5--deoxy-5-fluorocytidine and Neoplasms

Capecitabine (Cape) is a prodrug that is metabolized into 5'-deoxy-5-fluorocytidine (DFCR), 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5-FU) after oral administration. A liquid chromatography-tandem mass spectrometry method for the simultaneous determination of capecitabine and its three metabolites in human plasma was developed and validated. The ex vivo conversion of DFCR to DFUR in human blood was investigated and an appropriate blood sample handling condition was recommended. Capecitabine and its metabolites were extracted from 100 μL of plasma by protein precipitation. Adequate chromatographic retention and efficient separation were achieved on an Atlantis dC18 column under gradient elution. Interferences from endogenous matrix and the naturally occurring heavy isotopic species were avoided. Detection was performed in electrospray ionization mode using a polarity-switching strategy. The method was linear in the range of 10.0-5000 ng/mL for Cape, DFCR, and DFUR, and 2.00-200 ng/mL for 5-FU. The LLOQ was established at 10.0 ng/mL for Cape, DFCR, and DFUR, and 2.00 ng/mL for 5-FU. The inter- and intra-day precisions were less than 13.5%, 11.1%, 9.7%, and 11.4%, and the accuracy was in the range of -13.2% to 1.6%, -2.4% to 2.5%, -7.1% to 8.2%, and -2.0% to 3.8% for Cape, DFCR, DFUR, and 5-FU, respectively. The matrix effect was negligible under the current conditions. The mean extraction recoveries were within 105-115%, 92.6-101%, 94.0-100%, and 85.1-99.9% for Cape, DFCR, DFUR, and 5-FU, respectively. Stability testing showed that the four analytes remained stable under all relevant analytical conditions. This method has been applied to a clinical bioequivalence study.

Topics: Antimetabolites, Antineoplastic; Capecitabine; Chromatography, High Pressure Liquid; Deoxycytidine; Floxuridine; Fluorouracil; Humans; Male; Neoplasms; Tandem Mass Spectrometry; Therapeutic Equivalency

Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-β-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Capecitabine; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Female; Floxuridine; Gastrectomy; Humans; Male; Middle Aged; Neoplasms; Pharmacogenomic Variants; Prodrugs

Combination chemotherapy now becomes the most standard cancer treatment protocol. Here, we present a core-shell type polymeric microgel (CSPM) which combines photodynamic and chemo therapeutic modalities in one-pot system. CSPM localizes in the malignant lesion after intratumoral injection, releases reactive oxygen species (ROS) and anticancer drug (5'-deoxy-5-fluorocytidine; DFCR) under the near-infrared (NIR) laser treatment. Pheophorbide A (PheoA)-linked poly(hydroxyethyl methacrylate) (poly-HEMA) was designated to a ROS-generating core, and chemically covered with a chitosan shell. In addition, phenylboronic acid was employed in chitosan shells and linked to DFCR to form an ROS cleavable boronic ester. The core-shell structure of CSPM was determined by transmission electron microscopy. NIR-responsive photodynamic ROS generation was confirmed by the oxidative reduction of 9,10-dimethylanthracene (a fluorescent dye), and the cascadic release of DFCR by ROS was confirmed by a release study and a live and dead cell imaging study. Typically, poly-HEMA cored microgel increased its volume by 48.9-fold after absorption of body fluid. This swelling property ensured CSPM was retained in tumor tissues after subtumoral injection and the suitability of CSPM for locoregional phototherapy. The therapeutic effect of CSPM was attributed to the combined, cascadic deliveries of cytotoxic ROS and DFCR and confirmed by growth inhibition studies in in vitro pancreatic cancer cells and in vivo colon cancer mouse model.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chlorophyll; Combined Modality Therapy; Delayed-Action Preparations; Deoxycytidine; Humans; Infrared Rays; Laser Therapy; Mice, Inbred BALB C; Microgels; Neoplasms; Polyhydroxyethyl Methacrylate; Reactive Oxygen Species; Water