Paclitaxel-resistant tumors

Although paclitaxel was reported to be effective against ovarian and breast cancers resistant to other first-line anticancer drugs in clinics, the patients often relapsed and did not respond to these antimmor agents, including pachtaxel, anymore. Unfortunately, docetaxel was also inactive toward paclitaxel-resistant tumors. 

An example of particular interest is epothilone from Sorangium cellulosum So ce90, which has recentiy been approved for the treatment of breast cancer. Epothilone inhibits microtubule depolymerization and is active against multidrug-resistant cancer cell lines and paclitaxel-resistant tumors. The most comprehensively characterized and so far only epothilone derivative, which received FDA approval for clinical use, is ixabepi-lone. The compound is marketed in the US by Bristol-Myers Squibb (BMS) under the trade name Ixembra . 

The literature is also starting to show a significant volume of papers that concentrate on the possible mechanisms of paclitaxel resistance seen in tumors (15). These include ... 

Earlier data with both Oil Red-0 staining and diO-labeled LCM indicated that 9L tumor cells have a much slower LCM uptake than do C6 tumor cells, both in vivo and in vitro (ref. 531). That difference might be a factor in how fast the paclitaxel is consumed and internalized by the tumor cells. A study by Sharma et al- (ref-605) also suggests that 9L tumor is somewhat paclitaxel-resistant. Accordingly, the daily dose of paclitaxel-LCM was adjusted to 960 pg/kg for subsequent 9L tumor-treatment experiments (ref. 532) (see below). 

Epothilones retain significant activity against paclitaxel-selected cell lines that harbor a distinct set of tubulin mutations, and again this could perhaps translate into clinical utility in the treatment of Taxol-resistant tumors. However, any such predictions must be treated with great caution, as the clinical significance of individual resistance mechanisms identified in vitro has not been established. 

In 2002, it was found that a 2-diflurobenzoyl paclitaxel analog (60d) exhibited comparable activity with paclitaxel, are best in C-2 mono- and di-substituted benzoyl analogs and better than 9a and 9b in paclitaxel-resistant HCT-116/VM46 cancer cell lines. It was also reported that some 2-debenzoyloxy-2a-benzamido docetaxel analogs were comparably cytotoxic with paclitaxel toward some drug-resistant tumor cell lines. 

Bollag et al. (88)at the Merck Research Laboratories discovered that the epothilones stabilize microtubule assembly and thus inhibit cell division by the same mechanism as that of paclitaxel (see above). This observation, together with their less complex chemical structure, increased water solubility, more rapid action in vitro, and effectiveness against multidrug-resistant tumor cells, has prompted... 

Koziara, J. M. Whisman, X. R. Xseng, M. X Mumper, R. J. In-vivo efficacy of novel paclitaxel nanoparticles in paclitaxel-resistant human colorectal tumors. J. Control. Release 2006, 112, 312-319. 

Ganta, S. and Amiji, M. (2009) Coadministration of paclitaxel and curcumin in nanoemulsion formulations to overcome multidrug resistance in tumor cells. Molecular Pharmacology, 6 (3), 928-939. Sonneville-Aubrun, O., Simonnet, J.-T. and L Alloret, F. (2004) Nanoemulsions a new vehicle for skincare products. Advances in Colloid and Interface Science, 108-109, 145-149. 

While dEpoB performed similarly to paclitaxel in sensitive tumor xenografts (MX-1 human mammary and HT-29 colon tumor), clearly superior effects of dEpoB were observed against MDR tumors under these slow infusion conditions. Thus, dEpoB (6 h, Q2D, 30 mg/kg x 5 doses, i.v.) demonstrated a foil curative effect when administered to nude mice bearing the resistant human lymphoblastic T-cell leukemia,... 

Fig. 2.3 Therapeutic effect of dEpoB and padi- on days 6, 8,10,12 and 14. o, control with taxel (Taxol ) in nude mice bearing CCRF- vehicle only co, paclitaxel 20 mg/kg and X, CEM/paclitaxel xenografts (57-fold resistant to dEpoB 30 mg/kg. The average tumor volume of paclitaxel) following Q2D x 5, i.v. 6 h infusion. the control group on days 12,14,16,18, and 24...

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