The current arsenal of chemotherapy drugs consists primarily of cytotoxic agents, targeted therapy drugs, sex hormones, and immunostimulants. Each are discussed briefly below. The actions of some cytotoxic drugs are cell-cycle specific, and so we start with a quick review of cell division.
Most cells in adults do not divide frequently. Cell division is only necessary to repair wounds or in a few tissues that have unusually high turnover or replication rates. These tissues include the intestinal lining, bone marrow, and hair follicles. The intestinal lining protects the gut, and the bone marrow produces several cells, including red blood cells and white blood cells (immune cells).
When cells do need to divide, they do so in a tightly regulated process called the cell cycle. Once a cell enters the cycle, it takes about 24 hours to complete division, depending on cell type. Cells of some tissues take much longer than others. The cell cycle, which is illustrated in Figure 1↓, can be broken down into five phases:
- G1: The G1 (gap) phase begins when the cell is first stimulated to proliferate. During G1 cell contents other than the DNA are duplicated and the volume of the cell increases. At about 8-10 hours into G1, the cell crosses a restriction point, or a point-of-no-return. If the cell senses that it is capable of division, it passes this point and then cannot stop the replication process.
- S: The S phase is where DNA synthesis takes place. Many cell-cycle-specific drugs act only on cells that are in the S phase. These drugs interfere with DNA synthesis in some way.
- G2: During the G2 (gap) phase, the cell arranges chromosomes for later division (mitosis). At the G2/M checkpoint, a cell either continues with mitosis or, if DNA was not synthesized properly, it undergoes apoptosis (programmed cell death). It is better for the body if a damaged cell dies rather than having it pass on altered DNA to daughter cells. Cancer cells learn to ignore or override the suicide program, and therefore can divide even with malformed DNA.
- Mitosis: The cell physically divides in a process called mitosis. A copy of the DNA from the parent is passed along to the daughter cells.
- G0: Following mitosis, the cell can enter the G0 (resting) phase, which is outside the cell cycle proper. In G0 the cell is not actively proliferating. Cells can spend long periods in G0 before they reenter the cell cycle in G1. Cell-cycle-specific drugs cannot kill cancer cells that are in the resting phase. Typically, cells in G0 are termed quiescent.
1 Cytotoxic drugs
Cytotoxic drugs inhibit the proliferation of cancer cells, usually by interfering directly or indirectly with DNA replication. Most of these drugs were developed during the period 1950 to 1990. They target cells that proliferate frequently, but in so doing can affect normal cells that also proliferate frequently. These include bone marrow cells, cells of the gut lining, and hair follicles, as discussed above. Damage to these cells leads to the common side effects of immune suppression, nausea, and hair loss.
It is common to administer cytotoxic drugs in combinations, or cocktails, containing two to five drugs. Such combinations are generally more effective than single drugs. Note that drugs used in combination chemotherapy were first approved by the US FDA as single agent therapies. It is only after they were approved that researchers examined their effects in combinations. This is in contrast to the potentially more effective approach of designing combinations in the early (preclinical) phase of drug development, as New Earth BioMed is attempting to do. Designing combinations in the preclinical phase allows greater flexibility in choosing components, which can allow greater control of the biologic effects. Note that a large majority of approved cytotoxic drugs (~77 percent) derive either directly or indirectly from natural compounds.
There are several ways to categorize cytotoxic drugs, for example by their chemical structure, method of action, or source. Common categories include alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, corticosteroids, and differentiating agents. All are discussed below.
1.1 Alkylating agents
Alkylating agents directly damage DNA, thereby preventing cell division. For example, some can insert themselves into the DNA double helix, thereby providing a physical block to the replication of DNA. Alkylating agents may be further categorized into cell-cycle-specific and non-cell-cycle-specific drugs. As their title implies, cell-cycle-specific drugs only act during a specific phase of the cell cycle. Alkylating agents include mechlorethamine, cyclophosphamide, melphalan, carmustine, busulfan, dacarbazine, and thiotepa. The platinum drugs (cisplatin, carboplatin, and oxaliplatin) are sometimes grouped with alkylating agents.
1.2 Antimetabolites
Antimetabolites interfere with DNA and RNA synthesis by causing malformed nucleotides, the building-blocks for DNA and RNA. These agents damage cells during the S phase. Examples of antimetabolites include 5-fluorouracil, 6-mercaptopurine, methotrexate, gemcitabine, and cytarabine.
1.3 Anti-tumor antibiotics
One class of anti-tumor antibiotics is called anthracyclines. These interfere with enzymes involved in DNA replication and are not cell-cycle-specific. Heart toxicity is a common adverse effect. Examples include daunorubicin, doxorubicin, bleomycin, and mitomycin-C. The drug mitoxantrone is an anti-tumor antibiotic, but also works by inhibiting the enzyme topoisomerase II, which is used during DNA unwinding (DNA must be unwound prior to replication).
1.4 Topoisomerase inhibitors
As just mentioned, DNA must be unwound prior to replication. Several drugs inhibit the enzymes (topoisomerase I and II) that perform this function. Mitoxantrone has already been mentioned. Other topoisomerase II inhibitors include etoposide and teniposide. Topoisomerase I inhibitors include topotecan and irinotecan.
1.5 Mitotic inhibitors
Many of the mitotic inhibitors derive from plant alkaloids. As their name implies, they interfere with the mitosis phase of the cell cycle. They can also have effects in other phases. A common adverse effect is peripheral nerve damage. Mitotic inhibitors include taxanes such as paclitaxel and docetaxel, and also vinca alkaloids such as vinblastine and vincristine.
1.6 Corticosteroids
Certain steroids (hormones and hormone-like drugs) can be used to inhibit some types of lymphoma, leukemias, and multiple myeloma. Example steroids include prednisone and methylprednisolone.
1.7 Differentiating agents
The last category of cytotoxic drugs to be discussed is differentiating agents. While not formal cytotoxics, differentiating agents cause cancer cells to “mature” into cells that are more normal. Many cancer cells have an immature phenotype, which allows them to proliferate frequently. Example differentiating agents include the retinoids and arsenic trioxide.
2 Targeted therapy drugs
Targeted therapy drugs are designed to inhibit a specific protein involved in cancer progression. Target proteins are identified during the drug discovery process as being different in some way in cancer cells versus normal cells.
Only a handful of targeted therapy drugs have been approved so far. These include imatinib, gefitinib, erlotinib, sunitinib, and bortezomib. Imatinib inhibits an enzyme (BCR-ABL protein, a tyrosine kinase) that plays a role in chronic myelogenous leukemia and gastrointestinal stromal tumors. Both gefitinib and erlotinib are epidermal growth factor receptor (EGFR) inhibitors. EGFR is a type of receptor tyrosine kinase (RTK), which are a family of proteins involved in signal transduction. Sunitinib targets multiple RTKs. Bortezomib is a proteasome inhibitor. The proteasome degrades unneeded proteins, and proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of apoptosis (programmed cell death) in cancer cells.
3 Sex hormones
Certain sex hormones, or hormone-like drugs, can be effective against breast, prostate, and some other hormone-dependent cancers. They prevent a cancer cell from using the hormone as a growth factor, or prevent the body from making the hormone. Examples include estrogens, anti-estrogens, tamoxifen, anastrozole, progestins, and leuprolide.
4 Immunotherapy
Immunostimulants can be effective for some types of cancer. They act by stimulating the body’s own immune system or are antibodies or other immune system components made outside of the body. Examples include interleukin-2 (IL-2) and alemtuzumab. IL-2 is an immune system signaling molecule that plays an important role in the body’s response to microbial infection. Alemtuzumab is a humanized monoclonal antibody indicated for the treatment of Chronic lymphocytic leukemia.
