S-phase resistance of rat hematopoietic stem cells to 7,12-dimethylbenz(a)anthracene cytocide and its implications for leukemia development.
In the experimental rat leukemia system, induced by repeated 7,12-dimethylbenz(a)anthracene (DMBA) pulses, the sensitivity of the spleen colony-forming hematopoietic stem cells (CFU-s) to the cytocidal action of a challenging DMBA injection (35 mg/kg body weight) varied with the number of pulses already applied and the organ source of CFU-s (femoral bone marrow or spleen). Assessment of the fraction of DNA-synthesizing CFU-s with the [3H]thymidine suicide technique at the time of DMBA challenge and comparison with the 20-hr CFU-s reduction values by DMBA in vivo showed an inverse correlation (p less than 0.001). It was deduced, therefore, that S-phase CFU-s are relatively resistant to DMBA cytocide. Since initiation by chemical carcinogens has been shown to be relatively S-phase specific, S-phase-resistant cytocide would lead to a selection of initiated cells and, in the case of repeated applications, to a selection of cells with multiple successive initiation hits. Preferential differentiation and organ site of leukemia, as well as evolution in sequential morphological steps, fit this assumption.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D001853:Bone Marrow / Q000503:physiopathology; D004351:Drug Resistance; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D007399:Interphase / Q000187:drug effects*; D007942:Leukemia, Experimental / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000503:physiopathology
D001551:Benz(a)Anthracenes; D015127:9,10-Dimethyl-1,2-benzanthracene