Resistance of tumours to
taxanes causes
chemotherapy failure in numerous patients. Resistance is partly due to the low tumour uptake of
taxanes and their rapid metabolism. Structural modifications of
taxanes can reduce their
P-glycoprotein-related efflux or decrease metabolism and consequently increase
taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metabolism of novel
taxanes SB-T-1102, SB-T-1103,
SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with
paclitaxel in
paclitaxel-sensitive (MDA-MB-435) and
paclitaxel-resistant (NCI/ADR-RES) human
cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to
paclitaxel than MDA-MB-435 cells in correspondence to
P-glycoprotein overexpression and up to 20-fold lower uptake of the
drug in the resistant cells. The uptake of novel
taxanes was 1.2 to 3.8 times lower than that of
paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel
taxanes. Both cell lines showed minimal metabolism of the novel
taxanes which was therefore not responsible for their different sensitivity, the observed differences in their individual efficiency and higher effects than
paclitaxel. All novel
taxanes caused G(2)/M block of the cell cycle similar to
paclitaxel, but lower at concentrations by order of magnitude. Thus, structural modifications of
taxanes resulting in their decreased
P-glycoprotein-related transport probably caused their higher efficiency than
paclitaxel in multidrug-resistant NCI/ADR-RES tumour cells.