Chemotherapy drugs and the phases of the cell cycle
Chemotherapy drugs are cell-cycle-specific if they work mainly on cells at a particular stage of the cycle, and cell-cycle-non-specific if they act at any stage.
Remember
S stands for synthesis and M for mitosis: drugs that imitate the building blocks of DNA act mainly in S phase, drugs that disrupt the spindle (the structure that pulls the chromosomes apart) act in M phase, and drugs that damage DNA at any point in the cycle are phase-non-specific.
Cells pass through four active phases: G1 (growth), S, G2 (preparation) and M. A cell that has left the cycle rests in G0, the resting state. In S phase, the synthesis phase, the cell copies its DNA, and in M phase, which is mitosis, it divides.
Antimetabolites imitate the cell's normal DNA building blocks, or the vitamins that are used to make them, and so jam the enzymes that make or use those blocks. Copying DNA depends on those building blocks, so antimetabolites act mainly in S phase. Methotrexate, for example, blocks dihydrofolate reductase, an enzyme that regenerates tetrahydrofolate (a form of the vitamin folate), so the cell lacks the thymidine and purines it needs as DNA building blocks. 5-fluorouracil and cytarabine are also antimetabolites.
Vinca alkaloids such as vincristine, and taxanes such as paclitaxel and docetaxel, are M-phase specific because they act on microtubules, the hollow protein tubes that build the spindle. The spindle drags the copied chromosomes to opposite ends of the cell. Vinca alkaloids stop microtubules from forming, so no working spindle appears and cells are held in mitosis. Taxanes work the opposite way: they lock microtubules in place so they cannot disassemble, and the spindle is jammed again.
Alkylating agents such as cyclophosphamide (which attach chemical groups to DNA), platinum compounds such as cisplatin (which form cross-links within and between DNA strands) and anthracyclines such as doxorubicin (which slide between the bases of DNA) are phase-non-specific. They damage DNA at any point in the cycle, though dividing cells are hit hardest.
Most chemotherapy does not kill cells resting in G0, so resting cancer cells can survive treatment and be the source of a later relapse.
Key facts
- S-phase drugs
- antimetabolites such as methotrexate, 5-fluorouracil and cytarabine act mainly during DNA synthesis.
- M-phase drugs
- vinca alkaloids and taxanes target microtubule function during mitosis.
- Phase-non-specific drugs
- alkylating agents, platinum compounds and anthracyclines damage DNA at any point in the cycle, though dividing cells are hit hardest.
- Methotrexate
- it blocks dihydrofolate reductase, which is why it is an S-phase drug.
- Resting cells
- G0 cells are not killed by most chemotherapy, which is one reason cancers can relapse.
Exam traps
- A vinca alkaloid such as vincristine is phase-specific but is not an S-phase drug, because it stops microtubules from forming and arrests cells in M phase, so it targets mitosis rather than DNA synthesis.
- An alkylating agent such as cyclophosphamide is not S-phase specific even though rapidly dividing cells suffer most, because it damages DNA whichever phase the cell is in.
- Platinum compounds cross-link DNA, and the damage interferes with DNA copying, yet they are classed as phase-non-specific and act at any point in the cycle, so they are not the S-phase class.
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