Cytotoxic effects toward human hematopoietic progenitor cells and tumor cell lines of paclitaxel, docetaxel, and newly developed analogues IDN5109, IDN5111, and IDN5127

The growth inhibitory effect of paclitaxel, docetaxel, and newly developed taxanes IDN5109, IDN5111, and IDN5127 was assessed on peripheral blood (PB) CD34+ maintained in liquid culture and on three human cancer cell lines (M DA-MB231, MCF-7 ADRr, CEM VBLr). Concomitantly, DNA analysis was also perfo rmed. For unfractionated peripheral blood progenitor cells (PBPC) toxicity was also assessed by clonogenic assay. The cytotoxic effects induced by tax anes toward PBPC as measured by clonogenic assay were correlated with those found for multidrug resistance (MDR)-positive cell lines (IDN5109 > IDN511 1 >IDN5127 > docetaxel > paclitaxel). We established a therapeutic index (T I) between the antitumor activity in MDR-positive cells and the toxicity to ward PBPC. Paclitaxel and IDN5109, as determined by TI, showed the best val ue in MDR-negative and MDR-positive cells, respectively. The ranking of the cytotoxic effects observed in PB CD34+ was not correlated with that obtain ed in clonogenic assay and in cancer cells (IDN5127 > IDN5109 > docetaxel > IDN5111). Remarkably, in DNA analysis docetaxel induced the maximal cell c ycle blocking activity. Newly developed taxanes IDN5109 and IDN5111 are end owed of a profile of anticancer activity in MDR-bearing cells and toxicity toward hematopoietic progenitors better than that of docetaxel. However, me chanism(s) underlying toxicity toward hematopoietic progenitors could be, a t least in part, different from that of docetaxel and likely dependent on t he interaction with P-glycoprotein function in PB CD34+ cells.