Antimyeloma activity of NK012, a micelle-forming macromolecular prodrug of SN-38, in an orthotopic model.

NK012 is a micelle-forming macromolecular prodrug of 7-ethyl-10-hydroxy camptothecin (SN-38), an active metabolite of irinotecan. It is accumulated and retained in tumor tissues and gradually releases SN-38 in an enzyme-independent manner. NK012 was previously demonstrated to have stronger antitumor activity than irinotecan in a broad range of human solid-tumor xenograft models. In our study, we used an orthotopic multiple myeloma (MM) model created by injecting CD138-positive U266B1, a myeloma cell line that produces human IgE lambda light chain (monoclonal protein, M protein), into immunodeficient NOD/Shi-scid, IL-2Rγc (null) mice. This model shows typical bone marrow infiltration by the human myeloma cells. We evaluated the antimyeloma activity of intravenously administered NK012 in this model and showed that it suppressed the M protein concentration in the plasma and proliferation of myeloma cells in the bone marrow in a dose-dependent manner. NK012 suppressed the progression of hind-leg paralysis and prolonged the survival time of the mice compared to the untreated control group. In combination with bortezomib (BTZ), NK012 increased the median survival time compared to that with BTZ alone. In conclusion, these results suggest that NK012 is a potential candidate for use-alone and in combination-in the treatment of MM in humans.

Comparative study of peripheral neurotoxicity after injection of two different paclitaxel formulations in rats.

Paclitaxel Inj. [NK] (test; paclitaxel, CAS 33069-62-4) is a generic version of the drug from the originator (reference). Both drugs contain the same active ingredient and showed identical pharmacokinetics in patients in the previous study; however, these two drugs may have different safety profiles because they contain different inactive ingredients. Thus, in this study, peripheral neurotoxicity, one of the dose-limiting toxicities of the reference, was compared between the test and the reference in rats electrophysiologically and histopathologically. In a nerve conduction study, the amplitude of the caudal sensory nerve action potential decreased significantly after either the test or the reference administration, compared with the amplitude after saline administration, but no significant differences were observed between the two drugs. Histopathologically, apparent degeneration of the myelinated fibers in the sciatic and the sural nerves was seen after either the test or the reference injection, compared with after saline injection, but no apparent differences were observed between the two formulations. These results suggest that no significant difference in peripheral neurotoxicity exists between the test and the reference in rats.

High performance liquid chromatographic determination of acetoacetate by post-column derivatization with p-nitrobenzene diazonium fluoroborate.

We have applied a color-developing reagent, p-nitrobenzene diazonium fluoroborate (diazo reagent) as a post-column derivatization tool for the specific determination of acetoacetate (AcAc) in high performance liquid chromatography (HPLC). A mobile phase consisting of 50 mM KH(2)PO(4), 4 mM tetra-n-butylammonium phosphate (TBAP) as an ion-pair reagent and 2 v/v% methanol, pH 3.5, diazo reagent solution with 0.2% triton X-100, and alkaline solution of 1.5 mol/l NaOH were pumped using three independent pumps. Specific color development on-line was monitored at 645 nm. A calibration curve for AcAc standard solution with an injection volume of 20 microl showed a good linearity in the range 0.01-2.5 mM with a correlation coefficient of 0.999. For the determination of 3-hydroxybutyrate (3-HOBA), 3-HOBA was converted to AcAc by an enzymatic-coupling method using 3-HOBA dehydrogenase and lactate dehydrogenase. Analytical recoveries of AcAc and 3-HOBA added to serum and urine were satisfactory.