Rationale for combination therapy

Cytotoxic chemotherapy destroys cancer cells. Currently available drugs target:

♦ Chemistry of nucleic acids.

♦ Mechanics of cell division (e.g. spindle poisons).

The discovery and development of cytotoxics has paralleled the understanding of the chemical processes involved. The lack of selectivity inherent in this approach has limited the ability to kill cancer cells while leaving normal dividing cells unscathed. There are only rare examples where single-agent therapy is sufficiently active to eradicate the clinically apparent cancer totally and lead to a durable remission or cure. Cytotoxic agents can be classified by:

♦ Chemical properties or mechanisms of action (alkylators)

♦ Source (natural products).

♦ Propensity to be cell cycle or phase specific.

The following underlie the design of a potential combination therapy:

♦ Each drug should have single-agent activity in that tumour type.

♦ Each drug should have a different mechanism of activity.

♦ Drugs with non-overlapping toxicity patterns are preferable.

♦ Drugs that work in different parts of the cell cycle should be selected.

♦ Drugs should not all share the same resistance mechanisms. Combination therapy aims to increase 'fractional cell kill' leading to improved overall response of the tumour. Higher doses of cytotoxic drugs tend to produce increased cell kill (at least within certain limits) thus it is important not to compromise on the dose of each agent (hence the need to select drugs with non-overlapping toxicity).

Tumour growth also needs to be considered. Tumour mass is usually composed of cells that are asynchronously dividing—thus combinations of drugs that act at different points in the cell cycle will theoretically kill more cells.

'Multi-drug resistance' is displayed by some tumour types, resulting from expression of an efflux pump on the cell surface that pumps the drug out of the cell. This resistance is then apparent to a set of agents known collectively as natural products. The combination should, therefore, not include two such agents.

There are other considerations in developing a combination regimen, including:

♦ Schedule of administration.

♦ Frequency of administration.

♦ Possible synergistic or antagonistic interactions.

♦ Possible pharmacokinetic or pharmacodynamic interactions. Novel agents in development target other aspects of malignant behaviour, including:

♦ Angiogenesis.

♦ Autocrine and paracrine growth regulators.

♦ Cell matrix interactions.

The future challenge is to incorporate such drugs into new and existing combinations to improve patient outcomes

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