An Introduction to Cytotoxic Drugs

An Introduction to Cytotoxic Drugs

If you need drug product manufacturing services, please contact us at info@cdmoclinical.com 

Cytotoxic drugs are commonly used as treatment for different types of diseases, among which cancer stands out. Considering that the composition of cytotoxic drugs is poisonous to cells, chemotherapy has proven remarkably successful in destroying cancer cells or inhibiting their division. Read on to become acquainted with the most significant contributions of the main cytotoxic drugs employed in the field of oncology.

What Are Cytotoxic Drugs?

‘Cytotoxicity’ is the term used to refer to a substance or process that can damage living cells. Etymologically, the latinized word-forming element cyt– means ‘cell’, whereas toxicum means ‘poison’. [1] 

Since 1902, the pair of words ‘cytotoxic drugs’ has been used in modern medicine to define a series of medicines or substances containing certain chemicals which are poisonous or deadly to cells. Cytotoxic drugs, also known as antineoplastics, fulfill the function of either killing cells or interrupting their growth or replication. 

In this sense, they have been commonly used to treat not only cancer, but also other types of disorders, such as arthritis, rheumatoid, and multiple sclerosis. For all intents and purposes, cytotoxic drugs have contributed greatly to the progress of medicine and clinical research. 

Notwithstanding the foregoing, it is also true that cytotoxic drugs indiscriminately kill cancer cells as well as healthy cells. This phenomenon, together with the aggressive nature of these substances, explain why chemotherapy may lead to adverse effects, including hair loss, nausea, diarrhea, damage to bone marrow, among others. 

Certainly, the side effects of cytotoxic drugs are not restricted to patients. Indeed, anyone with direct contact to those individuals or animals receiving cytotoxic drugs —pharmacists, physicians, nurses, or laboratory staff— may be at risk. For this reason, it is imperative to follow preventive measures to ensure a suitable and careful handling of cytotoxic drugs when continued exposure to these chemicals proves necessary.

Cytotoxic Drugs: General Background and History

From the Ancient Age, surgeons and physicians already knew that cancer would probably return after surgical removal. Celsus, a prominent Roman physician, put on record that “after excision, even when a scar has formed, none the less the disease has returned.” Moreover, Galen, a highly respected medical authority in second-century Greece, strongly believed that cancer was incurable and, therefore, he concluded that cancer patients were condemned to a low life expectancy. [2] 

Nevertheless, during the auspicious years of the Renaissance, Europe witnessed a series of scientific breakthroughs and developments which paved the way for greater understanding of the human body. Some of the most distinguished scientists in this period include Galileo and Newton, who used the scientific method before it would be utilized to study illness, Versalius, considered the founder of modern human anatomy, and Harvey, an English physician who discovered the circulation of blood. 

In the midst of the age of the Enlightenment, Giovanni Morgagni of Padua conducted autopsies to correlate certain diseases with pathologic findings after a patient’s death, which set the ground for the study of cancer. Later on, the nineteenth century saw the flourishing of the technological advances and transformations brought about by the Industrial Revolution. In this context, Rudolf Virchow made his contribution by introducing the modern microscope to the examination of oncologic pathology. [3] 

At the turn of the twentieth century, transplantable tumors had already been inserted in rodents to analyze the potential effects of certain drugs, and thus determine their suitability for the treatment of cancer. Yet, it is more accurate to trace the origins of chemotherapy back to the Second World War. In this period, it was found that the bone marrow cells and lymph nodes of those men who had been exposed to the mustard gas —a highly corrosive substance used as a weapon— underwent toxic alterations. 

Against this background, Milton Winternitz, one of the founders of clinical medicine at Yale, started to study the chemical composition of the mustard gas. Together with other investigators, Milton discovered that the use of nitrogen mustard could lead to marked regression in lymphoma patients. This apparent success spread a dangerous illusion among the multitudes, who believed that cancer would be curable from that moment onwards. [4]

Image 1. Milton Winternitz and Yale Institute

Nonetheless, remissions turned out to be transient and incomplete, which generated a widespread sense of pessimism. In spite of this initial failure, not all hopes were lost. Far from that, the quest for a cure for cancer had only just begun. 

The following great discovery was that aminopterin, a compound derived from folic acid, could interrupt DNA replication by blocking a chemical reaction needed for this process. In 1948, Farber showed that this compound, the predecessor of methotrexate, produced unquestionable remissions in children with acute leukemia. [5] 

The importance of government efforts to design drug development programmes and the creation of the Cancer Chemotherapy National Service Center (CCNSC) in 1955 should not be overlooked either. From a scientific standpoint, the area of chemotherapy was very promising, which is why it was time to invest more in clinical infrastructure and research for its further expansion. 

A rare tumor called choriocarcinoma was the first to be cured in 1956, and the next decade saw the cure of testicular cancer. Since then, cytotoxic drugs and combined-modality therapy —consisting of the application of drugs in conjunction with radiation treatments and/or surgery— have been widely used to successfully cure or treat many other types of cancers, such as leukemia and Hodgkin’s disease (with the latter now being curable in 90% of cases). 

In the 1970s, adjuvant chemotherapy was born. It consisted of giving therapy after the primary treatment to maximize its efficacy and reduce the risk of cancer recurrence. Adjuvant therapy was first tested in breast, colon, and testicular cancers, and produced good results. 

More recently, another major discovery has been neoadjuvant chemotherapy. This treatment is used to shrink tumors at an early stage, before other treatments are administered. This facilitates the surgical removal of tumors and converts previously inoperable tumors into operable ones. 

Today, combined chemotherapy has become standard clinical practice, and the testing of new cytotoxic and cytostatic drugs still plays a leading role in the “war on cancer”. Indeed, as a result of all the progress achieved in the area of oncology over the last few decades, cancer mortality rates have fallen to levels never before seen, and the prognosis for cancer patients is increasingly favorable. 

Main Benefits and Advantages of Cytotoxic Drugs in Clinical Use

By now it has become clear that cytotoxic drugs are very potent medicines. As a matter of fact, the discovery of these powerful tools marked a turning point in the understanding and treatment of cancer. In this section, we will focus on the potential benefits provided by cytotoxic drugs. 

Here is a list of the main advantages associated with the use of cytotoxic drugs: 

  • Destruction of cancer cells or slowdown in their growth and replication 
  • Shrinkage of tumors to make surgery removal of cancer possible 
  • Reduction of the chances of cancer recurrence 
  • Maximization of the patients’ quality of life  

In any case, the efficacy of cytotoxic drugs may differ from one patient to another. Some factors which can potentially alter the course of treatment include the type of cancer, treatment goals, and the conduct of the patient out of treatment. Moreover, the prognosis will vary depending on whether the disease has been detected at an early stage or has already reached an advanced stage. 

Examples of Widely Known Cytotoxic Drugs

Cytotoxic drugs are classified into different categories according to their functions, chemical structure, and their compatibility with other drugs. Some examples of cytotoxic drugs include alkylating agents, antimetabolites, antibiotics, and mitotic inhibitors. Many of these medicines interfere with either the structure or synthesis of DNA in tumor cells. 

In order to determine which type of cytotoxic agent is more appropriate for cancer treatment, it is crucial to consider the disease to be treated as well as the side effects of each drug. These agents are often combined for the purpose of achieving more effective results. The general features and qualities of some widely sold and marketed cytotoxic drugs are described below. 

Alkylating drugs 

Alkylating agents disrupt the growth and multiplication of cancer cells by damaging their DNA. These drugs are used as treatment for various cancers, such as breast, lung, and ovary cancers, as well as lymphoma, leukemia, sarcoma, Hodgkin disease, and several other malignancies. 

The most popular and traditionally used alkylating drugs are also referred to as ‘classical alkylating agents’. Examples include altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, and uramustine. These agents, in turn, are divided into three groups: nitrogen mustards, nitrosoureas, and alkyl sulfonates. 

Nitrosoureas are a group of alkylating drugs that, unlike the previously mentioned agents, can reach the brain. For this reason, these cytotoxic drugs are frequently used to treat certain brain tumors. 

Antimetabolite drugs 

Antimetabolites are chemicals used in cancer treatment due to their capacity to interfere with RNA and DNA production. They interrupt the reproduction of cancer cells which, on account of this, can no longer make copies of themselves. 

These agents are often used in the treatment of leukemia, as well as cancers of the breast, ovary, and gastrointestinal tract. The following are examples of antimetabolite drugs: capecitabine, fluorouracil, gemcitabine, methotrexate, pemetrexed, among others. Some of the side effects of antimetabolite drugs are nausea, weakness, loss of appetite and dry, cracked skin. 

Cytotoxic antibiotics 

Antitumor antibiotics differ from the ones used in the treatment of bacterial infections. These powerful agents prevent the replication of cancer cells by modifying their DNA. Among the most widely used antitumor antibiotics are bleomycin, doxorubicin, and mitoxantrone. 

Anthracyclines are antibiotic drugs coming from Streptomyces bacterium. They are used to treat cancers of breast, bladder, stomach, lung, along with several other types of cancer. Examples of these potent anticancer drugs include doxorubicin, daunorubicin, and epirubicin. 

However, despite the benefits brought by anthracyclines, they can also produce serious adverse effects, such as heart-related illness. That is why their effects and dose limits remain a subject of ongoing concern and study. 

Mitotic inhibitors 

Mitotic inhibitors, also called ‘plant alkaloids’, are derived from natural materials. They disrupt microtubules, which helps inhibit cancer cell division (mitotic reproduction) and prevent further complications, such as metastasize. 

Taxanes and vinca alkaloids are two examples of mitotic inhibitors. On the one hand, although taxanes were originally derived from the western yew tree, they are today artificially synthesized agents. Their mechanism consists in the inactivation of the cell’s microtubule function. Examples include cabazitaxel, docetaxel, and paclitaxel. 

On the other hand, vinca alkaloids are compounds produced by the Madagascar Periwinkle plant. Like taxanes, they inhibit microtubule polymerization. Examples include vinblastine, vincristine, and vindesine. Both taxanes and vinca alkaloids are used as treatment for leukemia, lymphomas, breast cancer, lung cancer, and many other types of cancer. 

Cytotoxic Drug Management and Administration: Main Challenges and Difficulties

Thanks to recent medical advances in the field of cytotoxic chemotherapy, the world has currently experienced a considerable increase in the number of cancerous diseases that can be dealt with or cured. Nevertheless, despite the notable success achieved, there are still certain obstacles in effective treatment of cancer patients. 

A major threat posed by cytotoxic drugs is related to constant or prolonged exposure to these drugs. Actually, all people involved in the process of cytotoxic drug development and manufacturing, as well as health care professionals working with patients receiving chemotherapy medicines, may be affected by the toxic effects of these noxious substances. 

Adverse health effects usually result from the inadequate handling of cytotoxic drugs during the preparation and administration of these chemicals. These are a few examples of the effects caused by the exposure to hazardous chemotherapy drugs: [6] 

  • Allergic reactions, skin rashes, or contact dermatitis 
  • Alterations to normal blood cell counts 
  • Cytogenetic abnormalities and mutagenic activity 
  • Excretion of the drugs in the urine of exposed individuals 
  • Infertility, fetal loss, or malformations in the embryo 
  • Pain in the abdomen, nasal sores, hair loss, and vomiting 

In order to minimize these health risks, a series of proposals put forward by health care authorities should be considered. Some relevant laws regulating the use of cytotoxic substances at the workplace include the Health (Drugs and Poisons) Regulation (1996), Work Health and Safety Act (2011) and Waste Reduction and Recycling Act (2011). 

The following is a list of control and preventive measures aimed at ensuring the safe use, storage, handling, and transport of cytotoxic medicines: 

  • Establish engineering controls: enclosed systems, pharmaceutical isolators, CDSCs to minimize exposure to workers, etc. 
  • Implement administrative controls: surveillance, established work practices, safety data sheets, monitoring exposure in the workplace, etc. 
  • Provide all staff handling cytotoxic drugs (physicians, pharmacists, nurses, assistants, maintenance workers) with complete training programs, and promote safe handling techniques 
  • Use of personal protective equipment (PPE): disposable gloves and gowns, respiratory protection, and eye protection 
  • Lessen the quantities of drugs used, replace them by other less toxic ones, or substitute techniques and processes with less hazardous ones when possible 
  • Test cytotoxicity and keep a record of information on toxicity 
Image 2. Pharma isolator for handling cytotoxic compounds.

All things considered, it is unfeasible to eliminate all the risks posed by the use of cytotoxic drugs and related waste in the medical environment. However, the health risks of hazardous drugs can be reduced substantially by following safety recommendations, implementing appropriate control measures, handling cytotoxic drugs carefully, taking precautions, and preventing exposure to the extent possible. 

Current and Future Market of Cytotoxic Drugs

Nowadays, cancer continues to be a serious threat to human life and health across the world. In fact, the significant increase in the number of cancer diagnoses in recent years has clearly become a matter of the utmost concern. 

As an illustration, according to the National Cancer Institute, 18.1 million new cases of cancer were diagnosed in 2018, a number that is expected to rise to 29.5 by 2040. In addition, the global cancer mortality rate is estimated to increase from 9.5 million to 16.4 million cancer-related deaths over the same period. [7] 

In the United States alone, the numbers of new cancer cases and cancer deaths in 2021 were 1.9 million and 608,570, respectively. Although more and more cancer patients are responding well to medications, the report of new cancer cases per year suggests that the amount of new cancer cases will continue to grow in the near future. 

Figure 1. SOURCE: American Cancer Society
Figure 1. SOURCE: American Cancer Society

In light of this reality, many pharmaceutical companies have evinced their interest in producing new drugs and therapies to combat cancer. This tendency is evidenced by the great amounts of time, money, and effort invested in clinical research and new drug development. On these grounds, the market for cancer drugs has proliferated worldwide. 

Beyond doubt, the rapid and ever-increasing development of active cytotoxic and biological agents is having a tangible impact in the medical sphere. Bearing this in mind, the expectation is that the quantity of cancers successfully treated and cured using these products will continue to expand.

CDMO Clinical: A Partner for Cytotoxic Drug Development

Are you a biotechnology or pharmaceutical company involved in the development of cytotoxic drugs? CDMO Clinical provides cytotoxic compound development and manufacturing services in the context of phase I-III clinical trials. We facilitate drug manufacturing capabilities in the United States and Europe, according to the needs of our clients.

If you need drug product manufacturing services, please contact us at info@cdmoclinical.com 

References: 

  1. Online Etymology Dictionary. [Accessed 11 February 2022] https://www.etymonline.com/
  2. American Cancer Society. 2014. “History of Cancer Treatments: Surgery.” In The History of Cancer. [Accessed 15 February 2022] https://www.cancer.org/cancer/cancer-basics/history-of-cancer/cancer-treatment-surgery.html
  3. —. 2018. “Understanding What Cancer Is: Ancient Times to Present.” In The History of Cancer. [Accessed 15 February 2022] https://www.cancer.org/cancer/cancer-basics/history-of-cancer/what-is-cancer.html
  4. DeVita Jr., Vincent T. and Edward Chu. 2008. “A History of Cancer Chemotherapy.” Cancer Research 68: (21). Yale Cancer Center, Yale University School of Medicine, New Haven Connecticut.                                             DOI: 10.1158/0008-5472.CAN-07-6611
  5. American Cancer Society. 2014. “History of Cancer Treatments: Chemotherapy.” In The History of Cancer. [Accessed 15 February 2022] https://www.cancer.org/cancer/cancer-basics/history-of-cancer/cancer-treatment-chemo.html
  6. Queensland Government. 2017. “Guide for Handling Cytotoxic Drugs and Related Waste.” [Accessed 22 February 2022] https://www.worksafe.qld.gov.au/__data/assets/pdf_file/0024/22884/guide-handling-cytoxic-drugs-related-waste.pdf
  7. National Cancer Institute. 2020. “Cancer Statistics.” [Accessed 22 February 2022] https://www.cancer.gov/about-cancer/understanding/statistics 

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