Rationale for combination therapy

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

Cytotoxic chemotherapy destroys cancer cells. Currently available drugs target

  • Chemistry of nucleic acids
  • DNA or RNA production
  • 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.

Cytotoxic agents can be classified by the following:

  • Chemical properties or mechanisms of action
  • Source (e.g., 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 tumor 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 tumor.

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).

  • Tumor 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.
  • “Multidrug resistance” is displayed by some tumor types, resulting from, e.g., expression of an efflux pump on the cell surface that pumps the drug out of the cell.

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