The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and folic acid inhibitors. Cancer drug development since then has exploded into a multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply.

Principles Cancer is the uncontrolled growth of cells due to damage to DNA
(mutations) and, occasionally, due to an inherited propensity to develop certain tumours. Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body - in other words, the body attacks its own cells. In contrast, transplant rejection happens because a normal healthy human immune system can distinguish foreign tissues and attempts to destroy them. Also the reverse situation, called graft-versus-host disease, may take place.

Broadly, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called "cell suicide").

Unfortunately, scientists have yet to be able to locate specific features of malignant and immune cells that would make them uniquely targetable
(barring some recent examples, such as the Philadelphia chromosome as targeted by imatinib - (Gleevec® or Glivec®). This means that other fast dividing cells such as those responsible for hair growth and for replacement of the intestinal epithelium (lining) are also affected. However, some drugs have a better side-effect profile than others, enabling doctors to adjust treatment regimens to the advantage of patients in certain situations.

As chemotherapy affects cell division, tumours with high growth fractions
(such as acute myelogenous leukemia and the lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time.

Chemotherapeutic drugs affect "younger" tumours (i.e. less differentiated) more effectively, because at a higher grade of differentiation, the propensity to growth usually decreases. Near the center of some solid tumours, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumours is the fact that the chemotherapeutic agent often does not reach the core of the tumour. Solutions to this problem include radiation therapy (both brachytherapy and teletherapy) and surgery.

Types The majority of chemotherapeutic drugs can be divided in to: alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way.

Some newer agents don't directly interfere with DNA. These include the new tyrosine kinase inhibitor imatinib mesylate (Gleevec® or Glivec®), which directly targets a molecular abnormality in certain types of cancer
(chronic myelogenous leukemia, gastrointestinal stromal tumors).

In addition, some drugs may be used which modulate tumour cell behaviour without directly attacking those cells. Hormone treatments fall into this category of adjuvant therapies.

Where available, Anatomical Therapeutic Chemical Classification System codes are provided for the major categories.

Alkylating agents (L01A)

See main article: alkylating agent

Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells.

Anti-metabolites (L01B)

See main article: antimetabolite

Anti-metabolites masquerade as purine ((azathioprine, mercaptopurine)) or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.

Plant alkaloids and terpenoids (L01C)

These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloids and taxanes.

Vinca alkaloids (L01CA)

Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include: -

* Vincristine
* Vinblastine
* Vinorelbine
* Vindesine

Podophyllotoxin (L01CB)

Podophyllotoxin is a plant-derived compound used to produce two other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the G1 phase (the start of DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action still has to be elucidated.

The substance has been primarily obtained from the American Mayapple
(Podophyllum peltatum). Recently it has been discovered that a rare Himalayan Mayapple (Podophyllum hexandrum) contains it in a much greater quantity, but as the plant is endangered, its supply is limited. Studies have been conducted to isolate the genes involved in the substance's production, so that it could be obtained recombinantively.
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Taxanes (L01CD)

Taxanes are derived from the Pacific yew tree, Taxus brevifolia. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase. Taxanes include: -

* Paclitaxel
* Docetaxel

Topoisomerase inhibitors (L01CB and L01XX)

Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling.

* Some type I topoisomerase inhibitors include camptothecins: irinotecan and topotecan.

* Examples of type II inhibitors include amsacrine, etoposide, etoposide phosphate, and teniposide. These are semisynthetic derivatives of epipodophyllotoxins, alkaloids naturally occurring in the root of mayapple (Podophyllum peltatum).

Antitumour antibiotics (L01D)