THE CELL-CYCLE AND INDUCTION OF APOPTOSIS IN A HAMSTER FIBROSARCOMA CELL-LINE TREATED WITH ANTICANCER DRUGS - ITS IMPORTANCE TO SOLID TUMOR-CHEMOTHERAPY

The induction of apoptosis by anticancer drugs and its relationship to stages of the eel cycle was studied in cells derived from a solid tum our; a highly malignant hamster fibrosarcoma (Met B). Asynchronously p roliferating cells were treated with a wide variety of agents such as actinomycin-D, 1-beta-D-arabinofuranosyl cytosine, camptothecin, cispl atin, cyclophosphamide, daunorubicin, 5-flurouracil, 6-mercaptopurine, hydroxy urea, ionomycin, methotrexate and vincristine. With the excep tion of cyclophosphamide and hydroxyurea, a 36 h exposure to these dru gs resulted in inhibition of cell growth and apart from cyclophosphami de, hydroxyurea, 6-mercaptopurine and cisplatin the induction of apopt osis. Studies using a decreased concentration of drug and exposure tim e (12 h) followed by examination of cells using flow cytometry indicat ed that most drugs were capable of affecting cell cycle progression wi thout induction of apoptosis. However when cells were synchronised at G(0)/G(1), S and G(2)/M phases and then exposed to these decreased con centrations of drug apart from 6MP an HU, apoptosis was observed and f or the majority of drugs it took place in the same phase in which prog ression through the cell cycle was blocked by the drug. Cells synchron ised in G(0)/G(1) phase were more susceptible to methotrexate, whereas S-phase cells were more susceptible to camptothecin and 5-flurouracil and G(2)/M phase cells more susceptible to actinomycin D, 1-beta-D-ar abinofuranosyl cytosine, daunorubicin and cisplatin. In contrast, vinc ristine blocked cells in G(2)/M phase but exerted its apoptotic effect in S-phase cells, ionomycin had no effect on the cell cycle, but G(2) /M cells appeared to be more susceptible to the effect of this drug. T hese data indicate that entry into apoptosis by this fibrosarcoma may occur at any point in the cell cycle. They also demonstrate a correlat ion between the action of some anticancer drugs on the cell cycle and the subsequent induction of apoptosis which may be useful in chemother apeutic design.