Antineoplastic chemotherapy myelosuppression: mechanisms and new approaches

Most antineoplastic drugs have diverse effects on the hematopoietic system. Certain drugs are directly cytotoxic to myeloid stem cells or their progenitors whereas others affect hematopoiesis indirectly. In most instances, drugs with a direct effect cause reductions in circulating blood cells and in bone marrow cellularity, and at very high doses they may induce bone marrow aplasia. Usually this type of toxicity is reversible unless the aplasia is severe. Antineoplastic drugs can also alter normal hematopoiesis by their effect on the bone marrow microenvironment, by interactions with cells or factors that regulate normal hematopoiesis, or by interactions with lymphoid cells. The most common means of directly assessing the myelosuppressive effects of antineoplastic drugs involves measurement of circulating blood cells or of bone marrow cellularity. More detailed analyses include assessment of hematopoietic stem cells or of bone marrow reserve. Marrow microenvironmental abnormalities are difficult to evaluate critically in man, as are effects on the immune system. The recent development of assays of hematopoietic growth regulatory factors (erythropoietin, colony-stimulating activity, interleukins) permits a more precise basis for assessment of drug effects on bone marrow function. It is likely that an increased understanding of the mechanisms of myelosuppression induced by antineoplastic drugs will lead to the development of agents with an increased therapeutic ratio and to the more effective use of current drugs.