cabazitaxel and Pancreatic-Neoplasms

Cabazitaxel is a semisynthetic taxane approved for the treatment of patients with hormone-refractory metastatic prostate cancer (now known as metastatic castration-resistant prostate cancer) treated previously with a docetaxel-containing treatment regimen. The human plasma pharmacokinetics of cabazitaxel have been described previously, but detailed analyses of the metabolism and excretion pathways of cabazitaxel have not yet been published. Metabolite profiling, quantification, and identification as well as excretion analyses were carried out on samples from patients with advanced solid tumors who received an intravenous infusion of 25 mg/m [C]-cabazitaxel (50 μCi, 1.85 MBq) over 1 h. In plasma, cabazitaxel was the main circulating compound. Seven metabolites were detected, but with each accounting for 5% or less of the parent drug exposure, none were considered relevant metabolites. In excreta, 76.0% of the administered dose was recovered in feces within 2 weeks and 3.7% of the dose was excreted in urine within 1 week. Approximately 20 metabolites were detected in excreta; the main metabolites corresponded to combined mono-O-demethyl or di-O-demethyl derivatives on the taxane ring, with hydroxyl or cyclized derivatives on the lateral chain. Docetaxel (di-O-demethyl-cabazitaxel) was only detected at trace levels in excreta. These results suggest an extensive hepatic metabolism and biliary excretion of cabazitaxel in humans.

Topics: Antineoplastic Agents; Carbon Radioisotopes; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Sarcoma; Soft Tissue Neoplasms; Taxoids

Optimizing the currently available treatment options for pancreatic cancer (PC) is a priority. Cabazitaxel (CTX), a semisynthetic taxane, is mainly used for treating patients with PC who are resistant to paclitaxel (PTX) or docetaxel, due its poor affinity for P‑glycoprotein. However, there are only a few studies demonstrating the effect of CTX on PC. The present study aimed to investigate the efficiency and underlying mechanism of CTX in PC treatment. Cell proliferation, colony formation assay and apoptosis analysis were achieved in the two human PC cell lines AsPC‑1 and BxPC‑3. Drug sensitivity test was performed in BxPC‑3 tumor‑bearing mice. The results demonstrated that CTX had a lower half maximal inhibitory concentration compared with PTX for the inhibition of cell proliferation, both in vivo and in vitro. Furthermore, the nuclear factor‑κB (NF‑κB) pathway was activated following cell treatment with CTX, and NF‑κB p65 overexpression attenuated CTX cytotoxicity. In addition, the combined use of the specific NF‑κB inhibitor caffeic acid phenethyl ester (CAPE) with CTX significantly enhanced CTX effect, both in vivo and in vitro. Similarly, the mRNA and protein expression of B‑cell lymphoma-2 was decreased in AsPC‑1 and BxPC‑3 cells following treatment with CTX and CAPE, suggesting that NF‑κB may serve a crucial role in CTX efficiency. In conclusion, results from our previous study indicated that CTX could potentially replace PTX in the treatment of PC, and the present study demonstrated that CTX combination with an NF‑κB inhibitor may be considered as a potential therapeutic option for PC, which may improve the prognosis of patients with PC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caffeic Acids; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; NF-kappa B; Pancreatic Neoplasms; Phenylethyl Alcohol; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Taxoids; Xenograft Model Antitumor Assays