The Chemotherapy reference article from the English Wikipedia on 24-Jul-2004
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Chemotherapy

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Chemotherapy (pronounced keem-o-therapy) is the use of certain drugs to treat disease, as distinct from other forms of treatment, such as surgery. Chemotherapy dates at least as far back as the use, by the Indians of Peru, of cinchona bark in the treatment of fevers, such as malaria. The first modern chemotheraputic agent was Paul Ehrlich's arsphenamine, an arsenic compound discovered in 1909 and used to treat syphilis. This was later followed by sulfonamides discovered by Domagk and penicillin G discovered by Alexander Fleming.

Please note that today, the term chemotherapy is mostly used for the drug treatment of cancer, and the rest of this article discusses that topic. Antibiotics are referred to as antibacterial chemotherapy, but in medical practice this word is only used in the context of the treatment of tuberculosis.

Other uses of chemotherapy agents (including the ones mentioned below) are the treatment of autoimmune disease (DMARDs).

Table of contents
1 Chemotherapy for cancer
2 Types and dosage of drugs
3 Treatment schemes
4 Delivery
5 Side-effects
6 See also
7 References
8 External links

Chemotherapy for cancer

Cancer is the uncontrolled growth of cellss due to damage to DNA (mutations) and, occasionally, due to an inherited propensity to develop certain tumours.

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 commit apoptosis (effectively "cell suicide").

Unfortunately, scientists have yet to be able to locate specific features of malignant cells that would make them uniquely targetable (barring some recent examples, such as the Philadelphia chromosome as targeted by imatinib). This means that other fast dividing cells such those responsible for hair growth and replacement of epithelium in the intestine 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 a 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 tumour cells are undergoing cell division at any time.

Chemotheraputic drugs affect "younger" tumours (i.e. less differentiated) more effectively, because at a higher grade of differentiation, the propensity to growth decreases. In 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 brachytherapy and, of course, surgery.

Types and dosage of drugs

The majority of chemotheraputic drugs can be divided in to: alkylating agents, anti-metabolites, plant alkaloids, and antitumour agents. As all of the drugs affects DNA synthesis or function in some way, they are categorized by their effect on the cell cycle.

Some newer agents cannot be classified. This 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).

Dosage of chemotherapy can be difficult: if the dose is too low, it will be ineffective against the tumor, while at excessive doses the toxicity (side-effects, neutropenia) will be intolerable to the patient. This has led to the formation of detailed "dosing schemes" in most hospitals, which give guidance on the correct dose and adjustment in case of toxicity.

In most cases, the dose is adjusted for the patient's body surface area, a composite measure of weight and height that mathematically approximates the body volume. The BSA is usually calculated with a mathematical formula or a nomogram, rather than by direct measurement.

Alkylating agents

Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumour growth by cross-linking guanine basess in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide.

Anti-metabolites

Anti-metabolites masquerade as purine 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. An important example is 5-Fluoro Uracil (5FU).

Plant alkaloids

These alkaloids are derived from plants and block cell division by preventing microtubules being synthesized. These are vital for cell division and without them it can not occur. The main examples are vinca alkaloids such as vincristine.

Antitumour antibiotics

There are many differing antitumour antibiotics, but generally they prevent cell division by two ways: (1) binding to DNA making it unable to separate (2) inhibiting ribonucleic acid (RNA), preventing enzyme synthesis.

Hormonal therapy

A number of malignancies responds to hormonal therapy. Some other tumours are also hormone dependent, although the specific mechanism is still unclear.

Treatment schemes

There are a number of strategies in the administration of chemotheraputic drugs used today. Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery. Most cancers are now treated in this way. Combination chemotherapy is a similar practice which involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent.

Adjuvant Chemotherapy can be used when there is little evidence of cancer present, but there is risk of recurrence. This can help reduce chances of resistance developing if the tumour does develop. It is also useful in killing any cancerous cells which have spread to other parts of the body. This is often effective as the newly growing tumours are fast-dividing, and therefore very susceptible.

Most chemotherapy regimens require that the patient is capable to undergo the treatment. Performance status is often used as a measure to determine whether a patient can receive chemotherapy, or whether dose reduction is required.

Delivery

Most chemotherapy is delivered intravenously. Depending on the patient, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, IV chemotherapy may be given on either an inpatient or outpatient basis. A few agents are given orally, such as prednisone and melphalan. Chemotherapy may be delivered through a central line, giving more reliable access to the circulatory system while preventing phlebitis in peripheral veins.

Side-effects

The treatment can be physically exhausting for the patient. Current chemotheraputic techniques have a range of side effects mainly affecting the fast-dividing cells of the body. Important common side-effects include (dependent on the agent): Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells and platelets. The latter two, when they occur, are improved with blood transfusion. Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic G-CSF (granulocyte-colony stimulating factor, e.g. filgrastim, Neupogen®, Neulasta®.)

In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells which produce white and red blood cells) are destroyed, meaning allogenic or autogenic bone marrow cell transplants are necessary. (In autogenic BMTs, cells are removed from the patient before the treatment, multiplied and then re-injected afterwards; in allogenic BMTs the source is a donor.) However, some patients still develop diseases because of this interference with bone marrow.

Nausea and vomiting induced by chemotherapy can be alleviated with antiemetics. Usually metoclopramide or 5 hydroxytryptamine 3 (5-HT3) receptor antagonists (dolasetron, granisetron, ondansetron) are used.

Some studies1 and patient groups claim that the use of cannabinoids derived from marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat.

In particularly large tumors, such as large lymphomas, some patients develop tumor lysis syndrome from the rapid breakdown of malignant cells. Although profylaxis is available and is often initiated in patients with large tumors, this is a dangerous side-effect which can lead to death if left untreated.

Chemotherapy may increase the risk of cardio-vascular disease and occasionally leads to secondary cancer.

See also

References

  1. MR Tramer et al. Cannabinoids for control of chemotherapy-induced nausea and vomiting: quantitative systematic review. BMJ 2001 323: 16-21. http://www.bmj.com/cgi/content/full/323/7303/16

External links