cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance
Microtubules, which are composed of polymerized tubulin dimers, play an important role in various cell functions. For example, they maintain cell shape, form mitotic spindles in M phase of cell cycle, and carry an axonal transport in nerve cells. Microtubules have also been an important target of cancer chemotherapy. Vinca alkaloids depolymerize microtubules, the mechanisms of which action have extensively been investigated recently. Clinical trials of vinorelbine (navelbine), a new semisynthetic vinca alkaloid, are ongoing in Japan. One of advantages of the drug is reduced risk of neurotoxicity. Estramustine may act on microtubule-associated proteins (MAPs) as well as tubulin. It shows additive or synergistic cytotoxicity preclinically when used in combination with vinblastine. This combination was active against hormone-refractory prostate cancer. Another novel drug rhizoxin, which has a similar mechanism of action to that of vinca alkaloids, is also a promising cytotoxic agent and is examined clinically in Europe. Taxanes, which include paclitaxel (Taxol) and taxotere, are interesting drugs because they promote polymerization of tubulin and stabilize microtubules. They show promising antitumor activity against breast, ovarian and lung cancers. Phase I and II trials are ongoing in Japan. Paclitaxel may also potentiate cytotoxicity of radiation. There are several mechanisms of resistance to microtubule-acting drugs. One is multidrug resistance mediated by P-glycoprotein. Other mechanisms include mutation of tubulin.