Mechanisms of action of anthracyclines are (1) to inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells, (2) to inhibit topoisomerase II, preventing the relaxing of supercoiled DNA, and thus blocking DNA transcription and replication, and (3) to create iron-mediated free Inhibitors,research,lifescience,medical oxygen radicals

that damage the DNA and cell membranes. Anthracyclines-based combination chemotherapy has shown improved anticancer activity than anthracyclines alone. For example, doxorubicin has achieved response rate of 40–50% as single agent while 60–70% in combination [20]. These regimens include doxorubicin or epirubicin with cyclophosphamide (AC and

EC); doxorubicin, cyclophosphamide, and fluorouracil (FAC or CAF); epirubicin with cyclophosphamide and Inhibitors,research,lifescience,medical fluorouracil (FEC). Unfortunately, the clinical benefits of anthracyclines are limited by cardiotoxicity that can lead to the development of potentially fatal congestive heart failure [21]. The combination of anthracycline and cyclophosphamide (AC) is commonly used Inhibitors,research,lifescience,medical as first-line chemotherapy in metastatic breast cancer, with or without fluorouracil. Jassem et al. showed improved response rates of 37% to 57% and median time to progression ranging from 6 to 9 months for fluorouracil + AC-type regimens in phase III trials [22]. These regimens are more active but also more toxic than single

agent regimens or non5-FU in vitro anthracycline-based combinations [23, 24]. Joensuu et al. reported better response rate of 55% in patients treated with FEC than Inhibitors,research,lifescience,medical 48% in patients treated with epirubicin alone. However, most of FEC-treated patients (80%) suffered from total hair loss while majority of epirubicin-treated patients (59%) experienced little or no hair loss. Other chemotherapy-related toxicity were more common in FEC-treated patients including hematologic toxicity, nausea, and vomiting [24]. Furthermore, anthracycline-based regimens have not demonstrated Inhibitors,research,lifescience,medical a benefit in overall survival compared to single-agent anthracyclines. 2.1.2. Taxane-Based Regimens Taxanes are another class of chemotherapy agents originally derived from natural sources then medroxyprogesterone synthetically derivatized including paclitaxel (Taxol) and docetaxel (Taxotere). The mechanism of action of taxanes is to disrupt microtubule function. Microtubules are essential to cell division, and taxanes stabilize GDP-bound tubulin in the microtubule, thereby inhibiting the process of cell division. Therefore taxanes also can be classified as mitotic inhibitors. However due to their poor water-solubility, taxanes encounter difficulties in pharmaceutical formulation and this often results in reduced bioavailability. Different mechanisms of action of anthracyclines and taxanes provide the rationale of combination therapy of these two classes of drugs.