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PubMed1976

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.

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PubMedDate not supplied

Polyinosinic-polycytidylic acid, an interferon inducer, ameliorates bleomycin-induced lung fibrosis in mice.

The inhibitory effect of polyinosinic-polycytidylic acid (Poly IC), an inducer of interferons, on bleomycin-induced lung collagen accumulation was investigated in mice. Poly IC (10 mg/kg, intraperitoneally) or saline was given for 2 days and immediately prior to intratracheal instillation of bleomycin (0.125 units/mouse) or an equivalent volume of saline and thereafter daily for 13 days. Lung hydroxyproline levels in saline-saline (control), Poly IC-saline (Poly IC), bleomycin-saline and bleomycin-Poly IC groups averaged 279, 287, 459, and 358 micrograms/lung, respectively. The bleomycin + Poly IC mice had significantly less lung hydroxyproline than bleomycin mice, but significantly more hydroxyproline than control or Poly IC mice. Similarly, bleomycin + Poly IC mice had significantly less protein in bronchoalveolar lavage fluid (BALF) supernatant than bleomycin mice, but significantly more protein than control or Poly IC mice. Total cell counts for cells recovered from BALF showed significant increases of 174 and 167% in bleomycin and bleomycin + Poly IC as compared to controls, while the Poly IC group showed a significant decrease of 47% which was primarily due to a decrease in alveolar macrophages. The bleomycin group had significantly more neutrophils, monocytes, macrophages, and lymphocytes than control mice, while bleomycin + Poly IC mice lacked the significant increase in lymphocytes. Bleomycin + Poly IC mice had significantly more monocytes than the bleomycin group. All bleomycin-treated mice had lung lesions, but no lesions were observed in control or Poly IC mice. Bleomycin + Poly IC mice had significantly more (58%) lesions than bleomycin. In contrast, the volume of interstitial lesion in bleomycin + Poly IC mice showed significantly less extracellular fibers (decreased by 62%) and no difference in fibroblasts as compared to bleomycin mice. Fibrotic lesions in bleomycin mice were multifocal and varied from large areas of organized connective tissue to thickened septa lined by cuboidal epithelial cells. Interstitial lesions in bleomycin + Poly IC had a significantly greater volume of mononuclear phagocytes and lymphocytes, but less organized connective tissue than the bleomycin group. Poly IC treatment ameliorated bleomycin-induced lung collagen accumulation.

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