Paclitaxel resistance

Ranganathan S, Benetatos CA, Colamsso PJ et al (1998) Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 77 562-566... 

Rose PG, Blessing fA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma a Gynecologic Oncology Group study. Gynecol Oncol 2003 88 130-135. 

Huisman MT, Chhatta AA, van Tellingen O, Beijnen JH, Schinkel AH (2005) MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer 116 824—829. 

Pires MM, Emmert D, Hrycyna CA, Chmielewski J. (2009) Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly hnked quinine homodimers. Mol Pharmacol 75 92-100. 

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 ... 

Giannakakou P, Sackett DL, Kang YK, et al. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 1997 272(27) 17,118-17,125. 

Montgomery RB, Guzman J, O Rourke DM, Stahl WL. Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters beta-tubulin isotype expression. J Biol Chem 2000 275 17,358-17,363. 

Chabalier C, Lamare C, Racca C et al. BRCAl down-regulation leads to premature inactivation of spindle checkpoint and confers paclitaxel resistance. Cell Cycle 2006 5 1001-1007. 

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). 

Resistance to paclitaxel has been described in cultured cells, and it appears in several forms. In one, resistance is associated with altered expression or mutation in a- and (3-tubulins [148,149], whereas in another, paclitaxel resistance is associated with overexpression of Pgp and the MDR phenotype [150]. 

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. 

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. 

Microtubule dynamics alterations also showed impacts on resistance. Goncalves et al. found a 57% increase of microtubule instability in paclitaxel-resistant cell A549-T12 as compared with parental sensitive cell A549, and a 167% overall increase in the more resistant cell A549-T24. ° It is interesting to note that the resistant cells, in the absence of paclitaxel, suffered mitotic block as well, which suggests that both increased or suppressed microtubule dynamics can impair cell function and proliferation. 

Gonzalez-Garay, M. L. Chang, L. Blade, K. Menick, D. R. Cabral, F. A P-tubulin leucine cluster involved in microtubule assembly and paclitaxel resistance. J. Biol. Chem., 1999, 274 23875-23882. 

Monzo, M. Rosell, R. Sanchez, J. J. Lee, J. S. O Brate, A. Gonzalez-Larriba, J. L. Alberola, V. Lorenzo, J. C. Nunez, L. Ro, J. Y Martin, C. Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. J. Clin. Oncol., 1999, 17 1786-1793. 

Ferlini, C., Raspaglio, G., Mozzetti, S., et al. (2005) The seco-taxane IDN5390 is able to target class III P-tubulin and to overcome paclitaxel resistance. Cancer Research, 65, 2397-2405. 

George, J. A. Chen, T. Taylor, C. C. Src tyrosine kinase and multidrug resistance protein-1 inhibitions act independently but cooperatively to restore pacUtaxel sensitivity to paclitaxel-resistant ovarian cancer cells. Cancer Res. 2005, 65, 10381-10388. 

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. 

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 . 

Data on two of these new taxanes, namely BMS-184476 (29) and BMS-188797 (29a), were published by Bristol-Myers-Squibb (BMS), which also developed Paclitaxel [96]. In a comparative preclinical study, both analogues were found to have cytotoxic potency similar to Paclitaxel but overcome two different forms of Paclitaxel resistance. BMS-184476 was found to be clearly superior to Paclitaxel especially on A2780 ovarian carcinoma, HCT/pk, a moderately Paclitaxel-resistant colon carcinoma and L2987 lung carcinoma. BMS 184476 is currently in phase II clinical trials in breast, NSCLC, oesophageal and gastrointestinal cancers [97]. 

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