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Hematopoietic toxicity and cell cycle perturbations induced by new DNA minor groove–alkylating agents
Author(s) -
Filippini Cristian,
Bisiach Matteo,
Tagliabue Giovanna,
D'Incalci Maurizio,
Ubezio Paolo
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970904)72:5<801::aid-ijc16>3.0.co;2-b
Subject(s) - minor groove , toxicity , dna , haematopoiesis , cell cycle , dna damage , biology , hematopoietic cell , groove (engineering) , cancer research , cell , microbiology and biotechnology , genetics , medicine , stem cell , engineering , mechanical engineering
Abstract Some new alkylating agents which bind to the minor groove of DNA and have sequence‐specific patterns of alkylation have shown anti‐neoplastic activity in pre‐clinical systems. Two of them, carzelesin and tallimustine, are now in phase II. Considering the severe dose‐limiting bone marrow toxicity of both these drugs in clinical use, it was of interest to investigate the mechanism of their myelotoxicity in a detailed pre‐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 comparatively in mice, combining data on bone marrow and peripheral blood cellularity with data on the proliferative activity of bone marrow cells, obtained by in vivo administration of bromodeoxyuridine. Significant differences were found between the hematopoietic response to the 3 drugs, though all caused severe leukopenia. Carzelesin induced a short‐term increase in myeloid proliferative activity, which prevented the high leukocytopenia on day 3 observed with the other drugs. However, when this effect was exhausted, a second nadir was seen in peripheral blood, with 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 hematopoietic system response to tallimustine was dampened, with no overshoots, suggesting either lasting effects or extensive cytotoxicity from the early to late precursors of all lineages. Int. J. Cancer 72:801–809, 1997. © 1997 Wiley‐Liss, Inc.