Did You Ever Wonder How Chemotherapy Drugs Work?

A practical guide for the complementary health care practitioner

James Meschino DC, MS, ROHP
In the training of chiropractors and other complementary and alternative health care practitioners, a general understanding of how physicians decide upon which chemotherapy drugs to use on a particular cancer patient is usually not covered in the academic curriculum. In the course of running a practice certain patients and/or their family members, whom you have known over the years, on occasion develop cancer. In these cases it is not uncommon for them to consult with you regarding nutrition, supplementation and other adjunctive measures that can be considered as part of complementary management of their condition. As such, it is valuable to have a working knowledge of how medical interventions act to help reduce the tumor burden. This article provides a basic overview of the various classes of chemotherapy agents that are commonly used today, along with the mechanism of action through which they kill cancer cells or interrupt their growth.

The Cell Cycle
As many chemotherapy drugs exert their effects at specific points in the life cycle of the cell, a quick review of the cell cycle is in order.

The normal cell cycle consists of the following sequential stages:

G0 Phase – resting diploid cells that are not dividing

G1 Phase – cells that have recently divided and are committed to continued proliferation

S Phase – follows G1 phase whereby cells undergo DNA synthesis

G2 Phase – premitotic rest interval (check point to see if DNA has properly reproduced itself)

M Phase – mitotic phase, chromosome condensation with cell division

Of interest is the fact that solid malignant tumors contain the following three types of cells:

1. Cells that are not dividing and are terminally differentiated
2. Cells that continue to proliferate
3. Non-dividing cells that are currently quiescent but may be recruited into cell cycle

Large tumors harbor more non-proliferating cells, which potentially make them more resistant to agents that selectively target dividing cells

Combination Chemotherapy
Many oncologists use a combination of chemotherapy drugs concurrently in the treatment of most cancers. The thinking behind this method is as follows:

1. A combination of chemotherapy drugs allows the therapy to target all phases of the cell cycle (Go, G1, S, G2 and M-phases) – resulting in superior additive effects
2. Different classes of chemotherapy agents target specific phases of the cell cycle
3. The combination approach also reduces overall toxicity of chemotherapy by not compounding toxicities of drugs that work via a similar mechanism of action.
4. This approach has also been shown to reduce drug-resistance problems

Classes of Chemotherapy Agents
A standard way to classify chemotherapy agents is put them into one of two categories:

1. Cell Cycle or Phase-Specific Drugs
2. Non Cell Cycle or Non- Phase-Specific Drugs

The cell cycle or phase-specific drugs have their greatest killing effect when a cell is dividing whereby certain drugs target specific cell phases (e.g. M-phase).

Non cell cycle or non phase-specific drugs often remain in the cell and wait for cell division to occur, upon which they exert their anti-cancer effects, or bind to key enzymes inhibiting their function.

The following are some of the commonly used cell cycle dependent chemotherapy drugs and the specific stages of the cell cycle in which they exert their effects:

G1 Phase:
Asparaginase
Corticosteroids

S-Phase:
Anti-Metabolites – drugs that are structural analogues to naturally occurring metabolites involved in DNA and RNA synthesis. These drugs alter critical pathways to prevent cancer cells from synthesizing DNA or RNA. They exert their cytotoxic effects either by competing with normal metabolites for the catalytic or regulatory sites of a key enzyme or by substituting for a metabolite that is normally incorporated into DNA or RNA.

Examples Include: capecitabine, doxorubicin, floxuridine, gemcitabine, mercaptopurine, prednisone, thioguanine, cytarabine, fludarabine, hydroxyurea, methotrexate, procarbazine

G2 Phase:

• Bleomycin – an antibiotic that generates free radicals to destroy DNA. Thus, concurrent antioxidant supplementation may reduce its efficacy
• Irenotecan and Topotecan – derived from the chinese ornamental campotothecaacuminata, these agents inhibit DNA topoisomerase I, which interrupts the elongation phase of DNA replication. Topoisomerase enzymes normally separate the strands of DNA so they can be copied. Theses drugs are used in treatment of certain leukemias, lung, ovarian, GI, and other cancers.
• Mitoxantrone – also a topoisomeras II inhibitor

Use of topoisomerase II inhibitors increase risk of developing a second cancer – acute myelogenous leukemia, which can be seen as early as 2-3 years after drug was given

M-Phase Or Mitotic Inhibitors
Mitotic Inhibitors are often plant alkaloids and other compounds derived from natural products. They inhibit mitosis or inhibit enzymes from making proteins needed for cell replication. They work primarily in the M-phase, but can damage cells in all phases. They are used to treat many different cancers including – breast, lung, myelomas, lymphomas, and leukemias. They often cause peripheral nerve damage (supplementation with alpha-lipoic acid may reduce this side effect or help repair the nerve damage as it has been shown to do in diabetic neuropathy)

• Vinca Alkaloids – derived from the periwinkle plant (vincarosea) – block polymerization of microtubules resulting in impaired mitotic spindles (e.g. vinblasine, vincristine, vinorelbine)
• Podophyllotoxins or Epoipodophyllotoxins (compounds derived from the podophyllumpeltatum – inhibits DNA topoisomerase II activity, blocking DNA synthesis (e.g. etopiside)
• Taxanes (paclitaxel or Taxol, docetaxel) – semi-synthetic compounds from the yew plants. These promote microtubular assembly and stability blocking cell cycle mitosis
• Epithilones (e.g. Ixempra)

Note: it is most interesting to see how many chemotherapy agents are actually derive from natural botanical sources

The following are some of the commonly used non-cell cycle dependent chemotherapy drugs:

Alkylating Agents – impair cell function by forming covalent bonds with amino, carboxyl, sulfhydryl and phosphate groups in biologically important molecules – most important sites are DNA, RNA and cellular Proteins.

These are also known as intercalating agents

Examples of Alkylating Agents:

• Nitrogen Mustards – bind to DNA (e.g. cyclophosphamide)
• Nitrosureas – lipid soluble, can enter brain (forms free radicals) – (eg.streptozocin)
• Platinum Agents (heavy metal complex producing inter-strand breaks of DNA with cross-linking adducts – thus inhibiting DNA synthesis (cispatinum, carboplatinum, oxaplatinum)
• Alkyl Sulfonates: e.g. busulfan
• Triazines: e.g. Dacarbazine
• Ethylenimines: e.g. hexamethylmelaninine

Anthracyclines (tumor killing antibiotics) – these are antitumor antibiotics that interfere with enzymes involved in DNA replication. They work in all phases of the cell cycle and thus, are used widely in various cancers. They can permanently damage the heart if given in high doses. Lifetime dose limits are often placed on these drugs for this reason.

Concurrent supplementation with Coenzyme Q10 has been shown to protect the heart muscle in cases of Adriamycin use.

Examples of Anthracyclins:

• Doxorubicin
• Adriamycin
• Danorubicin
• Epirubicin
• Idarubicin
• Actinomycin-D
• Bleomycin – kills via free radical attack
• Mitomycin-C
• Mitoxantrone – an anti-tumor antibiotic that is similar to doxorubicin, including potential for heart damage. It is also a topoisomerase II inhibitor, and can lead to the development of leukemia. It is used in the treatment of prostate and breast cancer, and in lymphoma and leukemia

Some of the newer chemotherapy drugs are classified as Targeted Agents. Here are some examples:

1. Monoclonal Antibodies – antibodies that target specific protein antigens (receptors, signal transduction enzymes or proteins) that are dysregulated in a cancer cell. These drugs destroy the dysregulated protein (in some cases a protein receptor on the cell surface that is over-expressed or over active and is sending messages into the cell to encourage continued cell division).

Examples Of Monoclonal Antibodies:

• Rituxan – targets CD20 antigen found on B-cell lymphocytes in non-hodgkin lymphoma
• Herceptin – targets HER-2 receptor on breast cells that is over-expressed in up to 40% of breast cancer patients
• Campath – targets CD52 antigen in B-cell and T-cell lymphocytes in chronic lymphocytic leukemia
• Avastin and Related MAB’s – destroys receptors on blood vessels to prevent stimulation new blood vessels growing to feed the tumor.

2. Small Molecules – these inhibit some key pathways that drive cancer cell division (particularly tyrosine kinase inhibitors):

Examples:

• Imatinib (Gleevec) – binds to ATP binding site inhibiting tyrosine kinase from phosphorylating its substrates
• Gemfitinib – inhibits epidermal growth factor receptor-tyrosine kinase signal transduction
• Erlotinib – blocks HER-1receptor- tyrosine kinase signal transduction in non small lung cancer
• Sunitinib – tyrosine inhibitor associated with inhibiting signals from over active epidermal growth factor receptors and vascular endothelial derived growth factor (the chemical that stimulates growth of new blood vessels to feed the tumor)
• Sorafenib – another tyrosine inhibitor with similar function to Sunitinib
• Velcade – a proteoasome inhibitor used in multiple myeloma that ultimately blocks NF-Kappa beta and its effects promotional effects on cell division
• Torisel – blocks mTOR protein involved in proliferation and angiogenesis (the formation of new blood vessels)

3. Endocrine Therapy:

Tamoxifen and Raloxifen – selective estrogen receptor modulators (SERMs) that compete with estrogen for binding to estrogen receptors – slowing cellular proliferation

Aromatase Inhibitors – block aromatase enzyme (estrogen synthase) in fat cells, stromal cells, breast cancer cells, that converts androstenedione into estrone.

Summary
This article provides a general overview of the classes of chemotherapy agents that are commonly prescribed today by oncologists. Understanding the influence that these drugs have on killing cancer cells, or interrupting their mitotic potential, is a critical factor in deciding what dietary or supplementation practices would be synergistic to the action of the drug or would be in conflict. In addition to these chemotherapy agents there are also other oral drugs used (often off-label use) in the management of these cases, which should also be factored in to the nutrition and supplementation advice provided to a patient. A future article will address the off-label use of these drugs in cancer management.

One of the highlights of my professional career has been to teach  a course on the Adjunctive Nutritional Management of Cancer to medical doctors and oncologists who are candidates in the Fellowship In Integrative Cancer Therapy Program taught through a division of the American Academy of Anti-Aging Medicine. These doctors have been most receptive and appreciative of the evidence-based protocols I have provided to them, and many use this information for the purpose of incorporating targeted nutritional and supplementation practices into the management of the cancer patients they see. In return, I have learned a great deal about medical cancer therapy from these practitioners, and other speakers at these conferences, including much of the information presented in this article.