Abstract

An enormous literature has been amassed on the effects of various cytotoxic drugs on mammalian hemopoiesis in situ. Recovery patterns have been noted to differ markedly between drug groups although the initial cytotoxic effects of the drugs are very similar. The reasons for this discrepancy are not entirely clear. It has been possible to produce comprehensive mathematical models of hemopoiesis which reproduce much of the published experimental literature, including perturbations of erythropoiesis (anemia and plethoria), and stem cell behavior following acute and chronic whole body radiation. However, comprehensive models following drug therapy are unavailable due to the lack of sufficient comparative experimental data within a single animal model. Our purpose is to compare comprehensively the hematopoietic effects of two well-known but differently acting cytotoxic drugs, hydroxyurea and busulfan, within a single murine model. Both acute and long-term studies will be performed which will assess direct and long-term effects of each drug on several classes of hematopoietic cell progenitors via clonal cell assays performed in vitro (i.e., CFU-GEMM, BFU-E, CFU-E, CFU-GM) as well as in vivo (CFU-S). An attempt will be made to provide an answer to the question as to how cytotoxic drugs perturb hemopoiesis and whether their effects can be quantitated in terms different from mere survival ratios. Drug doses and injection schedules will be selected which will provide a severe but optimal hematopoietic stress equivalent to that produced by other experimental means so as to facilitate a direct comparison of the experimental data, thus permitting more accurate testing of model paradigms. The proposed work should provide a valuable data base for mathematical analysis and modeling than is presently available. Emphasis will be placed on the comparison of hematopoietic survival and recovery curves obtained from the proposed drug studies and those obtained from the extensive experimental literature analyzed to date via modeling. Hydroxyurea and busulfan will be administered separately and in combination to test the accuracy of specific predictions regarding their induced hematopoietic recovery patterns. It is hoped that this approach will permit a distinction to be made between the effects of cytotoxic drugs on hematopoietic cell progenitors vs. their additional affects on normal regulatory mechanisms. This study will also provide the means for evaluating the drug effects in a novel, quantitative, and analytical way via modeling.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037366-02
Application #
3236234
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1986-09-15
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Boston University
Department
Type
Schools of Arts and Sciences
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118