Antineoplastic agents frequently disrupt replication at the cellular level by obstructing the synthesis of new genetic material or by causing irreversible damage to the DNA itself. While this affects both normal and malignant cells, normal cells have a greater ability to repair minor damage and continue living. The increased weakness of malignant cells is exploited to achieve the therapeutic effects seen with the administration of antineoplastic agents.1
The mechanisms of action of antineoplastic agents are based on the concepts of cellular kinetics - cell cycle time, growth fraction, and tumour burden:5
- Cell cycle time is the amount of time needed for the cell to complete an entire cycle from mitosis to mitosis. Cycle times for cancer cells vary from 24 to 120 hours, with most ranging from 48 to 72 hours. Those cells that have shorter cycle times are more easily damaged by cell-cycle phase specific cytotoxic agents. Continuous infusions of these agents result in higher cell kill percentages as a greater number of cells are exposed to the agent.
- The growth fraction is the percentage of cells in the tumour that are reproducing (cycling). For cancer cells there is really no difference to that of normal cells - the main difference is that cancer cells proliferate continuously.6 Higher growth fractions result in higher cell kills with cell-cycle phase specific agents. In tumours that have most of the cells in G 0 or the resting phase, using cell-cycle phase non-specific cytotoxic agents results in a higher cell kill.
- The tumour burden is the number of cells in the tumour. Tumours with a small burden are more sensitive to antineoplastic agents. As the tumour burden increases, the growth fraction and sensitivity to systemic treatment reduces.
It is theorised that cancer cells exposed to a certain dose of antineoplastic agents will destroy a constant percentage of cells in the tumour. This concept is known as first-order kinetics.1, 7
In line with this theory, repeated doses of therapy are needed to reduce the total number of cells. The number of cells left after therapy depends on the results of previous therapy, the time between repeated doses, and the doubling time of the tumour. Repeated treatments are delivered to reduce the tumour to a small enough number of cells so that the immune system can kill any remaining cells.7
Access a current text and review the biology of the cell, including cell structures and functions.
Summarise the process of normal cell repair and contrast this with the process of malignant cell repair.
Identify the cell cycle time for the cells in the following tissues and describe the impact of this on the effects of antineoplastic agents:
- Bone marrow.
- Mucous membrane.
- Cardiac muscle.
Provide three examples of how cellular kinetics can be manipulated in the treatment of cancer.
Pharmacodynamic properties of antineoplastic agents, including their actions and behaviour in a body, define the therapeutic effects of the agent.1 The effective dose must be neither too high (side effects will be too severe) nor too little (the tumour will continue to grow, and may develop resistance.). Key pharmacological factors impacting on antineoplastic actions include:1
- Route of administration
Dictated by the characteristics of individual drugs and chosen to optimise drug availability. Anti-cancer effects may be improved with higher concentrations at the tumour site.
- Drug distribution
The distribution and transport of drugs within the body can affect the proportion of free or pharmacologically active drug in the bloodstream.
The metabolic biotransformation of antineoplastic agents includes oxidation, reduction, hydrolysis, or conjugation which is done mainly in the liver.
Agents are commonly excreted via the kidneys or liver.
- Drug interactions
Agents may either inhibit or potentiate the action of another, thus modifying the therapeutic or toxic effects, or its enzyme inhibition or induction.
- Drug resistance8, 9
Primary resistance refers to the lack of tumour response when agents are administered.
Secondary resistance occurs after initial tumour regression. Factors contributing to secondary resistance include:
- variations in drug bioavailability
- drug metabolism or elimination
- tumours possibly located in 'sanctuary sites'
- changes in cell kinetics
- drug-related toxicity in the recipient
- reduced blood supply to the tumour.
Choose two antineoplastic agents. For each drug summarise the pharmacodynamic properties and outline any considerations for nursing management:
- Route of administration
- Drug distribution
- Drug interaction.
Detail the proposed mechanisms of multidrug resistance.
Outline current evidence based strategies to overcome multidrug resistance.