HEMATOPOIETIC TOXICITY AND CELL-CYCLE PERTURBATIONS INDUCED BY NEW DNA MINOR GROOVE-ALKYLATING AGENTS

Some new alkylating agents which bind to the minor groove of DNA and h ave sequence-specific patterns of alkylation have shown anti-neoplasti c activity in pre-clinical systems. Two of them, carzelesin and tallim ustine, are now in phase II. Considering the severe dose-limiting bone marrow toxicity of both these drugs in clinical use, it was of intere st to investigate the mechanism of their myelotoxicity in a detailed p re-clinical study and compare it with a conventional alkylating agent, such as melphalan. The origin and progression of the myelotoxicity of carzelesin, tallimustine and melphalan were investigated comparativel y in mice, combining data on bone marrow and peripheral blood cellular ity with data on the proliferative activity of bone marrow cells, obta ined by in vivo administration of bromodeoxyuridine. Significant diffe rences were found between the hematopoietic response to the 3 drugs, t hough all caused severe leukopenia. Carzelesin induced a short-term in crease in myeloid proliferative activity, which prevented the high leu kocytopenia on day 3 observed with the other drugs. However, when this effect was exhausted, a second nadir was seen in peripheral blood, wi th a new wave of cell proliferation of all lineages in the bone marrow . Reconstruction of the lymphoid lineage was slow for all 3 drugs but particularly difficult with high-dose tallimustine. In general, the he matopoietic system response to tallimustine was dampened, with no over shoots, suggesting either lasting effects or extensive cytotoxicity fr om the early to late precursors of all lineages. (C) 1997 Wiley-Liss, Inc.