Chemical principles (Chemotherapy)

Cell growth is controlled via various mechanisms involving DNA and a variety of proteins. Healthy adult cells do not normally replicate extensively. However, mutations can lead to uncontrolled cell propagation and therefore growth of tumours. Chemotherapy drugs generally aim to kill malignant cells by targeting the molecules and mechanisms involved in cell division.

This is not to say only malignant cells are affected by chemotherapy; the substances used are intrinsically cytotoxic (toxic to living cells). Hair growth, maintenance of mucosa and blood cell production are processes in which healthy cells are also constantly dividing fairly rapidly and so are also affected by chemotherapy. Consequently side effects, such as hair loss, mouth ulcers or anaemia, can occur.

Figure 1 shows a sketch of two drug molecules commonly used in chemotherapy: cisplatin and carboplatin. Both are drugs that target genetic material in a living cell.

Figure 1: Sketch of the molecular structures of cisplatin (left) and carboplatin (right).

Cisplatin and carboplatin belong to the class of DNA crosslinking chemotherapy agents. They bond to DNA and in this way prohibit further cell division, and thus induce cell death (apoptosis). This mechanism, identical for cisplatin and carboplatin, is shown in Figure 2. Carboplatin is used in cases when cisplatin is not appropriate, such as where kidney function is impaired in a patient as carboplatin is slightly less nephrotoxic (harmful to the kidney) than cisplatin.

Figure 2: The interaction of the active part of the cisplatin or carboplatin molecules with the DNA helix strands.

Methotrexate and 5-fluorouracil are chemotherapy drugs that belong to the class of drugs known as antimetabolites. By closely mimicking molecules that are ordinarily consumed by the normal healthy cell cycle, these substances prevent the cycle from continuing and so induce apoptosis. Antimetabolites typically differ only very slightly in their molecular composition and structure from the molecules ordinarily used by the cell (see Figure 3). Yet these minute differences are enough to prevent normal cell function. As can be seen in Figure 3, the normal natural substrate uracil (left) differs from the chemotherapy drug molecule 5-fluorouracil (right) by just having replaced one H atom by a fluorine atom. Uracil is one of the four building blocks of RNA.

Figure 3: Sketch of the molecular structures of uracil (left) and 5-fluorouracil (right).

Some chemotherapy drugs interact with various specific proteins to inhibit cell processes involved in replication. Epidermal growth factor receptors (EGFR) regulate cell-signalling pathways, which are responsible for cellular propagation. When mutated this receptor can often be overactive. Cetuximab is a drug that inhibits the action of this protein and consequently suppresses cell proliferation. It is the only such drug currently used in head and neck cancer treatments.

Taxanes are a class of chemotherapy drugs that inhibit the function of microtubules (units that maintain the structure of cells and help with the assembly of new cells) in mitosis (the late stage of cell division where a new cell nucleus is formed) therefore preventing the successful completion of cell division.

Only limited roles have been identified for these two substances in the context of head and neck cancer.

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