Through continuous exposure to increasing concentrations of carboplatin, three novel platinum resistant variants of the human squamous carcinoma cell line, DLKP, were established. Cross resistance studies revealed that, while these variants exhibited resistance to the platinum analogues carboplatin and cisplatin, no significant resistance or sensitivity was observed against the classical MDR drugs, adriamycin and vincristine. Characterisation studies demonstrated that the resistant phenotype in the DLKPC variants did not appear to be to be either P-glycoprotein or topoisomerase mediated, nor did it appear to be related to alterations in either GST or glutathione levels. Metallothionein expression in two of the established variants, DLKPC 6.2 and DLKPC 14, was found to be increased, correlating with the degreee of platinum resistance. The increased level of metallothionein expression in the highest resistant variant, DLKPC 25, however, did not correlate with the platinum resistance level. This suggested the involvement of alternative mechanisms in mediating resistance in this variant, possibly through decreased intracellular platinum accumulation. Drug accumulation studies with adriamycin and vincristine, were carried out on a number of human MDR cell lines, demonstrating reduced cellular accumulation of drug. The subsequent addition of verapamil or cyclosporin A, agents known to interact with Pglycoprotein, resulted in complete restoration of cellular drug levels in the MDR cell lines SKMES-1/ADR, T24A, T24V, OAW42-A and OAW42-A1, suggesting that the accumulation defect observed in these cell lines was P-glycoprotein mediated and that, accordingly, these cell lines exhibited characteristics consistent with classical MDR phenotype. In contrast, although P-glycoprotein appears to mediate a reduction in the cellular accumulation of drug in the DLKPA10 cell line, an alternative transport mechanism also appears to be present. Adriamycin subcellular distribution studies revealed the presence of an ATP-dependent, vesicular sequestration mechanism, involved in reducing adriamycin nuclear accumulation. This was demonstrated through ATP inhibition and disruption of the cytoplasmic vesicles, resulting in increased adriamycin accumulation and redistribution to the nucleus. In addition, studies indicated that membrane fluidity may be altered in these cells and that this may also contribute to a reduction in drug accumulation. An antibody was also raised against the DLKPA10 cells to determine if decreased drug accumulation was associated with either overexpression or down regulation of an antigen in the resistant cells. While overexpression of a 170-180 kDa antigen was observed in the DLKP parental cells, its role in mediating resistance remains to be clarified, although preliminary studies suggest that this antibody may play a role in cell adhesion or intercellular communication.