Taxanes: Promising Anti-Cancer Drugs

Taxanes are amongst the most promising antitumor agents available at hand today, of increasing importancein Asia given that cancer is now one of the major public health problems which needs to be dealt urgently forthe benefit of affected patients. Several ongoing experimental and clinical trials have supported the fact thateven with their side effects and poor solubilities, taxanes are still the first lines of treatment chosen for breast,ovary, lung and other metastatic cancers. Prolonging the life of cancer patients is the main aim of all researchers,scientists, pharmaceutical companies and clinicians; therefore this review emphasizes the mechanisms of actionof taxanes and how they can play an important role in palliative treatment if not applied for curative purposes,hence being considered a boon for cancer management.     

Weekly taxane–anthracycline combination regimen versus tri-weekly anthracycline-based regimen for the treatment of locally advanced breast cancer: a randomized controlled trial

Background: Extensive studies have confirmed the efficacy of taxanes in combination with anthracycline-basedchemotherapy on breast cancer. However, few studies have assessed the efficacy of weekly taxane–anthracyclineregimens on locally advanced breast cancer. This study was to compare the efficacy and safety of a weekly taxane–anthracycline regimen with those of tri-weekly anthracycline-based regimen in patients with locally advanced breastcancer.Methods: Patients with locally advanced breast cancer were randomized to receive 4–6 cycles of neoadjuvant chemotherapywith tri-weekly 5-fluorouracil–epirubicin–cyclophosphamide (FEC) regimen or weekly paclitaxel–epirubicin(PE) regimen. The primary endpoint was the pathologic complete response (pCR) rate. Other endpoints included theclinical tumor response, breast-conserving surgery rate, and adverse events.Results: Between March 2010 and September 2013, 293 patients were randomized to the FEC (n = 151) and PE(n = 142) arms. The overall clinical response rate was significantly higher in the PE arm than in the FEC arm (76.06% vs.59.95%, P = 0.001). Consistently, the post-chemotherapy pathologic T and N stages were significantly lower in the PEarm than in the FEC arm (P < 0.001). However, the pCR rate was similar in the two arms (10.61% vs. 12.31%, P = 0.665).Overall, 36 (27.27%) patients in the FEC arm and 6 (35.28%) in the PE arm were qualified for breast-conserving surgery.Most adverse events were comparable in both arms, with more severe neutropenia in the PE arm than in the FEC arm(11.97% vs. 5.96%, P = 0.031).Conclusions: In patients with locally advanced breast cancer, weekly PE was not superior to FEC in terms of pCR.However, weekly PE has a higher response rate and superior down-staging effects. On this account, the PE regimenmay be considered an alternative option for locally advanced breast cancer. Long-term follow-up data are needed toconfirm the efficacy of this regimen on locally advanced breast cancer.     

Place de la chimiothérapie d’induction dans le traitement des carcinomes épidermoïdes des voies aérodigestives supérieures : contre

The treatment of locally advanced head and neck squamous cell carcinoma is based on concomitant chemoradiotherapy. A sequential treatment combining induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF), followed by (chemo)radiotherapy is frequently used as part of laryngeal preservation strategies. Apart from this particular situation, the benefit in terms of survival of induction chemotherapy has been much discussed in recent years. In five recent randomized trials, chemoradiotherapy was compared with TPF induction chemotherapy followed by chemoradiotherapy. Of these five trials, four concluded that these treatments were similar. A single trial reports a benefit for induction chemotherapy but its methodology is highly debatable. After TPF chemotherapy, chemoradiotherapy is less well tolerated. In patients with significant lymph node invasion (N2b-c-N3), induction chemotherapy reduces the occurrence of distant metastasis. The HPV status should not influence the therapeutic decision.     

Olesoxime prevents microtubule-targeting drug neurotoxicity: Selective preservation of EB comets in differentiated neuronal cells

Microtubule-targeting agents (MTAs), anticancer drugs widely used in the clinic, often induce peripheral neuropathy, a main dose-limiting side effect. The mechanism for this neurotoxicity remains poorly understood and there are still no approved therapies for neuropathies triggered by MTAs. Olesoxime (cholest-4-en-3-one, oxime; TRO19622) has shown marked neuroprotective properties in animals treated with paclitaxel and vincristine. The purpose of this study was to investigate its mechanism of neuroprotection against MTA neurotoxicity by using rat and human differentiated neuronal cells. We first showed that olesoxime prevented neurite shrinkage induced by MTAs in differentiated PC-12 and SK-N-SH neuroblastoma cell lines by up to 90%. This neuroprotective effect was correlated with enhanced EB1 accumulation at microtubule plus-ends, increased growth cone microtubule growing rate (20%) and decreased microtubule attenuation duration (54%). The effects of olesoxime on EB comets were specific for differentiated neuronal cells and were not seen either in proliferating neuroblastoma cells, glioblastoma cells or primary endothelial cells. Importantly, olesoxime did not alter MTA cytotoxic properties in a wide range of MTA-sensitive tumor cells, a prerequisite for future clinical application. Finally, olesoxime also counteracted MTA inhibition of microtubule-dependent mitochondria trafficking. These results provide additional insight into the neuroprotective properties of olesoxime, highlighting a role for microtubule dynamics in preservation of neurite architecture and axoplasmic transport, which are both disturbed by MTAs. The neuron-specific protective properties of olesoxime support its further development to treat MTA-induced neuropathy.     

Adjuvant chemotherapy in 2005: standards and beyond

The 2003 St. Gallen consensus panel divided the many available adjuvant chemotherapy (CT) regimens into those with "standard efficacy" (ACx4, CMFx6) and those with "superior efficacy" (FA(E)Cx6, CA(E)Fx6, A(E)-->CMF, TACx6, ACx4--> paclitaxel (P)x4 or docetaxel (D)x4) but also greater complexity, toxicity and cost. This paper will summarize the latest information on long-term side effects of the "superior" regimens and 5-year benefits reported in taxane trials, including those of a "new" sequential regimen, FECx3--> docetaxelx3. Rapidly expanding evidence of marked heterogeneity in the magnitude of CT benefits according to the tumour oestrogen receptor (ER) status, a claim made for many years by IBCSG investigators, will be reviewed; it will lead to the conclusion that a revolution needs to take place in the way oncologists think about the CT added value and design adjuvant clinical trials. The conclusions proposed to the 2005 St. Gallen consensus panel are that: adequately dosed anthracycline-based CT regimens remain an acceptable standard for many women; a lower threshold for using taxanes in sequence or combination with anthracyclines (A) is justified in the presence of an ER-negative or low-ER tumour status, other aggressive biologic features (such as HER-2 overexpression), fear about A-induced cardiotoxicity; no recommendation can yet be made as far as the optimal taxane-A regimen, the best taxane or the best taxane schedule.     

The dynamic variation of several important taxane content in post-harvest Taxus chinensis clippings

The dynamic variations of several important taxanes, taxol, baccatin III (B-III), 1-acety-5,7,10-deacetyl-baccatin I (DAB-I) and baccatin VI (B-VI), were investigated in post-harvest clippings of Taxus chinensis. The clippings were preserved over 20 days at two different temperatures (4°C and room temperature), or by cuttage in the light and in the dark, or promptly dried. The accumulation of taxol in needles of the clippings was found increase in the initial stages of the stored period and then decreased gradually. The maximum accumulation of taxol occurred in the case of cold storing (4°C) at day 3, doubling the data on the day when the biomass was harvested. In contrast, in the cases of cold storage and cuttage the contents of the other three taxanes showed a sharp decrease at the beginning and then an increase from 3 to 6 days, and subsequently a drop until day 20. The similar variation of taxane contents was not found in the needles of immediately dried clippings as well as in the stem samples of clippings. These results indicated that the content variation of taxol and related taxanes of post-harvest clippings was related to the manner of preservation, timing and plant tissue. Moreover, the mechanism of the fluctuation of the taxane contents in post-harvest clippings is discussed, in particular taxol biosynthesis in response to mechanical wounding of harvest.     

Treatment of ovarian cancer using intraperitoneal chemotherapy with taxanes: from laboratory bench to bedside

The combination of a taxane, paclitaxel or docetaxel, and a platinum compound has become the systemic chemotherapy of choice for primary ovarian cancer and has demonstrated high efficacy. However, ultimately most patients will die from this disease. Hence, there is a need for even more effective systemic chemotherapy or different treatment strategies. Intraperitoneal chemotherapy with taxanes is such an alternative treatment option. Ovarian cancer is theoretically an attractive malignancy for this regional treatment, because the disease remains largely confined to the peritoneal cavity. The choice of taxanes for this kind of chemotherapy is rational, because of its high activity against ovarian cancer cells and expected favourable pharmacokinetics because of limited absorption from the peritoneal cavity due to their large molecular weight and first-pass effect in the liver. In animal model and human pharmacokinetic studies, very high intraperitoneal drug concentrations and exposure and high peritoneal tumour concentrations were achieved, while systemic drug levels were low. The combination of intraperitoneal chemotherapy with hyperthermia enhances the penetration and cytotoxic activity of many drugs. Although data concerning thermal enhancement of taxane cytotoxicity are inconsistent, experimental studies show that at high locoregional concentrations there seems to be such an effect. Recently, feasibility and efficacy of this treatment have evidently been demonstrated in various clinical studies. A large randomized trial revealed improvement of outcome by intraperitoneal instillation chemotherapy with paclitaxel and cisplatin as first-line treatment. Moreover, promising results have been observed after intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel for recurrent disease.     

Microtubule stabilizing agents: their molecular signaling consequences and the potential for enhancement by drug combination

Microtubule stabilization by chemotherapy is a powerful weapon in the war against cancer. Disruption of the mitotic spindle activates a number of signaling pathways, with consequences that may protect the cell or lead to its death via apoptosis. Taxol, the first microtubule stabilizing drug to be identified, has been utilized successfully in the treatment of solid tumors for two decades. Several features, however, make this drug less than ideal, and the search for next generation stabilizing drugs with increased efficacy has been intense and fruitful. Microtubule stabilizing agents (MSAs), including the taxanes, the epothilones, discodermolide, laulimalide, and eleutherobin, form an important and expanding family of chemotherapeutic agents. A strong understanding of their molecular signaling consequences is essential to their value, particularly in regard to their potential for combinatorial chemotherapy - the use of multiple agents to enhance the efficacy of cancer treatment. Here we present a critical review of research on the signaling mechanisms induced by MSAs, their relevance to apoptosis, and their potential for exploitation by combinatorial therapy.