One of the most important groups of proteins are enzymes, which catalyze the chemical reactions in living cells. Enzymes are indispensable for the life of cells, since they enable their processes to take place readily at body temperature and with speed, and do not themselves enter into the reaction.

The majority of known biochemical differences between normal and cancer cells are quantitative, that is, there is more or less of a given substance or type of process. Some investigators believe there are also qualitative differences, as, for example, antigens (proteins that stimulate the production of antibodies in the blood serum) specific to cancer cells, and lack of an enzyme which makes some mouse leukemias and rat tumors dependent on an external source of an amino acid called L-asparagine.

Multiplication. The events leading to cell division and the act of division are a distinct and separate phase in the life of a cell. While some resting (nondividing) cells are susceptible to certain drugs, the complex events in the division cycle (mitotic cycle) create special, vulnerable situations in which cancer drugs can disrupt a cell.

The cell division cycle

The cell division cycle consists of four phases: G 1—postmitotic, S—DNA synthesis, G 2—pre-mitotic, and M— mitosis. G 1 and G 2 phases are pauses just after and just before mitosis; in the S phase, the DNA content of the nucleus is exactly doubled: mitosis is the phase during which the chromosomes split, the nucleus duplicates itself, and, finally, the cytoplasm divides, resulting in production of two daughter cells. The new cells may proceed into another division cycle or enter G 0, or resting (nondividing), phase. It has been estimated that about half of the time it takes to complete one division cycle is spent in the G 1 phase, 29 percent in the S phase, 19 percent in the G 2 phase, and 1 percent in the mitotic phase.

The division cycle consists of four phases: Gl—post-mitotic, S—DNA synthesis, G2— pre-mitotic, and M—mitosis. The time it takes for a cell to complete one entire division cycle is the generation time.

Gl and G2 phases are periods just after and just before mitosis. The Gl phase is a pause in which the cell is actively metabolizing; the G2 phase is another pause in which the cell is actively building up energy reservoirs, presumably to carry it through the mitotic process.

In the S phase, the DNA content of the nucleus is exactly doubled. DNA exists in the cell combined with protein, as nucleoprotein. Chromosomal proteins, such as histone, are synthesized more or less simultaneously with DNA. RNA synthesis is depressed during DNA replication but does not stop completely, probably because all the DNA does not replicate simultaneously and some fraction is always capable of templating RNA.

Mitosis is the phase during which the chromosomes split, the nucleus duplicates itself, and, finally, the cytoplasm divides, resulting in production of two daughter cells. Classically the M phase has been divided into four sub-phases: prophase, metaphase, anaphase, and telophase. During these phases the chromosomes become tightly coiled and shorten in length; they move to the cell equator and become aligned midway between the poles, with each sister chromosome attached to a different pole; then they split into two sister chromatids, each of which has half of the old and half of the new DNA; and finally, they separate, each sister chromatid moving to its pole, and membranes begin to form about each group of chromosomes. Then cell division occurs: the cell membrane and cytoplasm cleave along a line directly between the two new nuclei, creating two daughter cells each containing a membrane, cytoplasm, and nucleus. The chromosomes uncoil and reassume their configuration of fine filaments diffusely distributed throughout the nucleus. Cancer cells usually do not show this orderly pattern of division.

process of cell division

This is a summary view of the process of cell division. The chromosomes separate and membranes form about each new group of chromosomes. The cell membrane and cytoplasm cleave along a line directly between the two new nuclei, creating two daughter cells each containing a membrane, cytoplasm, and nucleus.

Certain cells, such as nerve and muscle cells, reach a high level of differentiation, and are then not able to divide or regenerate. Others, such as bone marrow and intestinal epithelium, multiply constantly. Some cells rarely divide, but are capable of regenerating to restore normal structures when needed. These are "germinal lines" or reserve cells in tissues capable of producing more differentiated cells when the proper stimulus occurs.

Cellular Resistance to Drugs. One of the major problems in cancer chemotherapy has been the development of resistance to the action of a specific drug to which a cancer was initially susceptible. Resistance is apparently due to the development of mutant or genetically altered cells that are no longer subject to damage by the drug. These mutations are generally stable and persist in the absence of the drug.

An explanation has been suggested for the acquired resistance of tumors to the drug 6-mercaptopurine, a purine antagonist. Susceptible tumors convert the drug to 6-mercaptopurine ribonucleotide, at which level it inhibits purine biosynthesis and is biologically active. Resistant tumors have cells with very low levels of the enzyme required for this conversion and cannot therefore utilize mercaptopurine.

cells resistant to the action of a specific drug

As suggested in this drawing, a small percentage of cancer cells may become resistant to the action of a specific drug to which a cancer was initially susceptible. Resistance is apparently due to the development of mutant or genetically altered cells (right) that are no longer subject to damage by the drug. However, such cells may be responsive to a different drug.