The Cancer Cell Cell cycle

All cells of the human body are derived from a single cell, the zygote, by a series of cell divisions following which they progress along a large number of differentiation pathways to acquire specialized functions. Specialized cells occupy a unique differentiation compartment within the organism, and once 'committed' to that lineage generally cannot change to another cell type. A limited number of progenitor 'stem

cells' occupy each compartment and are genetically controlled to proliferate continuously and repopulate it. As differentiating genes take over control, proliferative activity usually decreases. Once fully differentiated, cells enter a third sequence of genetic events, that of apoptosis or programmed cell death.

A characteristic of neoplastic cells is their unregulated progression through the cell cycle. It is now known that this cycle is driven by a family of proteins, cyclins, which form complexes with cyclin-dependent protein kinases. The most important trigger for mitosis occurs during the G1-phase of the cycle, which is effected by cyclins A, D and E in combination with a range of regulatory protein kinases, of which cdk 2 is particularly important. Once the cells pass through the synthetic phase and reach G2 they are committed to mitosis, which is initiated by the action of cyclin B complexed to cdk 1.

Regulatory steps, termed check-points, occur between G1 and S and G2 and M which, should there be damage to DNA allows time for repair so that errors in replication are avoided. Repair of DNA is brought about by topoisomerase I and II, enzymes which unwind the helix, and realign the strands. Inhibition of these enzymes causes cell death.

Chemotherapeutic drugs are now classified according to their cell-cycle specificity. Type 1 drugs, which include alkylating agents and platinum derivatives act by complexing DNA to cause irreparable damage by intercalation. Type 2 drugs specifically inhibit the 'engine' driving the cycle and are termed antimetabolites.

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