Effects of new anticancer drugs on cell growth, cell cycle progression, cell viability and cell differentiation will be investigated on: A) three different cell lines (L1210 murine leukemia, Friend murine erythroleukemia, Chinese hamster ovary (CH0) cells); B) normal human lymphocytes stimulated by mitogen; and C) multicellular tumor spheroid (V79 cells). The different cell models were chosen to distinguish drug actions that are universal from actions affecting a specific cell type, to compare the effect on transformed cells with normal human cells, of cycling with quiescent cells and to determine how growth in solid tumor masses affect drug action on the constituient cells. In addition to detailed descriptive studies, the mechanisms of drug action will be investigated by correlating the observations noted above with effects on chromatin structure, cell morphology, RNA/DNA and protein/DNA ratios. Thus, the degree of unbalanced growth can be correlated with cell cycle kinetic effects as can changes in chromatin structure, abnormalities of mitotic spindle etc. In selected cases, to elucidate the mechanism of drug action, its interactions with natural and synthetic nucleic acids will be studied. Flow cytomery, supported when necessary by autoradiography, will be the main method of analysing cell cycle effects. Electron microscopy, biochemical and biophysical methods will also be used when indicated to study mechanisms of drug action. In addition, we propose to further develop flow cytometric methods for the analysis of drug effects on cell metabolism, and to continue research on intracellular factors related to regulatory mechanisms of the cell cycle that may be targets for drug action. With a better understanding of the cell cycle, new, more effective drugs and drug combinations can be designed giving rise to more effective treatment protocols.
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