Histidinol-mediated improvement in the specificity of 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil in L 1210 leukemia-bearing mice.
We have demonstrated previously that L-histidinol, a structural analogue of the essential amino acid L-histidine, protects a variety of phenotypically normal cell lines from certain proliferation-dependent anticancer drugs without decreasing the toxicity of these agents for corresponding tumorigenic derivatives of the normal cells. Histidinol modulates the toxicity of selected anticancer drugs in tissue culture systems by its ability to arrest, specifically and reversibly, cells of normal phenotype in a G0-like, noncycling state while allowing continued cell cycle transit in most of their tumorigenic counterparts. Thus, in the presence of comparable levels of histidinol, the toxicities of the proliferation-dependent anticancer drugs 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil are eliminated for a variety of normal cell lines but significantly increased for a number of tumorigenic lines. We report here that histidinol confers substantial protection upon the bone marrow cells of DBA/2J mice from the drugs 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil. The protective responses were evaluated by quantitative cell survival assays and by animal survival studies. We report also that the histidinol-mediated protection to bone marrow cells persists in L1210 leukemia-bearing DBA/2J mice treated with combinations of histidinol and 1-beta-D-arabinofuranosylcytosine or 5-fluorouracil without diminishing the toxicities of these agents for in situ leukemia cells.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000008:administration & dosage*; D005472:Fluorouracil / Q000008:administration & dosage*; D006641:Histidinol / Q000008:administration & dosage*; D007093:Imidazoles / Q000008:administration & dosage*; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA
D007093:Imidazoles; D003561:Cytarabine; D006641:Histidinol; D005472:Fluorouracil