Chemotherapy: Agents, Pharmacology, Goals & Advances

Different types of chemotherapy drugs

Chemotherapeutic agents can be divided into several groups based on such factors as their mechanism of action, their chemical structure, and their relationship to another drug. Because some drugs act in more than one way, they may belong to more than one group. Knowing how the drugs work is important in predicting there adverse/side effects, when to use each drug and the best combination therapy to use.

Goal of Chemotherapy

There are 3 possible goals for chemotherapy treatment:

1. cure,
2. control and
3. palliation.

Chemotherapy treatment can be used alone, as adjuvant therapy or as neoadjuvant therapy.  These agents target rapidly dividing cells including those of the bone marrow/blood, cells of hair follicles, cells lining the digestive tract, cells lining the reproductive tract and their damages are responsible for most of the adverse effects associated with them.

Pharmacology of the different chemotherapeutic agents and other drugs

1. Alkylating agents

Alkylating agents directly damage DNA to prevent the cancer cell from reproducing. They are not phase-specific; i.e. they work in all phases of the cell cycle. Alkylating agents are used to treat many different cancers, including leukemia, lymphoma, multiple myeloma, and sarcoma, as well as cancers of the lung, breast, and ovary.
Because these drugs damage DNA, they can cause long-term damage to the bone marrow and in rare cases, lead to acute leukemia. The risk of leukemia from alkylating agents is “dose-dependent. The risk of leukemia after getting alkylating agents is highest about 5 to 10 years after treatment.
The different groups of alkylating agents include:

1. Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan
2. Nitrosoureas: which include streptozocin, carmustine (BCNU), and lomustine
3. Alkyl sulfonates: busulfan
4. Triazines: dacarbazine (DTIC) and temozolomide (Temodar®)
5. Ethylenimines: thiotepa and altretamine (hexamethylmelamine)

The platinum drugs (cisplatin, carboplatin, and oxalaplatin) are sometimes grouped with alkylating agents because they kill cells in a similar way. These drugs are less likely than the alkylating agents to cause leukemia later on.
Major side effects include alopecia, nausea and vomiting, myelosuppression, hemorrhagic cystitis

2. Antimetabolites

Antimetabolites are a class of drugs that interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. These agents damage cells during the S phase. They are commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract (colorectal), as well as other types of cancer.
Examples of antimetabolites include:

1. 5-fluorouracil (5-FU)
2. 6-mercaptopurine (6-MP)
3. Capecitabine (Xeloda®)
4. Cladribine
5. Clofarabine
6. Cytarabine (Ara-C®)
7. Floxuridine
8. Fludarabine
9. Gemcitabine (Gemzar®)
10. Hydroxyurea
11. Methotrexate
12. Pemetrexed (Alimta®)
13. Pentostatin
14. Thioguanine

Major side effects include; mucosal ulceration, bone marrow suppression, alopecia, diarrhea and vomiting, hyper pigmentation e.t.c

3. Anti-tumor antibiotics

A. Anthracyclines

Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. A major consideration when giving these drugs is that they can permanently damage the heart if given in high doses. For this reason, lifetime dose limits are often placed on these drugs.
Examples of anthracyclines include:

1. Daunorubicin
2. Doxorubicin (Adriamycin®)
3. Epirubicin
4. Idarubicin

Other anti-tumor antibiotics

Anti-tumor antibiotics that are not anthracyclines include: Actinomycin-D, Bleomycin, Mitomycin-C
Mitoxantrone is an anti-tumor antibiotic that is similar to doxorubicin in many ways, including the potential for cardiotoxicity. This drug also acts as a topoisomerase II inhibitor, and can lead to treatment-related leukemia. Mitoxantrone is used to treat prostate cancer, breast cancer, lymphoma, and leukemia.

4. Topoisomerase inhibitors

These drugs interfere with enzymes, topoisomerases, which help separate the strands of DNA so they can be copied. They are used to treat certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers.
Examples of topoisomerase I inhibitors include topotecan and irinotecan (CPT-11).
Examples of topoisomerase II inhibitors include etoposide (VP-16) and teniposide, Mitoxantrone.
Treatment with topoisomerase II inhibitors increases the risk of a second cancer; acute myelogenous leukemia (AML). With this type of drug, a secondary leukemia can be seen as early as 2 to 3 years after the drug is given.
5. Mitotic inhibitors
Mitotic inhibitors are often plant alkaloids and other compounds derived from natural products. They can stop mitosis or inhibit enzymes from making proteins needed for cell reproduction.
These drugs work during the M phase of the cell cycle but can damage cells in all phases. They are used to treat many different types of cancer including breast, lung, myelomas, lymphomas, and leukemias. These drugs are known for their potential to cause peripheral nerve damage, which can be a dose-limiting side effect.  Other adverse effects include alopecia, myelosuppression, ileus.
Examples of mitotic inhibitors include:

• Taxanes: paclitaxel (Taxol®) and docetaxel (Taxotere®)
• Epothilones: ixabepilone (Ixempra®)
• Vinca alkaloids: vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®)
• Estramustine (Emcyt®)

6. Corticosteroids

Steroids are natural hormones and hormone-like drugs that are useful in treating some types of cancer (lymphoma, leukemias, and multiple myeloma), as well as other illnesses. When these drugs are used to kill cancer cells or slow their growth, they are considered chemotherapy drugs.
Corticosteroids are also commonly used as anti-emetics to help prevent nausea and vomiting caused by chemotherapy. They are used before chemotherapy to help prevent severe allergic reactions (hypersensitivity reactions), too. When a corticosteroid is used to prevent vomiting or allergic reactions, it’s not considered chemotherapy.
Examples include prednisone, methylprednisolone, and dexamethasone.
Major adverse effects are adrenal suppression, lethargy, visual burning, drowsiness, ataxia, and rash.

7. Miscellaneous chemotherapy drugs

Some chemotherapy drugs act in slightly different ways and do not fit well into any of the other categories.
Examples include drugs like L-asparaginase, which is an enzyme, and the proteasome inhibitor bortezomib (Velcade®).

Other types of cancer drugs

Other drugs and biological treatments are used to treat cancer, but are not usually considered chemotherapy. While chemotherapy drugs take advantage of the fact that cancer cells divide rapidly, these other drugs target different properties that set cancer cells apart from normal cells. They often have less serious side effects than those commonly caused by chemotherapy drugs because they are targeted to work mainly on cancer cells, not normal, healthy cells. Many are used along with chemotherapeutic agents.

Targeted therapies

These drugs attack cancer cells more specifically. Most attack cells with mutant versions of certain genes, or cells that express too many copies of a particular gene. These drugs can be used as part of the main treatment, or they may be used after treatment to maintain remission or decrease the chances of recurrence.
Examples of targeted therapies include imatinib (Gleevec®), gefitinib (Iressa®), sunitinib (Sutent®) and bortezomib (Velcade®).

Differentiating agents

These drugs act on the cancer cells to make them mature into normal cells. Examples include the retinoids, tretinoin (ATRA or Atralin®) and bexarotene (Targretin®), as well as arsenic trioxide (Arsenox®).

Hormone therapy

Drugs in this category are sex hormones, or hormone-like drugs, that change the action or production of female or male hormones. They are used to slow the growth of breast, prostate, and endometrial (uterine) cancers, which normally grow in response to natural hormones in the body. These cancer treatment hormones do not work in the same ways as standard chemotherapy drugs, but rather by preventing the cancer cell from using the hormone it needs to grow, or by preventing the body from making the hormones.
Examples include:

1. The anti-estrogens: fulvestrant (Faslodex®), tamoxifen, and toremifene (Fareston®)
2. Aromatase inhibitors: anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®)
3. Progestins: megestrol acetate (Megace®)
4. Estrogens: diethylstilbestrol, ethinylestradiol
5. Anti-androgens: bicalutamide (Casodex®), flutamide (Eulexin®), and nilutamide (Nilandron®)
6. Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH) agonists or analogs: leuprolide (Lupron®) and goserelin (Zoladex®)
7. Dutastaride (AVODART) selective inhibitor of type 1&2 isoforms of steroid 5 alpha reductase, an intracellular enzyme that converts testosterone to dihydro testosterone

Immunotherapy

Some drugs are given to people with cancer to stimulate their natural immune systems to recognize and attack cancer cells. These drugs offer a unique method of treatment. Immunotherapy is still fairly new.
There are different types of immunotherapy. Active immunotherapies stimulate the body’s own immune system to fight the disease. Passive immunotherapies do not rely on the body to attack the disease; instead, they use immune system components (such as antibodies) created outside the body.
Types of immunotherapies and some examples includ:

• Monoclonal antibody therapy (passive immunotherapies), such as rituximab (Rituxan®) and alemtuzumab (Campath®)
• Non-specific immunotherapies and adjuvants (other substances or cells that boost the immune response), such as BCG, interleukin-2 (IL-2), and interferon-alfa
• Immunomodulating drugs, for instance, thalidomide and lenalidomide (Revlimid®)
• Cancer vaccines (active specific immunotherapies). In 2010, the FDA approved the first vaccine to treat cancer (the Provenge® vaccine for advanced prostate cancer);
• Two cervical cancer vaccines have Food and Drug Administration (FDA) approval in the U.S. — Gardasil, for girls and boys, and Cervarix, for girls only. Other vaccines for many different types of cancer are being studied.

Some advances made in chemotherapy application

• Development of liposomal therapy.  It uses chemotherapy drugs that have been packaged inside liposomes (synthetic fat globules). The liposome helps the drug penetrate the cancer cells more selectively and decreases possible side effects (such as hair loss and nausea and vomiting). Examples of liposomal medicines already being used are Doxil® (the encapsulated form of doxorubicin) and DaunoXome® (the encapsulated form of daunorubicin).
• Chemoprotective agents are being developed to protect against specific side effects of certain chemotherapy drugs. For example, dexrazoxane (Zinecard) helps prevent heart damage, amifostine (Ethyol) helps protect the kidneys, and mesna protects the bladder.
• Some new agents may be given along with chemotherapy to help overcome drug resistance. Cancer cells often become resistant to chemotherapy by developing the ability to pump the drugs out of the cells (efflux mechanism). These new agents inactivate the pumps, and allow the chemotherapy to remain in the cancer cells longer, which might make it more effective.

Resistance to chemotherapeutic drugs

This is a major challenge to successful treatment of neoplastic disease and the underlying mechanisms may involve the followings:

1. Pharmacokinetic changes which may include poor drug absorption and delivery as well as variability in drug transport, activation and clearance.
2. Molecular changes that involves mutations, amplification and deletions in molecular drug targets.

Cell cycle/mechanisms of action

Tumor cells undergo proliferation through the cell cycle stages that are sites of drug action. However, some drugs are not cycle specific. The phases of the cycles with examples of drugs are:

1. G1 phase. This phase of cell cycle precedes the synthesis of DNA.
2. S phase is a stage of DNA synthesis. Examples of drugs that act at this phase are methotrexate and 6-mercaptopurine.
3. G2 phase. This is a phase after DNA synthesis.
4. Mitotic phase. This is the phase where a cell divides into two daughter cells. Examples of drugs are Vincristine and Vinblastine. They inhibit the formation of functional mitotic spindle during cell mitosis which is a vulnerable phase for cell cycle.
5. G0 phase. This phase is one that is not active and takes time.

There are agents that do not have specific cell cycle site of action including alkylating agents, nitrosoureas, dacarbazine, procarbazine, cisplatin and anti-tumor antibiotics. 
Its notable that at each phase, there are specific proteins that monitor the integrity of DNA which if detected as damaged will initiate repair processes and or directs apoptosis. Also, certain proteins are activated at each phase of the cell cycle. For example, activation of specific cyclin-dependent kinases (CDKs) couples with the corresponding protein, cyclins. CDKs have profound influence on the relentless tumor cell proliferation. This proliferative impact of CDKs can be weakened by inhibitory proteins. Changes in tumor cell cycle regulation cause relentless cell proliferation. Such changes may be:

1. Mutations 
2. Loss of inhibitory proteins
3. Enhanced cyclin or CDK activity

Modalities of cancer therapy

The three basic modalities are:

1. Chemotherapy
2. Surgery
3. Irradiation 

Some of the patient’s factors that affect the achievement of optimum therapeutic goals are:

1. Renal and hepatic function
2. Bone marrow reserve
3. General performance status
4. Comorbidity 
5. Tumor history
6. Willingness to undergo treatment
7. Physical and emotional tolerance for side effects

Safety precautions

Many chemotherapy drugs are considered hazardous to healthy people. It takes about 48 hours for the body to break down and/or get rid of most chemo drugs. Most of these come out in the body fluids; urine, stool, tears, saliva, and vomit. The drugs are also found in the blood. When these drugs leave the body as waste, they can harm or irritate the skin, even other people’s skin.
Chemotherapy drugs can be dangerous to others in these ways:

1. They can cause abnormal changes in DNA. (They are mutagenic.)
2. They may be able to alter development of a fetus or embryo, leading to birth defects. (They are teratogenic.)
3. They may be able to cause another type of cancer. (They are carcinogenic.)
4. Some may cause skin irritation or damage.

Therefore;
The nurses and doctors who give chemotherapy should take precautions to avoid direct contact with the drugs while giving them to the patients.
Special gloves, goggles, and gowns should be worn by healthcare professionals when preparing and giving chemotherapy.
Pharmacists or nurses should prepare the drugs in areas with special ventilation systems to avoid spattering or inhaling the droplets that can form while mixing. Care givers and health care professionals should be careful while handling the patients’ urine and stool for a few days after treatment.
Special procedures are used to dispose of materials that were used to mix and give the drugs. There are separate plastic containers to dispose of sharp items, syringes, IV tubing, and medicine bags. Gowns and gloves are disposed of in special bags. If there are any visible leaks or spills, special precautions are used to clean up the drugs.
Toilets can be a hazard for children and pets and the patient should flush the toilet twice after use. Put the lid down before flushing to avoid splashing. If possible, use a separate toilet during therapy.  Both men and women should sit on the toilet to use it. This cuts down on splashing.
Proper hand washing hygiene to be maintained by caregivers and patients after using the toilet, cleaning vomits e.t.c
Drugs might also be found in saliva, so avoid deep kissing and sharing of food or drinks with others. Clean flatware and dishes thoroughly with soap and warm water and rinse well before washing a second time with the other dishes.  Any clothes or sheets that have body fluids on them should be washed in the patients washing machine not by hand. Wash them twice in hot water with regular laundry detergent. Do not wash them with other clothes. If they cannot be washed right away seal them in a plastic bag.
Throw-away adult diapers, underwear, or sanitary pads, should be sealed in plastic and thrown away with patients regular trash