An investigation of the effects of the anti-leukaemic drug Myleran on the regeneration of rat liver

Abstract

An investigation was undertaken into the effects of the anti-leukaemic drug Myleran on regenerating rat liver. The effects on DNA synthesis and the cell cycle were studied.

Random bred rats were subjected to partial hepatectomy and experimental animals given Myleran (1,4-dimethanesulphon-oxybutane) in dispersion. Controls were given dispersant lacking Myleran and analysed concurrently.

DNA synthesis was followed using radioactive thymidine. The specific activity of the DNA was measured over three days following partial hepatectomy. An investigation into 'apparent' thymidine kinase activity was undertaken in conjunction with the studies on DNA synthesis. Levels of nucleic acids were determined.

Regeneration in the weight of the liver remnant after partial hepatectomy was followed and a histological examination conducted in which the mitotic index and the incidence of mitotic abnormality were determined. The lengths of the individual mitotic phases and the phases of the cell cycle were found by the construction of mitotic labelling curves.

The drug was found to decrease the ability of the liver to regenerate and to partially inhibit DNA synthesis.These results are explained by a decrease in the 'apparent' thymidine kinase activity and are discussed. No significant effects were found on the RNA or DNA. contents of the liver remnant. The levels of mitotic abnormalities increased following Myleran treatment and were measured for the different phases of mitosis. Measurements of mitotic index over the first 26hr. following Myleran treatment gave variable results.The drug was found to shorten the length of mitosis, determined by summation of the individual mitotic phases or from the graphs of % labelled mitoses.

Analysis of the curves of labelled mitotic figures was complicated in the case of the Myleran-treated rats by the absence of a second wave of labelled mitoses; thus total cell cycle time (T_c) and the length of the G₁. phase could not be found. However the G₂ and S phases of the cell cycle were found to be lengthened for Myleran-treated rats; the significance of these findings is discussed.