From the beginning of the modern era of cancer chemotherapy research, attempts have been made to learn how cancer drugs attack cells. The classification system described in this section has been developed over a number of years as knowledge of the effects of drugs on cell chemistry has accumulated and drugs from new sources have been discovered.
This large group of chemically reactive compounds, which includes the well known drug nitrogen mustard, are general cell poisons. They are called alkylating agents on the basis of their chemical properties, since they are capable of reacting with, or alkylating, a number of chemical groupings, many of which are of vital importance in cell functions. These compounds are sometimes referred to as radiomimetic substances because they can produce cellular damage similar to that caused by X-ray. Studies have suggested that alkylating agents act by cross-linking bases, probably guanine components, in the DNA, thus inhibiting its replication.
Nitrogen mustard is in standard use for treatment of Hodgkin's disease, busulfan (My-leran) for chronic myelocytic (granulocytic) leukemia, L-sarcoIysin (melphalan) for multiple myeloma, and cyclophosphamide for acute lymphocytic leukemia and Burkitt's tumor. Alkylating agents are used also in lymphosarcoma, chronic lymphocytic leukemia, and some carcinomas of the lung, ovary, and breast.
The serious toxicity of the alkylating agents resides mainly in their effects upon the bone marrow. Cyclophosphamide, however, while exerting lethal effects on the white blood cells is relatively sparing of platelets, a lack of which leads to hemorrhage. A serious side effect of cyclophosphamide is a temporary loss of hair; it generally begins to grow back when a reduced maintenance dose is started and grows back completely when the drug is discontinued.
Cyclophosphamide is an unusual compound in that it is inactive in a test tube and is activated slowly in the body. It is composed of nitrogen mustard linked to a phosphoric acid derivative; the nitrogen mustard cannot exert its cell-destroying action until the bond is broken enzymatically. Studies have suggested that the drug is transported in its inert form and that its breakdown occurs in the liver and in tumor cells, which metabolize more rapidly and tend to have a higher content of the enzyme, phosphoramidase, than do normal cells (page 73).
The drug, HN2, nitrogen mustard, is called an alkylating agent because of its ability to react with, or alkylate, chemical groupings in a cell. Studies have suggested that HN2 kills a cell by cross-linking bases, probably guanine components, in the DNA and thus inhibiting its replication.