How Does Chemotherapy Work?

Over the past decades, the development of chemotherapy – application of powerful chemical agents to treat cancer – along with advances in surgery and radioactive therapy has resulted in dramatically improved cancer survival. Cancers such as melanoma, blood, breast, prostate, testicular, cervical, and thyroid cancer are now highly curable. However, the treatment of other cancers such as pancreatic cancer and aggressive brain and lung cancers remains challenging.

Chemotherapy studies started in the 1940s when researchers from Yale University decided to test mustard gases (which were used as chemical weapons in World War I) on patients with advanced lymphoma. The results of these studies led to the development of drugs such as chlorambucil that are presently used for cancer treatment.

The goal of chemotherapy is to kill cancer cells or stop their division, thus preventing the growth and spread of cancer into surrounding or distant tissues and organs.

Classification and mechanisms of action

Both malignant and healthy cells undergo a similar division process called a cell cycle, but malignant cells divide at a faster rate compared with normal cells. The cell cycle consists of four phases during which the cell increases in size, synthesizes DNA, prepares to divide, and eventually divides. Most chemotherapy drugs act on dividing cells. Moreover, certain drugs act only at specific cell cycle phases.

Based on the mechanism of action, chemotherapy drugs are classified as follows:

• DNA-binding drugs. These act on dividing cells, regardless of the cycle phase, by chemically changing the DNA or making links between DNA segments. Some examples of DNA-binding drugs are alkylating drugs (such as cyclophosphamide which is used to treat blood, breast, ovarian, and nervous system cancers) and platinum-based agents (such as cisplatin or carboplatin, which are used to treat ovarian, testicular, bladder, and other cancers.
• Antimetabolite. These act on dividing cells in a phase when DNA is synthesized. Antimetabolites mimic DNA building blocks, which results in defective DNA molecules and cell death. Methotrexate is a common antimetabolite that is used to treat blood, breast, lung, and bone cancers. Another example is 5-fluorouracil, which treats skin cancer.
• Antitumor antibiotics. These drugs act on dividing cells in a phase when cells prepare to divide by damaging their DNA. Some examples include bleomycin, which can treat skin, testicular, and blood cancers. Another is actinomycin D that treats muscle, testicular, and ovarian cancers.
• Mitotic spindle agents. These agents act on dividing cells in a phase when cells divide by disrupting tubules that pull chromosomes away from each other. Taxanes are one type of mitotic spindle agent. A common taxane is a paclitaxel, which treats breast, ovarian, and lung cancers. Another is docetaxel which is used to treat breast, head, neck, stomach, prostate, and lung cancers. Another type of taxane is vinca alkaloids, with the most common ones being vincristine, which treats blood, neural, and muscle cancers, and vinblastine which is used to treat blood and testicular cancers.
• Topoisomerase inhibitors. These inhibitors act on dividing cells in the DNA synthesis phase by blocking DNA breaks that are needed to initiate DNA synthesis. This eventually leads to cell death. There are Topoisomerase-1 inhibitors such as topotecan, which treat aggressive lung cancer and some other advanced cancers. There are also Topoisomerase-2 inhibitors such as etoposide are used to treat aggressive lung cancer and doxorubicin can treat many types of cancer.
• Corticosteroids. These hormones act on non-dividing cells by impairing their energy use and promoting “programmed death.” Corticosteroids include prednisolone and dexamethasone, which are both used to treat blood cancers.

A single chemotherapeutic drug is usually insufficient to kill all cancer cells. Therefore, several chemotherapeutic agents with different mechanisms of action are often combined to achieve the maximal effect. This approach also gives someone a better tolerance of chemotherapy as the additive effect on cancer destruction occurs without enhancing toxic potential.

Why might chemotherapy stop working?

Earlier researchers considered that all cancer cells arise from one mutated cell that endlessly divides and results in a tumor. All cells within the tumor were thought to be identical. Later, this hypothesis was proven false and research showed that cancer cells are heterogeneous. Since cancer cells divide frequently, they are prone to different mutations that may lead to the avoidance of immunological mechanisms that fight cancer, resistance to natural death processes, reduced dependence on environmental support, and an increased ability to spread. In this way, mutated cancer cells have a better chance at survival compared to unmutated cancer cells. This process, called clonal evolution, may lead to the development of more aggressive cancer forms and their resistance to drugs.

In addition, cancer cells may specifically gain functions that reduce the effectiveness of chemotherapy drugs. For instance, resistance to multiple chemotherapy drugs is often associated with the development of a structure in cancer cell membranes called p-glycoprotein. This acts as a transporter, which pushes the drugs out of the cancer cell. When drug resistance develops, alternative chemotherapy combinations or novel cancer therapies such as targeted therapy, immunotherapy, or cell therapy are used.

Side effects of chemotherapy

Because most chemotherapy drugs act on dividing cells, they affect not only cancer cells but also normal, fast-dividing cells in the body. Cells of the mouth, digestive tract mucosa, hair follicles, bone marrow, and reproductive system are the most sensitive to these drugs. Their destruction may lead to nausea, diarrhea, mouth ulcerations, hair loss, low levels of blood cells, and infertility. Low levels of blood cells are often associated with fatigue, dizziness, infections, and bleeding. Other side effects of chemotherapy include impaired attention and memory (known as “chemo fog”), heart and bone damage, changes in urination, early menopause, itchy skin, rashes, numbness, tingling, and more. Some side effects subside when chemotherapy ends, but others (such as heart damage) can be long-term. Certain chemotherapy drugs such as antimetabolites, platinum-based drugs, and topoisomerase-2 inhibitors may be associated with the development of secondary blood cancers that develop years after chemotherapy ends.

Many side effects can be adequately managed or prevented. For instance, certain medications effectively reduce nausea, hair loss can be prevented by cooling the scalp, and behavior therapy may reduce fatigue and emotional distress. When someone is undergoing chemotherapy, their long-term health is continuously monitored so doctors can catch changes early on and initiate appropriate treatments. In young women, fertility may be preserved by freezing eggs or ovarian tissue and using them for artificial fertilization in the future.

Even with the serious chemotherapy side effects, it is important to know that each cancer treatment has robust medical evidence from clinical trials. This means the treatments have been tested on thousands of patients and were determined to have the best possible risk-benefit ratio.