Chemotherapy

Published on 23/06/2015 by admin

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Chapter 39 Chemotherapy

Chapter contents

History 307
Uses of chemotherapy 307
The cell cycle 307
The aims of chemotherapy treatment 308
Terminology 308
Major groups of cancer 309
Chemotherapeutic agents 309

Chemotherapy is used in treatment of cancer. There are two types of chemotherapy:

• antineoplastic: anticancer
• cytotoxic: kills the cells.

History

The treatment of cancer by chemotherapy started in the 1940s after military personnel were accidentally exposed to mustard gas. Examination of their blood showed abnormally low white cell counts and it was thought that this might have an effect on patients with cancer. It was tried out on patients with advanced lymphomas and given intravenously. Their improvement, although temporary, was enough to start research into chemotherapy.

Uses of Chemotherapy

Chemotherapy is a systemic treatment and is therefore used when the cancer has spread to various sites in the body. Radiation and surgery are used when the problem is localized.

The Cell Cycle

To understand how chemotherapy works it is necessary to understand the lifecycle of a cell (Figure 39.1):

• G0 phase (resting stage): the cell is at rest and has not started to divide. This can last for a few hours to a few years, depending on the circumstances (reproductive cells have a very short resting phase whereas plant seeds have been known to germinate many years after they have been deposited). The cell becomes activated.
• G1 phase: the cell starts to make more proteins and is ready to divide. This usually lasts 18–30 hours.
• S phase: the deoxyribonucleic acid (DNA) chains are copied so that the new cell has the same DNA. This usually lasts 18–20 hours.
• G2 phase: this is just before the cell starts splitting into two cells. This phase usually lasts from 2–10 hours.
• M phase: the cell splits into two new cells. This phase usually lasts 30–60 minutes.
image

Figure 39.1 The phases of the cell cycle.

Chemotherapy works on actively reproducing cells. Different drugs act on different parts of the cycle. Oncologists use different groups of drugs to act on certain parts of the cycle. The problem with chemotherapy, however, is that it also acts on normal cells that are actively reproducing. The reproductive cells tend to be the ones that are most badly affected as they are multiplying relatively rapidly. The trick is to balance killing off too many good cells along with the bad cells.

The Aims of Chemotherapy Treatment

There are three aims.

• Cure: so the cancer does not return.
• Control: stopping the disease spreading and try to provide quality of life while the patient is alive.
• Palliative: if the cancer is in an advanced stage drugs are used to relieve the symptoms, even though they might not increase the patient’s life span.

Terminology

• Adjuvant therapy: postsurgical treatment to prevent the growth of any remaining cells and metastasis around the body.
• Benign tumour: remains confined to original location. There is no invasion of surrounding material or general dispersal. Can be removed by surgery. Generally not life threatening unless in an inoperable place, e.g. certain types of brain tumour.
• Malignant: tumour can invade surrounding material and generally disperse in the body. Often life threatening.
• Metastasis or secondaries: spreads from the main site of the tumour to a distant site, forming new centres of growth.
• Neoadjuvant therapy: can be used to shrink a large tumour so that it can be more easily removed by surgery.

Major Groups of Cancer

Carcinomas

• Solid tumours usually from epithelial cells.
• 90% of all human cancers.

Usually found in:

• Skin.
• Cells lining internal organs, e.g. lung and intestine.
• Glandular tissue e.g. breast and prostate.

Sarcomas

Tumours arising from connective tissue, for example bone primary tumours.

Leukaemia and Lymphomas

• From blood-forming cells and cells of the immune system.
• 8% of all human cancers.

Chemotherapeutic agents

The categories of drugs are based on:

• How the drugs affect specific chemical pathways within the cancer cells.
• How the drugs interfere with the cellular pathways.
• The specific cell phase.

This helps the oncologist to plan when to use a drug or which drugs are going to work best together. There are several forms of chemotherapy:

• alkylating agents
• cytotoxic antibiotics
• plant alkaloids: vinca alkaloids and taxanes
• antimetabolites
• hormones.

• Alkylating Agents

Work in three ways:

• Attach to alkyl groups of DNA bases: DNA becomes fragmented by repair enzymes trying to replace the abnormal units.
• Causing mispairing of the nucleotides, which leads to mutations.
• Formation of cross-bridges so that DNA is unable to unzip.

Cyclophosphamide is metabolized in the liver to form several active metabolites. Its adverse effects are that prolonged use can lead to secondary cancers, particularly leukaemias.

• Cytotoxic Antibiotics

• Squeeze between the base pairs, creating problems with DNA and RNA synthesis.
• Inhibit the enzyme that ‘unknots’ the DNA so that it can unzip and form RNA.
• These work at all phases of the cycle.

• Plant Alkaloids

• Mitotic inhibitors.
• These work in the M phase of the cell cycle.

Vinca Alkaloids

Vincristine prevents cell division (mitosis) at a point where the cell pulls duplicated DNA chromosones to either side of the cell in special structures called spindles. Vincristine binds to tubulin which makes up the spindles thus preventing the formation of the spindles and cell division.

Taxanes

Work in the opposite way to the vinca alkaloids by forcing the spindles together, creating abnormal bundles of microtubules and thus disrupting mitosis.

• Antimetabolites (Figure 39.2)

• Compete with the essential components of metabolic processes and inhibit those processes.
• Interfere with DNA and RNA growth.
• Phase specific: work in the S phase.
• Used to treat leukaemias and tumours of the breast, ovary and gastrointestinal tract.

Methotrexate

Is an analogue of folic acid and interferes with folic acid metabolism. Folic acid is vital for normal cell function.

Azathioprine (AZA)

Becomes metabolized to mercaptopurine using glutathione. Although mercaptopurine can be used as a cytoxic agent in its own right, azathioprine has a longer duration of action than mercaptopurine.

image

Figure 39.2 A ntimetabolite drugs used in chemotherapy, showing the similarity in structure to normal metabolites. Methotrexate highlights the differences between the drug and the metabolite; azathioprine highlights the similarity.

• Hormones

• Alter the action or production of female or male hormones.
• Can be used to slow the growth of breast, prostate and endometrial cancers.
• Do not work in the same way as standard chemotherapy drugs.

Glucocorticoids

• Steroids are used to kill cancer cells or slow their growth.
• They are often combined with other types of chemotherapy drugs to increase their effectiveness.
• They are useful with brain tumours to reduce the swelling.
• Prednisolone.

Tamoxifen is an oestrogen receptor antagonist. It is the hormonal treatment of choice in women with oestrogen-receptor-positive breast cancer. Buserelin is used for prostate cancer.

Factors Considered in the Treatment of Chemotherapy

• Type of cancer.
• Stage of cancer (has it spread?).
• Age.
• General state of health.
• Any serious health problem (e.g. kidney or liver problems).
• Any anticancer treatments given in the past.

Cure requires complete eradication of tumour cells. By and large, the drugs kill a constant proportion of cells rather than a constant number. The fewer cells there are, the better the chance of recovery.

Why does Chemotherapy Fail?

• Anticancer drugs are still not specific enough for the cancer they are treating: the drugs rely on the biochemistry of the cancer cells being different to that of the biochemistry of the normal cells. In real life this is not really the case. Note: this principle is the same as antibiotics killing off the entire gut flora not just the bad bugs.
• Tumour cells can develop resistance to anticancer drugs: they divide rapidly and, like bacteria, a mutation of one cell, which develops resistance, will produce resistant progeny very quickly.
• Drugs might not be able to get to the site in high enough concentrations: a large mass means that the cells at the centre are not exposed to the blood supply that brings the drugs to the cells.

What Affects the Survival Rate of the Patient?

• Nature of the Cancer

• The stage it is at when diagnosed.
• How fast can it divide and multiply.
• If all the cells in the cancer are slightly different it makes it more difficult to choose the right chemical for chemotherapy.
• The phase in which the cell cycle is treated.

• Pharmacology

• How far on treatment is given.
• The gaps between treatments.
• The combination of drugs used.

• Patient

• The health of the patient.
• How efficiently the patient’s blood supply is working. This is a double-edged sword. The tumour needs a good blood supply to deliver the drug, but this will also mean the tumour is well nourished.
• Whether the immune system of the patient is able to attack the tumour itself.

The Theory and Reality of Chemotherapy

• The Theory

• The drugs should vary in lethal toxicity around the cell cycle.
• If the drugs are specific enough to a specific point in the cycle then all those cells not at that point will not be affected immediately. Eventually, with enough therapy, all the cells will reach the same stage in the cycle at the same time to become synchronized. This makes killing more of them easier.
• Repeated chemotherapy in a consecutive treatment will maximize the effect of the treatment by eventually catching the cells it missed on the last round in the phase when they are most vulnerable.

• The Reality

• This is difficult to apply clinically: every person, and every cell, is unique.
• The tumour might regrow between treatments.
• Drug resistance.
• Not all the tumour sites might be exposed to a high enough level of chemical.

Adverse Effects

• Decrease of white blood cells, red blood cells and platelet counts: can lead to infections, anaemia and haemorrhage.
• Nausea and vomiting: due to stimulation of the vomiting centre in the CNS.
• Dysphagia, diarrhoea, pain and bleeding: due to the damage of proliferating mucosa of the gastrointestinal tract.
• Partial or complete alopecia: damage to hair follicles.
• Menstrual irregularities, premature menopause: fetal abnormalities. Oligospermia (decrease in sperm count) and infertility in males.
• Cancer patients might have an increase of second malignancies: the immune system might have been damaged by treatment, e.g. leukaemia.

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