The effects the anthracycline Doxorubicin exerts on variants of the human lung carcinoma cell line DLKP was investigated in this thesis, in an attempt to understand the means by which the chemotherapeutic agent exerts its cytotoxic and cytostatic effects on human lung tumours. Sensitive DLKP-SQ and resistant variants DLKP-SQ/A250 10p#7, DLKP-A2B and DLKPA5F were exposed to equitoxic doses of Doxorubicin, which resulted in approximately 50% cell kill after 72 hours. The subsequent effects on the cell cycle and apoptosis induction were studied in an attempt to identify any differences between sensitive and resistant cells, that may contribute to the resistant state. Doxorubicin treatment induced a permanent G2/M arrest in sensitive cells by 24 hours, and a temporary arrest in resistant variants at an earlier time of 12-16 hours with a subsequent bypass of the G2/M arrest to re-emerge in and accumulate in G l. The transient G2/M arrest and subsequent progression into G l indicated insufficient checkpoint monitoring of DNA damage induced by doxorubicin treatment in the resistant variants. The G2/M checkpoint controller complex cyclin B-cdkl , was investigated in an attempt to explain the G2/M over-ride seen in drug resistant cells. Doxorubicin treatment did not alter cyclin B or cdkl protein levels, or the complex-forming ability of cdkl. The G2/M arrest seen in sensitive cells may be due to an increase in inhibitory phosphorylation on cdkl. In contrast Tyrl5 phosphorylation did not change in resistant variants and cdkl kinase activity seems to increase following drug treatment, unlike the sensitive cells which displayed little alterations in kinase activity upon drug treatment. Further investigation of the mechanism of G2/M override in the resistant variants involved examination of the cdkl regulators weel kinase and cdc25 phosphatase. Initial studies on these regulators raised some mechanistic possibilities of G2/M override. Apoptosis occurs in each of the four cell lines after Doxorubicin treatment, with kinetics of cell death dependent on the concentration of Doxorubicin and exposure tune used. The mechanism of apoptosis induction in the cell lines was investigated. Analysis of procaspase expression revealed that caspase-3 is greatly downregulated in resistant cell lines, and caspase-8 is reduced to a lesser extent. Levels of procaspases did not decrease during apoptosis, indicating lack of caspase activation in general, and very low caspase-3 activation occurs during doxorubicininduced apoptosis, raising doubts about caspase-3 involvement in the apoptotic pathway. The caspase-3 substrate PARP was not cleaved in any of the cell lines during apoptosis, although the cytoskeletal protein fodrin was cleaved in all four cell lines. Furthermore the caspase inhibitors zYAD-ftnk, YVAD-fmk and DEVD-fmk which readily cross cell membranes, failed to protect the cells from doxorubicin-induced apoptosis, raising the possibility of caspase redundancy or a caspase-independent mechanism in these cells. Involvement of the Fasmediated pathway was also investigated, and resistant variants do not express altered levels of CD95 receptor compared to sensitive cells. When the cells were treated with inhibitors of the Fas signalling pathway, or with a combination of caspase inhibitors and CD95 inhibitors, they continued to die by apoptosis. The fact that cell permeable inhibitors of both caspases and CD95 signalling do not prevent doxorubicin-induced death lends further weight to the possible existence of a caspase-independent pathway.