Natural and Semisynthetic Taxoids Overcoming Multidrug Resistance MDR

4 NATURAL AND SEMISYNTHETIC TAXOIDS OVERCOMING MULTIDRUG RESISTANCE (MDR) 

MDR is one major reason for the failure of chemotherapy. Overexpression of P-glycoprotein (P-gP), which results in massive transport of anticancer drugs and other hydrophobic substrates out of cells, is the best known contributing factor to MDR. Also, other factors attributing to the failure of taxane anticancer drugs, such as inherently insensitive isotypes of tubulin and amino acid mutations in mbulin, will also be discussed in this section. 

1 Structure-Modified Taxoids With Better Activity Toward MDR 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. 

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. 

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