PROPHYLACTIC PRETREATMENT OF MICE WITH HEMATOPOIETIC GROWTH-FACTORS INDUCES EXPANSION OF PRIMITIVE CELL COMPARTMENTS AND RESULTS IN PROTECTION AGAINST 5-FLUOROURACIL-INDUCED TOXICITY

The aim of this study was to expand the primitive and committed hemato poietic cell compartments in vivo in order to confer resistance of the blood cell forming system against the cytotoxic, cell cycle specific drug 5-fluorouracil (5-FU). Possible chemoprotective effects of such a pretreatment could result from increased numbers of hematopoietic cel ls, present before 5-FU administration. In addition, we hypothesized t hat an enhanced number of primitive and progenitor cells would result in a reduced cycling activity, ie, 5-FU sensitivity, of these same cel ls, due to normal physiological feedback loops. Administration of stem cell factor (SCF) plus interleukin-11 (IL-11) to mice was shown to re sult in expansion of the various immature cell compartments in marrow and, in particular, spleen. The total body content of the primitive co bblestone area forming cells (CAFC)-day 28 was increased to 140%, wher eas the more committed cells (CAFC-day 7, erythroid and granuloid prog enitors) were increased to 500%. This in vivo expansion resulted in a decreased 5-FU sensitivity of the hematopoietic system. In particular, mice that had received 5-FU 24 hours after discontinuation of growth factor pretreatment showed significantly less toxicity of committed ce ll stages. Compared with mice not pretreated, it appeared that in pret reated mice, 24 hours after 5-FU administration, the absolute number, but also the fraction of surviving CAFC, was much higher in both marro w and spleen. This was caused by a decrease in the cycling activity of all primitive cell subsets. To explore the possible use of this findi ng in a chemotherapeutic setting, we determined the interval between t wo subsequent doses of 5-FU (160 mg/kg) that was required to prevent d rug-induced mortality. When control mice received a second dose of 5-F U 7, 10, or 14 days after the first, respectively 0%, 20%, and 80% sur vived. In contrast, 40% and 100% of mice that received SCF + IL-11 bef ore the first dose of 5-FU, survived a second dose of 5-FU given respe ctively after 7 or 10 days. To assess whether chemoprotection in this setting could be ascribed to protection of the hematopoietic system, w e transplanted a high number of normal bone marrow cells (sufficient t o compensate for any hematopoietic deficiency) to normal and pretreate d mice after they had been administered 2 doses of 5-FU, given 7 days apart. Bone marrow transplantation (BMT) could only rescue 50% of mice not pretreated, showing that a significant part of the mortality was because of nonhematologic toxicity. However, a BMT given to growth fac tor pretreated mice saved all mice, indicating that in this setting SC F + IL-11 had additional protective effects on cell systems other than hematopoiesis. In conclusion, our study showed fundamental knowledge about the behavior of primitive cells in vivo and has shown that manip ulation of these and other cell compartments with appropriate growth f actors may confer resistance against cytotoxic drugs. (C) 1996 by The American Society of Hematology.