The long term goal of the project is to develop a myelostatic agent to protect human hematopoietic precursor cells from the destructive effects of chemotherapeutic agents currently used in the treatment of tumors. The Applicants propose that protection of precursor cells by inhibition of growth during cancer treatment would reduce the toxicity associated with standard chemotherapy or permit the administration of higher doses of chemotherapeutics without compromising the ability of the patient to regenerate mature functional blood cells. They have identified a family of novel chemokine-based agents, which reversibly inhibit human stem cell proliferation in vitro at very low concentrations. Their initial plan is to test the agents' efficacy for temporarily inhibiting proliferation of murine hematopoietic progenitor cells in vivo. Successful completion of this goal may lead directly to a new clinical candidate. In parallel, the Applicants propose to express, purify, and test in an in vitro stem cell proliferation assay additional novel agents. The hypothesis is that the determination of the protein domains within the chemokine proteins which are required for biological activity will lead to peptide mimetics or small organic molecule drug candidates for evaluation in both in vitro and in vivo assays to assess their clinical potential.
