The Cell Reproductive Cycle and Cytotoxic Drugs

Understanding how cells divide can help us understand how chemotherapy works to destroy cancer cells.

Both normal healthy cells and malignant cells reproduce in a process called mitosis.  The chromosomes in the cell nucleus build copies of themselves and the nucleus splits followed by splitting of the cytoplasm.  Two daughter cells are the result.

Cells are either interphase or miotic phase at any given time.  Most of the time cells are interphase – they are not reproducing.  Different types of cells divide at different rates.  The miotic phase can be further divided to mitosis proper (division of the cell nucleus) and cytokinesis (division of the cytoplasm),

The whole cycle of somatic cell division typically lasts from 8 to 24 hours in humans although some cells rarely reproduce and the time scale is much longer.  About 90 percent of the cell’s time is spent in interphase.

Another way of classifying the cell cycle includes prophase (DNA lines up for replication), metaphase (formal replication), anaphase (split of chromosomes), and telophase (cell membrane closes so two cells are produced).

A further method classifying the process (and the method most used in medicinal chemistry for oncology) has four phases: the G1, S, G2, and M phases.  The cell progresses through these phases in order.  Cell-cycle specific chemo agents act in one (or two) parts of the cycle.  cell-cycle nonspecific agents are active in all phases.

G1 is when the cell is doing its normal living.  Most protein production happens in this phase.  The DNA is coiled up and not being replicated.  S stands for synthesis and it is in this phase is that DNA is copied.  G2 is when RNA is replicated and M stands for mitosis – when the cell divides.

Most cytotoxic drugs used to treat cancer work in the cell reproduction process.   Some are called cell-cycle specific (CCS) drugs that interfere within the cell’s processes on one phase.  Taxanes and vinca alkaloids do their biochemical work in the M phase.  Antibiotics, PARP inhibitors, and antimetabolites work in the S phase.  Alkylating agents can work in any phase.

When formulating combination chemotherapy regimens, oncologists often look for two drugs that work in different parts of the cycle.

Other chemotherapeutic agents kill multiplying cells in all phases.  They are not phase-specific and are sometimes called CCNS, cell-cycle non-specific.

Enzymes called cyclin-dependent kinases are part of the biochemical process involved in starting the cycle, and in moving from G1 to S and from G2 to M.  By inhibiting these kinases, some drugs are able to slow or stop cell proliferation.  Several CDK-inhibitors are in use for cancer treatment.

Some quantitative characteristics that can be used to describe tumors are:

Mitotic Index (MI): proportion of cells in mitosis
Labeling Index (LI): proportion of cells in S phase
Growth fraction: ratio of the number of cells number of cells proliferating cells to the total number of cells. This fraction is typically 30 percent to 50 percent.