Summary
FCE 24517, a derivative of distamycin A, exhibits an unusual antitumor profile in experimental models. As part of its preclinical development, we evaluated thein vitro myelotoxicity of FCE 24517 to human, canine and murine hematopoietic cells. Marrow cells were exposed to the agent (2.7×10−5−2.7 nM) for 4 h and then assayed in capillary (human) or Petri dish (canine, murine) clonal cultures. FCE 24517 inhibited myeloid (CFU-gm), erythroid (BFU-e, CFU-e) and megakaryocytic (CFU-meg) colony formation in a concentration-dependent manner. The progenitor cells were generally similar in their response to FCE 24517 within a species. Comparing the different progenitor cell response to FCE 24517, canine CFU-gm and CFU-e were 26- to 221-fold more sensitive to this drug's toxic effects than their human and murine counterparts. This was demonstrated by extremely low IC70 values for the canine CFU-gm (0.001 nM) and CFU-e (0.007 nM). Murine progenitors displayed 1.3- to 10.9-times higher IC70 values than human CFU-gm, BFU-e and CFU-e following 4 hr exposure to FCE 24517. The data demonstrated that a mouse model may better predict humanin vitro myelotoxicity to FCE 24517 than beagle dogs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arcamone FM, Animati F, Barbieri B, Configliacchi E, D'Alessio R, Geroni C, Giuliani C, Lazzari E, Menozzi M, Mongelli N, Penco S, Verini MA: Synthesis, DNA-binding properties, and antitumor activity of novel distamycin derivatives. J Med Chem 32:774–778, 1989
Barbieri B, Giuliani FC, Pezzoni G, Lazzari E, Arcamone F, Mongelli N:In vivo antitumor activity of FCE 24517, a novel distamycin A derivative with specificity for A-T rich sequences of DNA (Abstract). Proc Amer Assoc Cancer Res 29:330, 1988
Pezzoni G, Grandi M, Biasoli G, Capolongo L, Ballinari D, Giuliani FC, Barbiera B, Pastori A, Pesnti E, Mongelli N, Spreafico F: Biological profile of FCE 24517, a novel benzoyl mustard analog of distamycin A. Brit J Cancer 64:1047–1050, 1991
Broggini M, Erba E, Ponti M, Ballinari D, Geroni C, Spreafico F: Selective DNA interaction of a novel distamycin derivative FCE 24517. Cancer Res 51:199–204, 1991
Broggini M, Ponti M, Ottolenghi S, D'Incalci M, Mongelli N, Mantovani R: Distamycins inhibit the binding of OTF-1 and NFE-1 transfactors to their conserved DNA elements. Nucleic Acids Res 17:1051–1059, 1989
Du DL, Volpe DA, Murphy MJ: Microcapillary clonogenic assays for human bone marrow hematopoietic progenitor cells. Int J Cell Cloning 7:303–313, 1989
Du DL, Volpe DA, Grieshaber CK, Murphy MJ: Comparativein vitro myelotoxicity of fostriecin, hepsulfam and pyrazine diazohydroxide to human and murine hematopoietic progenitor cells. Invest New Drugs 9:149–157, 1991
Du DL, Volpe DA, Grieshaber CK, Murphy MJ:In vitro myelotoxicity of 2′,3′-dideoxynucleosides on human hematopoietic progenitor cells. Exp Hematol 18:832–836, 1990
Volpe DA, Du DL, Pohl KP, Campbell JP, Murphy MJ: Utility of human bone marrow obtained incidental to orthopedic surgery for hematopoietic clonal assays. Pathobiology 59:53–56, 1991
Burgess AW, Wilson EM, Metcalf D: Stimulation by human placental conditioned medium of hematopoietic colonyformation by human marrow cells. Blood 49:573–583, 1977
Gallicchio VS, Murphy MJ:In vitro erythropoiesis. II. Cytochemical enumeration of erythroid stem cells (CFU-e and BFU-e) from normal mouse and human hematopoietic tissues. Exp Hematol 7:219–224, 1979
McLeod DL, Shreeve MM, Axelrad AA: Improved plasma culture system for production of erythrocytic coloniesin vitro: quantitative assay method for CFU-e. Blood 44:517–534, 1974
Sheridan JW, Metcalf DW: A low molecular weight factor in lung-conditioned medium stimulating granulocyte and monocyte colony formationin vitro. J Cell Physiol 81:11–24, 1972
Murphy MJ, Sullivan ME: Culture of erythroid stem cells from murine and human marrow and blood. In: Murphy MJ (ed.),In vitro Aspects of Erythropoiesis. Springer-Verlag, New York, 1978, pp. 262–265.
Johnson GR, Metcalf D: Pure and mixed erythroid colony formationin vitro stimulated by spleen-conditioned medium with no detectable erythropoietin. Proc Natl Acad Sci USA 74:3879–3882, 1977
Kuriya S, Kwak J, Tajika K, Minoda Y, Nomura T, Murphy MJ: Cloning of murine megakaryocyte progenitor cells in a fibrin clot culture system. Exp Hematol 15:896–901, 1987
Nakeff A, Daniels-McQueen S:In vitro cloning assay for a new class of megakaryocyte precursor: colony-forming unit megakaryocyte (CFU-M). Proc Soc Exp Biol Med 151:587–590, 1976
Grieshaber CK, Marsoni S: Relation of preclinical toxicology to early clinical trials. Cancer Treat Rep 70:65–72, 1986
Rozencweig M, Von HoffDD, Staquet MJ, Schein PS, Penta JS, Goldin A, Muggia FM, Freireich EJ, DeVita VT: Animal toxicology for early clinical trials with anticancer agents. Cancer Clin Trials 4:21–28, 1981
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Volpe, D.A., Du, DL., Zurlo, M.G. et al. Comparativein vitro myelotoxicity of FCE 24517, a distamycin derivative, to human, canine and murine hematopoietic progenitor cells. Invest New Drugs 10, 255–261 (1992). https://doi.org/10.1007/BF00944178
Issue Date:
DOI: https://doi.org/10.1007/BF00944178