By Andrea S. Blevins Primeau, PhD, MBA
There are many different types of agents used in the treatment of cancer, and they can generally be classified according to molecule type or their basic mechanism of action. Different cancer types have different types of agents approved for their treatment.
Molecules that prevent the cell cycle from progressing are considered chemotherapy.1 The cell cycle is a process with different phases that cells must progress through in order to eventually divide through mitosis. Cells that are unable to progress through the cell cycle eventually undergo apoptosis, or cell death. Cancer cells have high rates of division; therefore, chemotherapy agents prevent cancer cells from dividing by halting the cell cycle, forcing the cells to undergo apoptosis. Because chemotherapy results in cell death, it is referred to as cytotoxic medication.
There are several different classes of chemotherapy agents in existence, categorized according to their specific mechanism of action. These include alkylating agents, which bind to proteins, DNA, and RNA to impair cell function; antimetabolites, which act as substitutes for normally occurring metabolites used in DNA or RNA; antitumor antibiotics, which integrate with DNA and cause DNA breaks; topoisomerase inhibitors, which prevent DNA replication; and tubulin-binding agents, which prevent microtubules from forming during mitosis.
Chemotherapeutic agents from different classes are often combined together because each class targets a different phase of the cell cycle. Therefore, the combination of several different cytotoxic agents may increase overall efficacy.
The common adverse effects (AEs) associated with chemotherapy are typically a result of their cytotoxic effects against normal, noncancerous cells. However, the types of AEs vary widely between classes, specific agents, doses and dose schedules. AEs can also be patient-specific and can rely on a patient’s specific disease characteristics.
The administration of chemotherapy depends on the specific agent.2 In general, chemotherapy can be given orally, intravenously, subcutaneously by injection, intrathecally (into the space between the brain and spinal cord), intraperitoneally (within the space where the stomach and intestines are located), intra-arterially, or topically.
Small-molecule drugs are agents that are small enough to easily enter their target cells to induce their effects. Most small-molecule drugs used as cancer treatment target specific factors within the cell that are involved in cell proliferation, survival, migration, and angiogenesis, among others.3 Because small-molecule drugs have specific targets, they are frequently referred to as targeted agents. However, other types of drugs, such as monoclonal antibodies, may also be considered targeted agents.
There are many different classes of small-molecule drugs, which are categorized by the factor or process that they inhibit. For example, a major class of small-molecule drugs are tyrosine kinase inhibitors, which are molecules that inhibit proteins (tyrosine kinases) that are inside cells or expressed by cells. A more specific example includes epidermal growth factor receptor (EGFR) inhibitors, which are small-molecule drugs that prevent the EGFR from binding to its ligand, thereby preventing the activity of EGFR.
The AEs associated with small-molecule drugs are typically due to the inhibition of a target when that target is located on normal cells and/or because the inhibitor is not entirely specific to a single target. The specific AEs that can occur vary according to a medication’s mechanism of action, and most AEs are considered to be mild.
The administration of small-molecule drugs is typically through the oral route, making them convenient for most patients.
Monoclonal antibodies (mAbs) are large biologic agents — meaning they are created from living organisms — that are developed in a laboratory and designed specifically to recognize and bind to targets on the outside of cancer cells or in the circulation. By doing so, they either inhibit a receptor and downstream cell signaling, stimulate a function such as apoptosis, or indirectly induce activity of the immune system. Some monoclonal antibodies are considered to be targeted therapies, as they target a specific protein involved in a signaling pathway.3 Examples of this would be trastuzumab, which targets the HER2 receptor, or bevacizumab, which targets the vascular endothelial growth factor (VEGF). Other mAbs induce the immune system to recognize a cancer cell as foreign, thereby prompting cancer cell death, and are referred to as immunotherapy. An example of this would be immune checkpoint inhibitors.
The AEs associated with mAbs depend on their specific mechanisms of action. However, all monoclonal antibodies may cause allergic responses such as an anaphylactoid reaction or an infusion-related reaction. Most AEs are considered to be mild.
Due to their large size and the fact that they consist of molecules that are typically degraded in the acidic environment of the stomach, mAbs are administered intravenously.
Antibody-drug conjugates (ADCs) have a dual mechanism: they home in on a specific target expressed by cancer cells, and once the target is reached, a cytotoxic agent is released and delivered to induce cell death.4 ADCs are able to function in this way because they consist of 3 parts, including a mAb that serves as the homing agent, a small molecule that acts as the cytotoxic agent, and a linker that binds the small molecule to the antibody. Because these agents are targeted to the cancer cells, more potent small molecules can be used with fewer off-target effects than are typically seen with conventional chemotherapy.
The mechanisms of AEs associated with ADCs are not yet well understood, but seem to be primarily related to the mechanism of action of their associated small molecule. Allergic reactions are also possible because ADCs contain antibodies, which are immunomodulatory components. Similar to mAbs, ADCs are typically administered intravenously.
This article was published by Cancer Therapy Advisor.