Nerdy Science Blog

Chemotherapy – in the general sense, means using chemical agents to kill cells, and in most cases, specifically those of cancer. In its non-oncological use, the term may also refer to antibiotics, used to kill micro-organisms.

Brief History
History of chemotherapy can be traced back to the discovery of nitrogen mustard (used as a chemical warfare agent), as an effective treatment of cancer. Two pharmacologists, Louis S. Goodman and Alfred Gilman had discovered lymphoid and myeloid suppression on people exposed to the mustard gas. Soon after that, they tried to inject a related agent, called mustine, into a patient with non-Hodgkin’s lymphoma. They then documented the significant reduction in the patient’s tumor masses. After World War II, Sidney Farber, a pathologist at Harvard Medical School, together with Harriett Klite and Lederle Laboratories chemists, used folate analogues (now methotrexate), which is antagonistic to folic acid, to block the function of folate-requiring enzymes. This analogue became the first drugs to induce remission in children with Acute Lymphocytic Leukemia.

What is cancer?
Before we proceed into knowing how chemotherapy works, types of chemotherapy and its side effect, it is important to know the definition of cancer. Cancer can be defined as the uncontrolled growth of certain group of cells with malignant behavior like invasion and metastasis. Metastasis is the spread of a cancer from one organ or part to another non-adjacent organ or part. Invasion is the spread of a cancer to another adjacent organ.

Mechanism of action of chemotherapy
Chemotherapeutic drugs damage cell divisions, called mitosis, and effectively affecting cells which are dividing in a fast pace. The drugs are termed cytotoxic because they cause damage to the cells. Some of them cause apoptosis of cells (programmed cell death). As chemotherapy affects cell division, high growth fractions tumors are more sensitive to chemotherapy. Malignancies with slower growth rates tend to respond to chemotherapy much more modestly. The same concept can be used to explain why chemotherapy affect ‘younger tumors’ more effectively. It is because the mechanisms regulating cell growth are usually still preserved. With succeeding generations of tumor cells, the differentiation is typically lost and growth become less regulated, and tumors become less responsive to most chemotherapeutic agents.

Objectives of Chemotherapy
There are few kinds of strategies in the administration of chemotherapeutic drugs for desired effects:

1. Combined modality chemotherapy – chemotherapeutic drugs are used together with other cancer treatments like radiation therapy or surgery. Most of the cancer patients receive this kind of treatment now. Combination chemotherapy also involves treating the patient with a number of different drugs simultaneously. The advantage of this type of strategy would be the ability to minimize the chances of resistance developing to any one agent.
2. Neoadjuvant chemotherapy – chemotherapeutic drugs are used with the aim to shrink the primary tumor, so that local therapy like surgery or radiotherapy will be less destructive and more effective. This strategy is also one kind of preoperative treatment.
3. Adjuvant chemotherapy – chemotherapeutic drugs are used when there is little evidence of cancer present, but there is risk of recurrence. Adjuvant chemotherapy is usually given postoperatively. During this period, the newly growing tumors are fast-dividing, and therefore very susceptible. This can also help to reduce chances of resistance developing if the tumor does develop.
4. Palliative chemotherapy – chemotherapeutic drugs are given without curative intent but simply to decrease tumor load and increase life expectancy.

Most of the chemotherapeutic drugs today can be divided into antimetabolites, topoisomerase inhibitors, anthracyclines, plant alkaloids, alkylating agents and other antitumor agents. These mentioned groups of drugs affect DNA synthesis or cell division in some way. Some newer chemotherapeutic agents like monoclonal antibodies and the tyrosine kinase inhibitors (e.g. imatinib mesylate) do not directly interfere with DNA. They target a molecular abnormality in some types of cancer for example gastrointestinal stromal tumors and chronic myelogenous leukemia.

Different types of chemotherapeutic drugs

Alkylating antineoplastic agent
Alkylating agnets are active under conditions which are present in cells. The mechanism makes them toxic and allows them to be used as anti-cancer drugs. They stop the growth of the tumor by cross-linking some of the nucleobases in the double-helix strands of the DNA., directly destroying the structure of DNA. This makes the strands separated and thus unable to divide. Examples: Busulfan, Cyclophosphamide, Mechlorethamine, Cisplatin and etc.

Antimetabolites
An antimetabolite is a similar structure required for normal biochemical reactions, yet different enough to interfere with cell division. They masquerade as purine or pyrimidine – which are the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during S phase of the cell cycle and thus stopping normal development and division.

Anthracycline
Antrhacycline inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, inhibits topoisomerase II enzyme, preventing the relaxing of supercoiled DNA thus blocking DNA transcription and replication, and creates iron-mediated free oxygen radicals that damage the DNA and cell membranes. However, their main adverse effects are heart damage (cardiotoxicity) and vomiting. These adverse effects limit their usefulness. Some of the available agents include: Daunorubicin, Epirubicin and etc.

Topoisomerase inhibitor
These isomerase enzymes act on the topology of DNA. There are 3 kinds of topology: supercoiling, knotting and catenation. When outside of replication or transcription, DNA is kept as compact as possible. Topoisomerases upsets the proper DNA supercoiling during transcription and replication. Examples: irinotecan, amsacrine, etoposide and etc.

Monoclonal antibodies
By creating monoclonal antibodies that bind only to specific antigens of the cancer cell, immunological response could be induce, against the target cancer cell. Example: trastuzumab (anti-cancer therapy for a specific kind of breast cancer), alemtuzumab (used in B cell leukemia), gemtuzumab (use during relapsed acute myeloid leukemia).

The side effects of chemotherapy differ for each drugs, drug’s doses and individuals.
Some of the common side effects of chemotherapy are: nausea, vomiting, hair loss, fatigue, anemia, mouth sores, taste and smell changes, infection, diarrhea, infertility, fluid retention, rashes, irritated bladder, swelling, soreness of mucous membranes, numbness, aching joints and etc. Thus, it is important for each individual to research on each drug before trying them as side effects varies for each of them. Even though chemotherapy is designed to kill cancerous cells, it is so aggressive that it works against healthy cells as well. Since chemotherapeutic drugs travel everywhere in the body, damage of healthy cells can occur at various places in the body.

Proper diagnosis of cancer and careful administration of chemotherapy should be practised to ensure that the benefits of the therapy outstrip its unwanted effects.

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