Autologous marrow rescue in the treatment of acute non- lymphocytic leukemia (ANLL) is limited by the presence of occult viable clonogenic leukemia cells in the marrow graft. Preclinical studies in a rodent model of ANLL have demonstrated efficacy of in vitro purging of marrow suspensions containing small (approximately 5%) numbers of leukemia cells with 4- hydroperoxycyclophosphamide (4HC) and infusion after myeloablative therapy. Clinical trials have shown high relapse rates and with substantial hematopoietic toxicity with this approach. In the proposed research project, strategies to improve the tumoricidal ability of purging regimens in ANLL and to decrease toxicity to normal hematopoietic progenitors will be examined. Using a rodent model of ANLL the investigator plans to more completely define the tumor biology of this leukemia and will investigate the utility of bleomycin, amsacrine and actinomycin-D, alone and in combination with 4HC of purging suspensions of rat bone marrow cells contaminated with varying amounts of rat ANLL cells. Combination pharmacologic therapy will be evaluated using measurement of in vitro killing in clonogenic assay for normal bone marrow and leukemia cells. These combinations will then be evaluated for their ability to provide leukemia-free survival in rats that receive injections of treated leukemia cells and/or marrow rescue with treated suspensions of marrow and tumor cells in transplant experiments. The investigator will develop a battery of in vitro tests, including cell cultures, measurement of drug effects on DNA cross links, and perturbations in cell cycle, in an attempt to delineate in vitro observed correlates with in vivo effects against ANLL and normal progenitor cells effect. Using tumor necrosis factor, the enhancement of the differential cytotoxicity of the combination agents on rodent ANLL and on a human erythroleukemia cell line (K562) will be studied, to further investigate methods that protect normal bone marrow progenitors from the cytotoxicity of these agents. These comprehensive preclinical studies will develop principles for the application of combination purging with chemotherapeutic agents and biological response modifiers in clinical treatment of leukemic marrow and form the basis for the applicant's career development as an independent investigator.
| Wiley, J M; Yeager, A M (1991) Predictive value of colony-forming unit assays for engraftment and leukemia-free survival after transplantation of chemopurged syngeneic bone marrow in rats. Exp Hematol 19:179-84 |
