An Overview of Oncology Treatments

Chemotherapy is used in conjunction with surgery and radiation therapy to stop cancer cells from dividing uncontrollably. Other conditions that chemotherapy can also treat include bone marrow diseases, in which chemotherapy can prepare the patient for a bone marrow transplant, and hyperactive immune system disorders such as lupus and rheumatoid arthritis.

Successful chemotherapeutic treatment is about balance: distributing a regimen strong enough to defeat the cancer without also defeating the patient. New philosophies for chemotherapy distribution seek to adhere to this idea. For example, metronomic chemotherapy, as seen in Figure 1, requires frequent, regular administration of drug doses. The goal of this strategy is to use a sort of low-intensity warfare, keeping low but active concentrations of drugs in the patient’s system for long periods of time. One reason this is done is in hopes of preserving Quality of life (QoL), which is defined by the World Health Organization as the comparison of a person’s current life in comparison to the life they had thought they would or wish that they do live (“What Is QOL?,” n.d.).

Another factor to consider is that different concentrations and schedules of chemotherapy can affect anti-tumor action. Especially with combination therapy, the effects of chemotherapy on cancer can vary (“Pharmacokinetics of Metronomic Chemotherapy,” n.d.). Generally, standard chemotherapy looks to administer a “maximum tolerated dose”, but this doesn’t address cancer’s nature as a “chronic disease” because versions of cells that can outlast the initial chemotherapy could still persist (Scharovsky et al., 2009). Metronomic chemotherapy requires 2-3 week breaks between successive cycles, and it is administered at very high doses that can often have maladaptive effects and may not be tolerated by some patients. In some models, metronomic chemotherapy can be effective in cancer cells that have resistance to those very chemotherapeutics. (“The Anti-Angiogenic Basis of Metronomic Chemotherapy,” n.d.).

Chemotherapy treatments can also vary in pediatric conditions. Because so many signaling patterns coexist in the child as they grow, receiving chemotherapy can be extremely dangerous because it may affect other biological pathways. Another problem is that children who are on a pediatric oncology ward might not be able to communicate their tolerance of a specific regimen, and their QoL can sink dramatically as a consequence (“Palliative Care in Children with Cancer,” n.d.). Additionally, children are in a state of constant and rapid growth.  Healthcare Providers and cancer scientists need to account for varied biochemical compositions, such as variations in signaling pathways, when designing chemotherapy schedules (“Palliative Care in Children with Cancer,” n.d.).

Advantage and Disadvantages

One of the greatest advantages of chemotherapy is its applicability in the treatment of many different cancer types; the different forms of chemotherapy include curative, adjuvant, neoadjuvant, and palliative. Curative chemotherapy is implemented exclusively or primarily to eliminate all cancer cells. Adjuvant chemotherapy is used to fight hidden cancer cells that could be left in the body after surgery or to prevent future recurrences. Neoadjuvant therapy is effective for treating sizable tumors that cannot be directly operated on; the therapy functions by shrinking the tumor enough to enable treatment via radiation and surgery. Lastly, palliative chemotherapy is used to relieve symptoms or improve the quality of life of the patient for terminal forms of cancer.

Since chemotherapy attacks all rapidly dividing cells, the cytostatics (drugs that target cell growth) can also attack healthy cells, such as red blood cells. This drop in red blood cell count can weaken the immune system, causing a variety of short-term side effects. Hair loss, anemia, nausea, vomiting, diarrhea, and infections in the mouth are all common side effects that can occur as a result of chemotherapy treatment. However, these side effects can be prevented or relieved through other treatments. For example, blood transfusions can help ease the effects of anemia, anti-nausea drugs can relieve nausea and vomiting, and infection can be prevented with antibiotics or antifungal drugs. The long-term side effects of chemotherapy often emerge months or years after treatment, and these effects can depend on the type of chemotherapy treatment that the patient received. Damage to lung tissue, heart problems, infertility, nerve damage, and recurrence are all possible long-term effects that can threaten the patient’s health.

Alkylating Agents

One of the first types of chemotherapy drugs to be developed historically were the so-called alkylating agents. Derived from mustard gas—a toxic gas first used in World War I as an agent of chemical warfare—alkylating agents were introduced as chemotherapeutic agents in 1946 (Brookes, 1990). Early studies of these compounds found that they were incredibly effective against a wide variety of cancers, particularly lymphomas; however, they were often non-specific and could cause tremendous side effects if given in high doses (Brookes, 1990). Ultimately, further study produced much more useful compounds, such as cyclophosphamide and busulfan, which continue to be used as chemotherapeutic agents today (Colvin, 2003).

Alkylating agents, which are typically composed of electron-rich substituents, act by forming covalent bonds with DNA. Most alkylating agents work by transferring an alkyl group—a chemical substituent made entirely of carbons and hydrogens—to a DNA molecule (Prendergast & Jaffee, 2007). This inhibits the transcription of a cancer cell’s DNA to its corresponding RNA, thereby inhibiting its translation to the proteins that it requires to grow and replicate. The effectiveness of alkylating agents is mediated by the ability of the cell to recognize and repair the DNA damage they cause (Prendergast and Jaffee, 2007).

In modern treatment, there are two main classes of alkylating agents. Classical alkylating agents, like cyclophosphamide and melphalan, attach a methyl group —a central carbon with three connected hydrogen atoms —directly to DNA (Colvin, 2003). Typically, these agents are not bioactive until introduced in the body; from here, they can decompose into reactive groups like chloroethylaziridine that alkylate DNA. Classical agents have been used to treat multiple myeloma, ovarian cancer, and breast cancer (Colvin, 2003). The other common type of alkylating agents are the “alkylating-like” agents. These complexes, which do not actually affix an alkyl group to DNA, still operate in the same way, with platinum metal complexes coordinating to DNA and hindering its ability to be transcribed (Colvin, 2003). Examples of these compounds include cisplatin (used against testicular cancer) and its less cytotoxic variant, carboplatin (Colvin, 2003). 

Mitotic agents  

For a long time, anti-mitotic agents have been used to fight cancer, as they target the crux of the disease: abnormal mitosis or cell division. There are different checkpoints in the process of mitosis to prevent abnormally formed cells from multiplying. Some of these checkpoints fix the issue present in the premature cell, by slowing down the cell cycle and stopping the cell from proliferating into a tumor, while other checkpoints initiate cell death to prevent abnormal cells from proliferating.

Microtubule-targeting agents (MTAs) are common antimitotic agents and function by targeting kinase pathways. MTAs trigger the spindle assembly checkpoint (SAC) to hold the cells in a static, non-dividing state, so as to ensure that chromosomes segregate correctly and that mitosis creates identical daughter cells (Dominguez-Brauer et al., 2015). MTAs also work to inactivate the dynamics of microtubules so that cell death eventually occurs. MTAs are relatively effective in preventing the metastasis (spreading) of some cancers; however, they can also cause harmful side effects, and can result in toxicity and cancer resistance to the drug.

Anti-kinase agents are a class of drugs that target entry and mitotic kinases. Entry kinases are responsible for leading cells into the mitotic phase of the cell cycle. The Cdk1 kinase, for example, is part of a complex that initiates mitosis, so when it is inhibited by a drug, it causes the cell to die. The theory that Cdk1 kinase would be a good cancer treatment has not held up in clinical trials, however, as the drug has proven to have significant harmful side effects. There are other kinases like Chk1 and Chk2, which are checkpoint kinases, that have been used as drug targets, but these kinases demonstrate negative side effects that outweigh their limited efficacy as well (Dominguez-Brauer et al., 2015).

Anti kinase agents have the ability to act on mitotic agents, but they are of the Aurora kinase and polo-like kinase (Plk) classes. Aurora kinases tend to be overexpressed in many cancers, and consequently scientists have target them using a cocktail of drugs. Plks are also overexpressed in many cancers, and thus specific Plks have been identified as targets for anti-kinase agents. In particular, inhibition of Plk1 and Aurora A kinases has been shown to induce cell death. The various types of Plks and Aurora kinases affect different parts of mitosis. Anti-motor protein agents target kinesins, which are proteins that help the cell transport molecules down microtubules, structures that make up the skeleton and “transportation highway” of the cell. Research suggests that the drug Monastrol was able to effectively inhibit the mitotic kinesin, Eg5, firmly preventing cancerous cells from progressing in the process of mitosis. This finding has encouraged scientists to explore kinesins further as drug targets. While drugs like Monastrol have proven to show no toxicity to cells and are associated with minimal drug resistance, the cancer finds another path through which to proliferate, they have not yet been tested extensively in clinical drug trials (Chan et al., 2012).

Antitumor Antibiotics

Antitumor antibiotics, also known as anticancer antibiotics and antineoplastic antibiotics, are a class of anticancer drugs that block cell growth by interfering with DNA. Three DNA-damaging metabolite families are considered antitumor antibiotics: Enediynes, Mitomycin, and Bleomycin (Galm et al, 2005). In 1985, enediynes were the first class of antitumor antibiotics to be discovered. These antibiotics are derived from bacterial sources and work by self-activating, they activate when they enter a certain chemical environment, three functional domains allow them to cause DNA damage. The first domain is a “warhead” which “explodes” when activated and damages DNA. The second is a delivery system that can deliver this “warhead” to its target. The third is an activation device that is specifically triggered and then itself triggers a cascade that leads to activation of the warhead. Using these three mechanisms, the antibiotic molecules can enter and damage cancer cell DNA (Nicolaou & Dai, 1991).

Mitomycins are a class of antitumor antibiotics that have been researched for their DNA damaging abilities for over 30 years. In particular, one subtype of the mitomycin family, mitomycin C (MMC), has been widely investigated in the context of cancer therapy. MMC works by inhibiting the synthesis of DNA. Because cancer cells replicate DNA and divide at a much faster rate than healthy cells, they are therefore more vulnerable to this treatment. Oxidized MCC is inactive and can be activated by enzymatic reduction. Once active, MCC binds DNA with either mono- or bi- functional alkylation, or the addition of a carbon group. When DNA is bifunctionally alkylated, it is crosslinked to MCC and cannot be used for replication, leading to eventual death of the affected cell (Verweij & Pinedo, 1990).

Bleomycin antitumor antibiotics, another type of antibiotic, produce double-strand breaks in DNA at specific sites. These breaks are likely a result of two independent single-strand breaks at nearby sites on opposite strands of the DNA. Bleomycin antibiotics generally cleave DNA at GC and GT sequences, and occasionally at AT sites. This cleavage activity is also enhanced by reagents like 2-mercaptoethanol and ferrous ions. Ferrous ions are actually such a potent supplement that in their presence bleomycin cleaves DNA at TT, AT, and TA, as well as at GC and GT sequences (D’Andrea & Haseltine, 1978).

Finally, anthracyclines are a modern class of antitumor antibiotics that are widely used as a chemotherapy treatment. Anthracyclines are extracted from Streptomyces bacteria, and they interfere with enzymes involved in DNA replication during all phases of the cell cycle. They are widely prescribed for a variety of cancers and include common chemotherapy drugs such as Daunorubicin, Doxorubicin (Adriamycin®), Epirubicin, and Idarubicin (Longdom Publishing, 2021).

Overall, antitumor antibiotics are effective in their treatment of cancer. The drugs are delivered to the body intravenously and then enter cells, damaging DNA and therefore killing cancer cells. There are some concerns with this method as the DNA damaging abilities of the antibiotics can also damage healthy cells, specifically increasing the risks of permanent heart and bone marrow damage. To combat these risks, many of the treatments are only allowed at maximum time intervals. For example, MCC is only given every six weeks, and dosages are carefully controlled (Longdom Publishing, 2021).

Topoisomerase inhibitors

Topoisomerases inhibitors are a class of chemotherapy that targets the function of Topoisomerase enzymes. Topoisomerase enzymes are responsible for controlling, maintaining and modifying the topology of DNA during replication and transcription. Topoisomerases are separated into two classes of enzymes: I and II. While many of their functions are the same there are a few key differences: Topoisomerase I (Topo I) is not a cell cycle specific enzyme whereas Topoisomerase II (Topo II) is highest in log phase, a phase of the cell cycle where cell growth is defined by a logarithmic curve, and replicating tumors. Topo I only induces single stranded breaks whereas Topo II induces both single and double stranded breaks (Sinha, 1995). The fact that Topo-II is a cell cycle dependent enzyme makes Topo-II inhibitors less desirable as an anti-cancer therapy. But Topo-I inhibitors have proven successful.

Topoisomerase I Inhibitors were first discovered in extracts from the plant species Camptotheca accuminata, which had significant anti-tumor activity in leukemia. Later, camptothecin was discovered to be the active agent in this extract. In order to use camptothecin in clinical trials, a more water soluble analog was synthesized: NSC-603071 (9-Aminocamptothecin). NSC-603071 successfully bound and acted on Topo I and initiated DNA damage and cell death in human trials. One drawback of this drug is that in higher doses it can lead to bone marrow and gastrointestinal toxicity, but this has been managed with dose regulations. Topotecan is another Topo I inhibitor that has been shown to be effective against a variety of cancers including refractory colorectal cancer, cancers of the head and neck, and malignant glioma. But its wide use also leads to a significant chance of hematological toxicity in the patients who take it. Finally, Irinotecan is another Topo I inhibitor that is another water-soluble camptothecin analogue that has shown significantly better activity against a wide range of cancers such as colon, breast, and small cell lung cancer as well as leukemia (Sinha, 1995).

Plant-Based Alkaloids

Alkaloids are a broad class of nitrogen-containing organic compounds found in nature. Typically produced by plants but also present in some microorganisms and animals, alkaloids are biologically-active compounds – some of which contain antitumor properties (“Alkaloids,” 2014). Plant-based alkaloids are often used as chemotherapeutic agents that prevent tumor growth by inhibiting cell division (“Types of Chemotherapy Drugs,” n.d.).

There are many different types of plant-based alkaloid drugs that act at different stages of the cell cycle; however, many are most effective during the S and M phases, during which DNA is replicated and cell division occurs, respectively (“Types of Chemotherapy Drugs,” n.d.). Three classes of mitotically-active alkaloids commonly used in chemotherapy are the vinca alkaloids, the epipodophyllotoxins, and the taxanes, which famously include paclitaxel (sold under the brand-name Taxol) (“Plant Alkaloids,” 2014). Although all of these drugs target steps of cell division, they are derived from different plants and have different mechanisms of action. For instance, Taxol binds to microtubules during mitosis, stabilizing the structures and preventing further spindle fiber formation (“Plant Alkaloids,” 2014). Without functional spindle fibers, the cell cannot equally divide chromosomes into two daughter cells and cell division halts. On the other hand, epipodophyllotoxins, such as the drug etoposide, prevent entry into M phase, the phase of the cell cycle where mitosis or cell division occurs, altogether by inducing DNA damage and inhibiting topoisomerase II during S phase, the cell cycle when the DNA is replicated (“Etoposide,” n.d.).

Plant-based alkaloids include a vast array of compounds which are instrumental in treating cancer. As such, they are the focus of many synthetic organic chemistry labs, which aim to design synthetic routes to mass-produce these compounds rather than harvesting them from plants. Exciting research in this field, from the discovery of new alkaloids to the development of new methods to synthesize them, is critical in the fight against cancer.

Immunotherapy

Overview

Immunotherapy is a cancer treatment that makes use of the immune system. These therapies can either boost the natural defense mechanisms of the immune system, enabling it to attack cancer cells more aggressively, or it can supplement these natural defense mechanisms with exogenous components. The immune system is not always able to destroy cancer cells because cancer cells evolve from normal, healthy cells before mutating into cancer cells that divide uncontrollably. Hence, the immune system cannot always recognize cancer cells as foreign cells to attack. Sometimes, the immune system may recognize cancer cells but not respond strongly enough to destroy them. In other cases, cancer cells might release substances that prevent the immune system from recognizing and attacking them. Immunotherapy serves as a means to get around these problems. Depending on the type and stage of the cancer, among other factors, immunotherapy can be used as the sole form of treatment or it can be used in combination with other types of treatment (“How Immunotherapy Is Used to Treat Cancer,” 2019). Many types of immunotherapy exist, including T-cell therapy, monoclonal antibodies, cancer vaccines, and cytokine inhibitors (“Understanding Immunotherapy,” 2020).

One benefit of immunotherapy is that it can supplement other therapies, including chemotherapy, which function better if prescribed in combination with immunotherapy. Furthermore, immunotherapy may be an effective treatment when other treatments fail; some cancers—skin cancer, for example—do not respond well to chemotherapy or radiation. Patients may experience fewer side effects than when undergoing radiation or chemotherapy, because immunotherapies only target one’s own immune system. Additionally, cancer is less likely to recur following immunotherapy, since the immune system has gained an immunological memory for attacking cancer cells (“Immunotherapy: What Patients Need to Know,” 2019).

However, a disadvantage of immunotherapy is that the stimulated immune system can also fight healthy cells (“Immunotherapy to Treat Cancer,” 2019). Patients may feel side effects such as flu-like symptoms, weight gain, or diarrhea, as well as pain, itching or swelling in the region where the medication was applied. Furthermore, immunotherapy may have a longer onset of action than other treatments. It is currently only successful for less than half of patients, and even if immunotherapy works at first, it sometimes loses its effectiveness in the later stages of treatment (“Immunotherapy: What Patients Need to Know,” 2019).

CAR T cells  

The body possesses both innate and adaptive immune response mechanisms to defend against invasion by foreign bodies and the proteins they express, known as antigens, which determine their immunogenicity (ability to induce an immune response). An immune response is usually induced once the antigen’s epitope, the part that the antibody binds, binds with receptors on an immune cell (Dunn et al., 2002). A healthy immune system will regulate and eliminate mutated cells, decreasing the rates of tumorous incidences that arise spontaneously during the cell cycle. This regulation is possible because most of the cancerous cells contain defective or mutated cell receptors that segregate them from normal cells, making them unique and therefore susceptible to attack by lymphocytes, which are a type of immune cell. However, most neoplastic (cancer-related) cells express many of the same receptors as normal cells and are able to avoid lymphocytic binding and killing (Messerschimdt et al., 2016).

When the tumors evade immune action, the role of immune cells is essentially impaired, allowing the cancer cells to proliferate unchecked and eventually metastasize (spread throughout the body). For most cancer therapies, initial remission usually occurs with introduction of chemotherapeutic agents, which induce neoplastic cell death. However, with continual use, the tumors can develop resistance and become unresponsive to both chemotherapies and immunotherapies. With the advent of genetic editing tools, immunologists have been able to engineer antigen specific T cells targeting specific receptors on tumor cells. This new generation of repurposed cell lineages have been termed Chimeric Antigen Receptor T cells (CAR-T).

The process of engineering CAR-T cells involves harvesting T- cells from a patient and genetically modifying them to express a receptor that will bind to a surface antigen expressed on the patient’s own tumor cells. After infusion, CAR-T cells are able to migrate to the tumor and replicate. The earliest CAR-T cells consisted of an extracellular antigen recognition site linked via a transmembrane domain to an intracellular signaling domain. This setup worked to activate the CAR-T cells once they encountered the tumor. While effective in lysing (bursting opne) tumor cells in vitro, the clinical utility of these first-generation CAR-T cells was limited by their inability to sufficiently activate and sustain themselves while in the body. Second generation CAR-T cells, with the addition of costimulatory domains (including CD28) to the intracellular portion, have been engineered to enhance cytokine secretion, a single for inflammation and immune response, and effector cell expansion, and prevent activation-induced apoptosis and immune suppression by tumor-related metabolites (Carpenito et al., 2009; Eshhar et al., 1993).