Intracellular distribution of (14C)bleomycin and the cytokinetic effects of bleomycin in the mouse tumor.

The differential effects (BLM) on cycling and noncycling cells were investigated with a mouse ascites tumor in vivo. An i.p. injection of 37.0 or 111.1 mug BLM per g caused a decrease in tumor cell number but an increase in percentage of tumor cells in mitosis. There are no significant differences between the percentage labeled mitoses at various times after pulse labeling by tritiated thymidine of BLM-treated tumor cells and by that of an untreated control, except that the height of the second peak was significantly lower in the treated cells. Hence BLM may be cell cycle nonspecific, and the BLM-induced decrease in cell number, i.p., may stimulate some nondividing cells to reenter the division cycle. However, the fact that percentage of cells in mitosis versus time after the administration of BLM showed two peaks indicates the possibility that another cause of the increase in mitotic figures might be a relative increase of cycling cells due to higher sensitivity of noncycling cells to the agent. Autoradiographic studies on the intracellular distribution of [14C]BLM revealed the following. (a) There were few necrotic cells in mitosis that incorporated much [14C]BLM into the cytoplasm at each time point and the mitotic figures gradually increased with time after i.p. injection of the isotope, while necrotic cells other than in mitosis, most of which were heavily labeled, increased in number with time. These findings seem to be related to the possibility that cycling cells may be less sensitive to BLM. The mode of intracellular distribution of [14C]BLM in mitotic cells changed with time and appeared to reflect the drug susceptibility depending on the cell cycle phase when labeled.