Michael George Hunter

Engineering, Biology, and Clinical Development of hMIP-1α

The side effects of anticancer chemotherapy on normal cells often limit the severity of treatment that can be tolerated. If side effects could be reduced or managed effectively, then escalation of chemotherapy may lead to better clinical responses. Typical side effects of chemotherapy include depletion of bone marrow causing neutropenia, gastrointestinal mucositis, and hair loss. Of these, perhaps the most limiting is the effect of chemotherapy on bone marrow. Bone-marrow recovery after treatment with cytotoxic drugs depends on the survival of hematopoietic stem cells with the ability to replenish the hematopoietic progenitor pool indefinitely. Such cells are normally quiescent, rendering them insensitive to cycle-specific cytotoxic therapy. However, prolonged doses or repeat cycles of chemotherapy stimulate the division (self-renewal) of these multipotent stem cells and their differentiation into more committed progenitors (1). Therefore, once dividing, their survival is in jeopardy during cytotoxic drug therapy and a specific inhibitor of stem cell division might be expected to find use as an adjunct to chemotherapy. In clinical oncology, the expectation would be that stem-cell protection could provide a means of facilitating the recovery of circulating blood cells that have been depleted by multiple cycles of chemotherapy. Because the depletion of circulating neutrophils and platelets during cytotoxic drug therapy is the major dose-limiting toxicity, the use of a recombinant stem-cell inhibitor during such treatment should allow dose intensification and, therefore, more effective therapy. Here we describe the evaluation of the clinical potential of the stem-cell inhibitor macrophage inflammatory protein-1a (MIP-1α), a multifunctional CC chemokine.