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S-Phase Resistance of Rat Hematopoietic Stem Cells to 7,12-Dimethylbenz(a)anthracene Cytocide and Its Implications for Leukemia Development¹

Pathologisches Institut der Universität Köln, Cologne, Federal Republic of Germany

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 < 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.

¹ This study was supported by the Deutsche Forschungsgemeinschaft (Fo/115).

² To whom requests for reprints should be addressed, at Pathologisches Institut der Universität, Joseph-Stelzmann-Str. 9, D-5000 Köln 41, Federal Republic of Germany.

Received 3/27/84. Accepted 5/29/84.