCh neutralizing/degrading agents”.7

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An additional study performed by Changhan Lee in 2012 linked the effects of nutrition and chemotherapy-induced toxicity to healthy cells.13 This study was based on the hypothesis that “normal cells and cancer cells differ in their ability to respond to fasting”.14 When a patient fasts, the normal cells are able to switch their metabolism by utilizing maintenance pathways; however, cancer cells are unable to perform this task. Therefore, by utilizing short-term fasting during chemotherapy treatment, the risk of toxicity can be lessened greatly by starving the cancer cells to death.15 A pilot trial to this hypothesis was conducted, which produced promising results. The trial included thirty patients aged 30-74 years, who underwent a minimum of four chemotherapy cycles. The patients fasted intermittently for half of the chemotherapy cycle, making sure they still received enough nutrition during the non-fasting periods of intermittent fasting. For the second half of the cycle, patients maintained a normal diet. The results indicated that utilizing modified short-term fasting (mSTF) during treatment can both reduce the chemotherapy-induced toxicities and enhance the tolerance of chemotherapy (Figure 3).16 

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It is well known that diet plays a role in many aspects of human health. Interestingly, this extends to the influence of cancer development. The source for this is epigenetic reprogramming: a mechanism through which certain substances introduced through diet can influence gene expression, and can cause changes in cell proliferation and growth. Recent research has been conducted that explores the effects of fasting and ketogenic diets on chemotherapy outcomes. The main goal and determining success factors being reducing toxicity and improving the quality of life. 17

With regard to fasting, through many studies it has been found that intermittent and short-term fasting during chemotherapy is safe and well-tolerated. Even more so, it may reduce fatigue, side effects, and improve one’s overall quality of life. A cohort study was conducted which found that fasting for around 48 hours is safe and feasible for cancer patients. It may reduce DNA damage in leukocytes. This study also demonstrated that fasting reduces DNA damage in mononucleated blood cells and may promote DNA recovery after chemotherapy. Another study was conducted that found that fasting may reduce nausea, vomiting, diarrhea, abdominal pain, and reported fewer side effects in patients who fasted for the entire duration of chemotherapy. Although promising results, further research is needed to confirm these findings.17

The use of ketogenic diets (KD’s) in cancer treatment was also explored. KD’s mimic the metabolic state of fasting and elevate ketone bodies above the reference range. Several studies have explored the feasibility and effects of KD’s in cancer patients. A pilot study found that KD’s were tolerable and safe in advanced metastatic tumors, and five patients completed a 3-month intervention period, reporting improved emotional functioning and less insomnia. Another study found that KD’s were well-tolerated and potentially useful in controlling tumor growth in patients with recurrent glioblastoma. The effects of KD’s in combination with bevacizumab treatment were also explored in a study with 53 patients observed compared to those treated with bevacizumab alone. Additionally, a randomized controlled trial found a significant improvement in adjusted physical function scores in women with ovarian or endometrial cancer who followed a KD for 12 weeks compared to those following the ACS diet.17

The study conducted by Caffa, Irene, and colleagues in 2015 aimed to investigate whether combining fasting with tyrosine kinase inhibitors (TKIs) could enhance the efficacy of cancer treatment. TKIs are drugs that inhibit the activity of enzymes called tyrosine kinases, which are often overactive in cancer cells and contribute to tumor growth and survival. While TKIs have shown promise in cancer treatment, they often have limited efficacy and can cause side effects.18

The researchers used mouse models and human cancer cell lines to demonstrate that fasting increased the sensitivity of cancer cells to TKIs, leading to enhanced tumor suppression. Specifically, they found that fasting activated the MAPK signaling pathway, which is involved in cell proliferation, differentiation, and survival. The activation of this pathway led to a decrease in the activity of the MAPK proteins, which are often overactive in cancer cells and contribute to tumor growth and survival. By inhibiting the MAPK signaling pathway, fasting enhances the anti-cancer effects of TKIs.18

The study concluded that combining fasting with TKIs could be a promising strategy for improving cancer treatment outcomes. Fasting has been shown to have several health benefits, including reducing inflammation, improving insulin sensitivity, and enhancing cellular stress resistance. By combining fasting with TKIs, it may be possible to enhance the anti-cancer effects of the drugs while minimizing side effects. However, further research is needed to determine the optimal fasting regimen and to assess the safety and efficacy of this approach in clinical trials.18

Another study investigated the effects of a fasting mimicking diet (FMD) in combination with neoadjuvant chemotherapy (NAC) on breast cancer treatment. The study was a randomized phase 2 clinical trial conducted at multiple centers, and it involved women with early-stage breast cancer who were scheduled to undergo this type of chemotherapy.19

The study found that adding an FMD to NAC significantly increased the rate of pathologic complete response (pCR), which is a marker of treatment efficacy. The FMD group had a 36% pCR rate compared to 20% in the control group. The FMD also improved overall survival, disease-free survival, and quality of life in the patients.19

The study suggests that FMD can enhance the anti-cancer effects of chemotherapy and may have potential as an adjuvant therapy for breast cancer treatment. However, further research is needed to confirm these findings and to identify the optimal FMD regimen for breast cancer patients.19

Conclusion

Bispecific antibodies have emerged as promising therapeutic tools for the treatment of various diseases, including cancer, autoimmune disorders, and infectious diseases. Their ability to be manufactured to meet the needs of a particular disease or match the specificity of a multitude of antigens and other proteins allows them to be incredibly versatile. They offer several advantages over traditional monospecific antibodies, such as the ability to simultaneously target two different antigens, their enhanced resistance to immunity, and the ability to treat complex diseases with multiple pathogenic pathways. As research in this field continues to advance, it is likely that bispecific antibodies will play an increasingly important role in the development of new and effective treatments for a wide range of diseases.

References

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  2. Liu, L.P., et al., Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm ,2021. 2(3): p.315-340 

  3. Kocakaya, S., et al., Chemotherapy increases long-term survival in patients with adult medulloblastoma: a literature based meta-analysis. Neuro Oncol., 2016. 18(3): p. 408-416. 

  4. Glimelius, B., et al., Chemotherapy increases survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol, 1996. 7(6): p. 593-600. 

  5. Akhlaghi, E., et al., Chemotherapy and quality of life in cancer patients at the end of life: an integrative review. Health Qual Life Outcomes, 2020. 18(1): p. 332. 

  6. Mihlon, F., et al., Chemotherapy Agents: A primer for the interventional radiologist. Semin Intervent Radiol, 2010.  27(4): p. 384-390. 

  7. Mittra, I., et al., Prevention of chemotherapy toxicity by agents that neutralize or degrade cell-free chromatin. Ann Oncol, 2017. 28(9): p. 2119-2127. 

  8. May, J.E., et al., Chemotherapy-induced genotoxic damage to bone marrow cells: long-term implications. Mutagenesis, 2018. 33(3): p. 241-251. 

  9. Leone, G., et al., The incidence of secondary leukemias. Haematologica, 1999. 84(10): p. 937-45. 

  10. El-Ebiary, A.A., et al., Evaluation of genotoxicity induced by exposure to antineopastic drugs in lymphocytes of oncology nurses and pharmacists. J App Toxicol, 2013. 33(3): p. 196-201. 

  11. Rekhadevi, P.V., et al., Genotoxicity assessment in oncology nurses handling anti-neoplastic drugs. Mutagenesis, 2007. 22(6): p. 395-401. 

  12. Helleday, T., Chemotherapy-induced toxicity-a secondary effect caused by released DNA? Ann Oncol, 2017. 28(9): p. 2054-2055.   

  13. Lee, C., et al., Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med, 2012. 4(124): p. 124ra27. 

  14. Laviano, A. and F. Rossi Fanelli, Toxicity in chemotherapy--when less is more. N Engl J Med, 2012. 366(24): p.  2319-20. 

  15. Gabel, K., et al., Current Evidence and Directions for Intermittent Fasting During Cancer Chemotherapy. Adv Nutr, 2022. 13(2): p. 667-680. 

  16. Zorn, S., et al., Impact of modified short-term fasting and its combination with a fasting supportive diet during chemotherapy on the incidence and severity of chemotherapy-induced toxicities in cancer patients - a  controlled cross-over pilot study. BMC Cancer, 2020. 20(1): p. 578. 

  17. Plotti, F., et al., Diet and Chemotherapy: The Effects of Fasting and Ketogenic Diet on Cancer Treatment.  Chemotherapy, 2020. 65(3-4): p. 77-84. 

  18. Caffa, I., et al., Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget, 2015. 6(14): p. 11820-32. 

  19. Vernieri, C., et al., Fasting-mimicking diet plus chemotherapy in breast cancer treatment. Nat Commun, 2020. 11(1):  p. 4274. 

  20. Agarwala, V., N. Choudhary, and S. Gupta, A Risk-benefit Assessment Approach to Selection of Adjuvant Chemotherapy in Elderly Patients with Early Breast Cancer: A Mini Review. Indian J Med Paediatr Oncol, 2017. 38(4): p. 526-534.  

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