A CLINICIAN'S COMMENTS ON THE CYCLOPHOSPHAMIDE HEMATOTOXICITY BIOLOGICALLY BASED RISK ASSESSMENT MODEL

Circulating blood cells are derived from precursor cells that reside in the bone marrow. The most primitive blood-forming cells, the hematopoietic stem cells (HSCs) can undergo extensive proliferation and can give rise to all the different blood cell types present in the peripheral blood. Most HSCs are not actively dividing. These “resting” HSCs provide a reservoir of cells that maintain blood cell production for the life of an animal. The HSCs start dividing as they mature and differentiate toward their ultimate goal, the formation of circulating blood cells. As blood-cell precursors mature, there is an ever-increasing restriction in their ability to self-renew and proliferate. During the first step in this maturation process, the HSCs differentiate into colony-forming cells that are able to form only cells belonging to the myeloid blood lineages (CFU-multi). As maturation proceeds, the CFU-multi give rise to daughter cells able to differentiate into only one or two types of blood cells. For the granulocyte blood-cell lineage, this cell is called a CFU-GM or CFU-G. Similar precursor cells exist for each of the other blood cell lineages. Further hematopoietic development results in the appearance of morphologically recognizable blood-cell precursors. The late marrow precursors are unable to proliferate and form a pool of maturing cells. Mature cells transit into the peripheral blood and circulate. In a normal animal, production of new blood cells by the hematopoietic system is balanced with the destruction of old blood cells, resulting in near constant numbers of circulating blood cells. This is the result of a complex homeostatic mechanism in the form of soluble and cellassociated growth factors that are triggered by environmental signals. Clinically, this knowledge provides the conceptual framework for understanding the recovery of bone marrow cells from toxins. This has lead to the development of techniques that allow hematopoietic cell rescue for patients that have received doses of chemotherapy and radiation that are high enough to permanently destroy the bone marrow.