Paclitaxel studies

Vinorelbine, a microtubule interactive agent, also has shown impressive response rates in metastatic breast cancer.60 Vinorelbine was approved by the FDA in 1994 for the treatment of non-small cell lung cancer. It is not approved for breast cancer, but response rates to vinorelbine range from 30% to 50%, with an overall 5% complete response rate in phase I and phase II studies in patients with advanced breast cancer. Importantly, paclitaxel, docetaxel, and vinorelbine do not appear to be cross-resistant with anthracyclines, which are arguably considered first-line treatment of metastatic breast cancer. 

Neijt IP, Engelholm SA, Tuxen MK, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carbo-platin in advanced ovarian cancer. J Clin Oncol 2000 18 3084-3092. 

Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer a gynecologic oncology group study. J Clin Oncol 2003 21 3194-3200. 

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. 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

Zakharian, T.Y., Seryshev, A., Sitharaman, B., Gilbert, B.E., Knight, V., and Wilson, L.J. (2005) A fullerene-paclitaxel chemotherapeutic synthesis, characterization, and study of biological activity in tissue culture./. Am. Chem. Soc. 127, 12508-12509. 

Other applications include bioequivalent measurements of bromazepam, an anticonvulsant, in human plasma. The lower limit of quantitation (LLOQ) was 1 ng/mL (Gongalves et al. 2005). Kuhlenbeck et al. (2005) studied antitussive agents (dextromethorphan, dextrophan, and guaifenesin) in human plasma LLOQ values were 0.05, 0.05, and 5 ng/mL, respectively. Other compounds studied were nucleoside reverse transcriptase inhibitors, zidovudine (AZT) and lamivudine (3TC) (de Cassia et al. 2004) and stavudine (Raices et al. 2003) in human plasma, and paclitaxel, an anticancer agent, in human serum (Schellen et al. 2000). 

The advantages of MAE are short extraction times (10 min), extraction of many samples at one time (up to 14, depending on the system), and less organic solvent consumed. In one recent study [29], MAE was used to extract paclitaxel from Iranian yew trees. The needles of the tree were air-dried and ground. The needles were covered with methanol-water and placed in the MAE apparatus. Extractions took 9-16 min. The extracts were filtered and analyzed by HPLC. Further optimization of the method resulted in less than 10% RSDs for precision and greater than 87% recovery. The overall benefits of the MAE method are reduced extraction times (15-20 min versus 17 h), minimal sample handling, and 75-80% reduction in solvent consumption [29]. 

Gordon AN, Granai CO, Rose PG, et al. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000 18 3093. 

Tumor Growth Inhibition Study with DQAsomal Encapsulated Paclitaxel (43)... 

Figure 9 Tumor growth inhibition study in nude mice implanted with human colon cancer cells. The mean tumor volume from each group was blotted against the number of days. Each group involved eight animals. For clarity, error bars were omitted. Note that after 1.5 weeks the dose, normalized for paclitaxel, was tripled in all treatment groups. Source. From Ref. 43...

Taxol (Paclitaxel) 137, a natural product derived from the bark of the Pacific yew, Taxus brevifolia [213-215], and the hemisynthetic analogue Docetaxel (Taxotere) 138, two recent and promising antitumour agents, have been the matter of extensive in vivo and in vitro animal metabolic studies. The major metabolites of taxol excreted in rat bile [216] were identified as a C-4 hydroxylated derivative on the phenyl group of the acyl side chain at C-13 (139), another aromatic hydroxylation product at the mefa-position on the benzoate group at C-2 (140) and a C-13 deacylated metabolite (baccatin III, 142) the structure of six minor metabolites could not be determined. The major human liver microsomal metabolite, apparently different from those formed in rat [217], has been identified as the 6a-hydroxytaxol (141) [218, 219]. A very similar metabolic pattern was... 

Jones RJ, Hawkins RE, Eatock MM, Ferry DR, Eskens FA, Wilke H, Evans TR. (2008) A phase II openlabel study of DHA-paclitaxel (Taxoprexin) by 2-h intravenous infusion in previously untreated patients with locally advanced or metastatic gastric or oesophageal adenocarcinoma. Cancer Chemother Pharmacol 61 435 41. 

In most studies where a supraadditive interaction was seen, cells were incubated with the drug prior to irradiation (38). In general the use of moderate concentrations (5-100 nmol/L) of paclitaxel in the culture medium for over 24 h lead to maximum sensitization. Most studies used actively proliferating cells in order to conduct their experiments and most investigators reached the conclusion that maximal radiosensitization occurred when cells were arrested in G2 and M, as this part of the cell cycle is the most sensitive to radiation damage. This assumption does, however, presuppose that the majority of the G2/M arrested cells will not die unless they are exposed to ionizing XRT. Plateau phase, i.e., nonproliferating, cells were found to be sensitized to radiation... 

There is also a single study looking at the addition of paclitaxel to adjuvant radiation for patients with high-risk early stage carcinoma of the endometrium (107). Essentially they have shown that post total abdominal hysterectomy, bilateral salingo-oopherectomy,... 

The common link with many clinical studies of chemoradiation in head and neck cancers is the significant mucositis that patients experience during therapy. Acrein has reported on a trial that attempts to deliver Ethyol as a protective agent to lessen the side effects of weekly paclitaxel (134). 

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