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Dynamic Chiropractic Canada – September 1, 2010, Vol. 03, Issue 05
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How Chemotherapy Drugs Work

A Practical Guide for Complementary Health Care Practitioners

By James P. Meschino, DC, MS

In the course of running a practice, certain patients and/or their family members may 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 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.

Our academic curriculum generally does not provide information on how physicians decide which chemotherapy drugs to use on a particular cancer patient. This article provides a basic overview of the various classes of chemotherapy agents that are commonly used, 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 - stage at which divided cells undergo DNA synthesis;
  • G2 Phase - premitotic rest interval (checkpoint to see if DNA has properly reproduced itself);
  • M Phase - mitotic phase; chromosome condensation with cell division.

Of particular interest is the fact that solid malignant tumors contain the following three cell types: cells that are not dividing and are terminally differentiated; cells that continue to proliferate; and non-dividing cells that are currently quiescent but may be recruited into the cell cycle. Large tumors harbor more non-proliferating cells, which potentially makes 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, 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: cell cycle (phase-specific drugs) and non-cell cycle (non-phase-specific drugs). The cell cycle (phase-specific) drugs have their greatest killing effect when a cell is dividing; certain drugs target specific cell phases (e.g., M phase). Non-cell cycle (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 during which they exert their effects. It is most interesting to note how many chemotherapy agents are actually derived from natural botanical sources.

G1 Phase: Asparaginase and corticosteroids.

S Phase: Anti-metabolites. These drugs are structural analogues to naturally occurring metabolites involved in DNA and RNA synthesis. They 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, and procarbazine.

G2 Phase: Some of the phase-specific agents that target cancerous cells include the following:

  • Bleomycin. An antibiotic that generates free radicals to destroy DNA. Thus, concurrent antioxidant supplementation may reduce its efficacy.
  • Irenotecan and topotecan. These drugs are derived from the Chinese ornamental Camptotheca acuminata; they 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. These drugs are used in the treatment of certain leukemias, as well as lung, ovarian, GI, and other cancers.
  • Mitoxantrone. Also a topoisomeras II inhibitor. Note: The use of topoisomerase II inhibitors increases the risk of developing a second cancer - acute myelogenous leukemia, which has been seen as early as 2-3 years after the drug was given.

M Phase:

  • Mitotic inhibitors. These 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 cancer, lung cancer, 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. They are derived from the periwinkle plant (Vinca rosea) and block polymerization of microtubules, resulting in impaired mitotic spindles. Examples: vinblasine, vincristine, vinorelbine.
  • Podophyllotoxins or Epoipodophyllotoxins (compounds derived from Podophyllum peltatum) inhibit DNA topoisomerase  II activity, blocking DNA synthesis. Example: etopiside.
  • Taxanes are semi-synthetic compounds from the yew plant. They promote microtubular assembly and stability, blocking cell cycle mitosis. Examples: paclitaxel or Taxol, docetaxel.
  • Epithilones (e.g., Ixempra).

Non-cell-cycle (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 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. The most important sites are DNA, RNA and cellular proteins. These are also known as intercalating agents. Examples: nitrogen mustards, which bind to DNA (e.g., cyclophosphamide); nitrosureas - lipid soluble, can enter brain (forms free radicals)(e.g., 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; and ethylenimines (e.g., hexamethylmelaninine).

Anthracyclines (tumor-killing antibiotics) 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 include:

  • 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.

Targeted Agents: Some of the newer chemotherapy drugs are classified as targeted agents. Examples include monoclonal antibodies, small molecules and endocrine therapy agents. Here is a brief discussion of each, including a few examples:

Monoclonal antibodies 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 overactive and is sending messages into the cell to encourage continued cell division). Examples include Rituxan, which 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 percent of breast cancer patients; Campath - targets CD52 antigen in B-cell and T-cell lymphocytes in chronic lymphocytic leukemia; and Avastin and related MAB's - destroys receptors on blood vessels to prevent stimulation of new blood vessels growing to feed the tumor.

Small molecules inhibit some of the key pathways that drive cancer cell division (particularly tyrosine kinase inhibitors): Examples include:

  • 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-cell 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 on cell division.
  • Torisel - blocks mTOR protein involved in proliferation and angiogenesis (the formation of new blood vessels).

Endocrine therapy: Tamoxifen and Raloxifen are 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, which converts androstenedione into estrone.

Relevance to Your Practice

Understanding the influence these drugs have on killing cancer cells or interrupting their mitotic potential is critical when deciding what dietary or supplementation practices are synergistic to or in conflict with the action of the drug. 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, and many use this information for the purpose of incorporating targeted nutritional and supplementation practices into the management of their cancer patients. 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.


Click here for more information about James P. Meschino, DC, MS.

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