Drug Use Andtumour Cell Kinetics

Evidence from leukaemia in laboratory animals shows that:

• survival time is inversely related to the initial number of leukaemia cells, or to the number remaining after treatment

• a single leukaemia cell is capable of multiplying and eventually killing the host.

Cytotoxic drugs act against all cells which are multiplying. Bone marrow, mucosal surfaces (gut), hair follicles, reticuloendothelial system, germ cells, are all dividing more rapidly than many cancers and so are also damaged by cytotoxic drugs, as is shown by the occurrence of adverse effects experienced by patients receiving chemotherapy. In contrast to haematological cancers, most solid tumours in man divide slowly and recovery from cytotoxic agents is slow, while normal marrow and gut recover rapidly. This rapid recovery of normal tissues is exploited in devising intermittent courses of chemotherapy.

In cancer, the normal feedback mechanisms which mediate cell growth are defective and cell proliferation continues unchecked. Cancer cells continue to multiply, at first exponentially. Cancers with high growth fractions (e.g. acute leukaemias, high-grade lymphomas) may visibly enlarge at an alarming rate, but may also be highly sensitive to cytotoxic chemotherapy. In later stages, the growth rate of many cancers slows and the volume-doubling time becomes prolonged due to several factors, most of which conspire to render the advanced cancer less susceptible to drugs:

• Increased cell cycle (division) time

• Decrease in the number of cells actively dividing, with more in the resting state (decrease in growth fraction)

• Increased cell death within the tumour as it ages

• Overcrowding of cells leading to necrotic, avascular areas which cannot easily be penetrated by drugs.

Whilst selectivity of drugs for cancer cells is generally low compared with selectivity of antimicrobial drugs, in some tumours it can be substantial, as in lymphoma, in which the tumour cell kill with some drugs is 10 000 times greater than that of marrow cells. Cell destruction by cytotoxic drugs follows first-order kinetics, i.e. a given dose of drug kills a constant fraction of cells (not a constant number) regardless of the number of cells present. Thus treatment reducing a cell population from 1 000 000 to 10 000 (a two log cell kill) will reduce a cell population of 100 to 1. Furthermore, cell chemosensitivity within a cancer is not homogeneous due to random mutations as the tumour grows and cells remaining after initial doses are likely to become resistant to treatment. Therefore, combining several drugs may be more effective than administration of a single agent, with repeated administration to the limit of patient tolerance.

The selection of drugs in combination chemotherapy is influenced by:

• Choosing drugs which act at different biochemical sites in the cell

• Using drugs that attack cells at different phases of the growth cycle (see Fig. 30.1)

• The desirability of attaining synchronisation of cell cycling to achieve maximum cell kill. For example, cells are killed or are arrested in mitosis by vincristine, which is then withdrawn. Cells then enter a new reproductive cycle more or less synchronously and when the majority are judged to be in a phase sensitive to a particular phase-specific drug, e.g. methotrexate or cytarabine, it is given.

• Lack of evidence of cross-resistance (see below)

• Non-overlapping adverse effect profiles

• Empirical evidence of efficacy against a particular tumour type.

Considerations of pharmacokinetics in relation to cell kinetics are of great importance, as drug treatment alters the activity of both malignant and normal cells.

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