Other Biological Actions of Paclitaxel

Considering the reductive condition in the anaerobic environment in the center of tumor tissue, Damen et al. designed and prepared 2 -carbonate and 3 -A -carbamate prodrugs of paclitaxel that release the parental drug targeting hypoxic tumor tissue. Two of 11 prodrugs are selected for additional investigation.  

In 2004, Liu et al. made an effort to incorporate estradiol into C-2, 7, and 10 positions in Taxol to target the drug to estrogen receptor (ER) positive breast cancer. For C-2 and C-7 conjugates, no satisfactory results were obtained for either activity or selectivity. But a 7-epi-lO-conjugated taxoid (119) did exhibit some selectivity between ER-positive and negative cancer cells, and ER-(3 (MDA-MB-231 cell) and ER-a expressing (MCF-7) cancer cells.  

Apoptosis is another important mechanism for cell poisoning, in addition to tubulin assembly promotion and microtubule stabilization for paclitaxel, especially at a high concentration (sub pM to pM level). It is also observed that in higher concentrations (5 to 50 pM), paclitaxel induced tumor necrosis through microtubules rather than apoptosis. Note that paclitaxel concentration in the clinic is lower than pM. 

The involvement of many biochemical pathways and cytokines in paclitaxel-induced apoptosis has been extensively investigated. Among them, bcl-2, the well-known apoptosis inhibitor, was found to be phosphorylated in the presence of paclitaxel, with its inhibitory effect on apoptosis downregulated. One phosphorylation position is Ser-70, and the cells with Ser70 to Ala mutant showed lower reponse to paclitaxel-induced apoptosis. Deletion of the bcl-2 loop area comprising 

60 amino acids suppressed its anti-apoptotic effect completely.Other investigations indicated that phosphorylation is a marker of mitotic arrest rather than a determinant of paclitaxel-induced apoptosis. Interested readers can refer to several recent reviews, especially on bcl-2 related apoptosis. ° 

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