A water-soluble selenoxide reagent as a useful probe for the reactivity and folding of polythiol peptides.

A water-soluble selenoxide (DHS(ox)) having a five-membered ring structure enables rapid and selective conversion of cysteinyl SH groups in a polypeptide chain into SS bonds in a wide pH and temperature range. It was previously demonstrated that the second-order rate constants for the SS formation with DHS(ox) would be proportional to the number of the free SH groups present in the substrate if there is no steric congestion around the SH groups. In the present study, kinetics of the SS formation with DHS(ox) was extensively studied at pH 4-10 and 25 °C by using reduced ribonuclease A, recombinant hirudin variant (CX-397), insulin A- and B-chains, and relaxin A-chain, which have two to eight cysteine residues, as polythiol substrates. The obtained rate constants showed stochastic SS formation behaviors under most conditions. However, the rate constants for CX-397 at pH 8.0 and 10.0 were not proportional to the number of the free SH groups, suggesting that the SS intermediate ensembles possess densely packed structures under weakly basic conditions. The high two-electron redox potential of DHS(ox) (375 mV at 25 °C) compared to l-cystine supported the high ability of DHS(ox) for SS formation in a polypeptide chain. Interestingly, the rate constants of the SS formation jumped up at a pH around the pK a value of the cysteinyl SH groups. The SS formation velocity was slightly decreased by addition of a denaturant due probably to the interaction between the denaturant and the peptide. The stochastic behaviors as well as the absolute values of the second-order rate constants in comparison to dithiothreitol (DTT(red)) are useful to probe the chemical reactivity and conformation, hence the folding, of polypeptide chains.

Phase I clinical and pharmacokinetic study of 3-weekly, 3-h infusion of ixabepilone (BMS-247550), an epothilone B analog, in Japanese patients with refractory solid tumors.

BACKGROUND: Ixabepilone (BMS-247550) is the first in a new class of anti-neoplastic agents, the epothilone analogs, and is a highly active non-taxane anti-microtubule agent. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety profile, pharmacokinetics, and antitumor activity of ixabepilone in Japanese patients. PATIENTS AND METHODS: Patients with solid tumors previously treated with up to four chemotherapy regimens received a 3-h intravenous infusion of ixabepilone every 3 weeks. RESULTS: Fourteen patients received 43 cycles (median 3, range 1-8). The most common adverse events were neutropenia, mild-to-moderate fatigue, anemia, and peripheral neuropathy. DLTs occurred in one patient receiving 40 mg/m2 (grade 4 neutropenia for 9 days) and in two patients receiving 50 mg/m2 (grade 3 mucositis, ileus and febrile neutropenia; grade 4 neutropenia for 10 days). One paclitaxel- and docetaxel-pretreated patient with non-small cell lung cancer achieved a partial response lasting for 3 months; six additional patients (43%) achieved disease stabilization with tumor shrinkage of 3-35%. The plasma concentration-time profiles of ixabepilone during cycle 1 were similar across all doses evaluated. CONCLUSIONS: The MTD of ixabepilone is 50 mg/m2 given over 3 h every 3 weeks. The recommended phase II dose is 40 mg/m2, which is well tolerated and active. Data from Japanese patients are consistent with published phase I data from non-Japanese patients.

Phase I pharmacokinetic and pharmacogenomic study of E7070 administered once every 21 days.

E7070 is a novel sulfonamide anticancer agent that disrupts the G1/S phase of the cell cycle. The objectives of this phase I study of E7070 were to estimate the maximal tolerated dose (MTD), to determine the recommended dose for phase II, and to clarify the pharmacokinetic profile of E7070 and its relation to polymorphisms of CYP2C9 (*2, *3) and CYP2C19 (*2, *3) in Japanese patients. Patients received 1-2-h i.v. infusions of E7070 (400, 600, 700, 800 or 900 mg/m2) on day 1 of a 21-day cycle. Twenty-one patients received between one and eight cycles of E7070. The dose-limiting toxicities (DLT) comprised leukopenia, neutropenia, thrombocytopenia, elevation of aspartate aminotransferase, colitis, and ileus. The mean area under the plasma concentration-time curve (AUC) for successive dose levels increased in a non-dose-proportional manner. Two patients were heterozygous for the CYP2C9 mutation. For CYP2C19, eight patients were wild type and the remainder had heterozygous (n = 8) or homozygous mutations (n = 5). Regarding the CYP2C19 genotype, the AUC of patients with mutant alleles were higher than those of patients with wild type at a dose of 600 mg/m2 or more. The severity of toxic effects, such as myelosuppression, seemed to depend on the AUC. No partial responses were observed. One patient treated at a dose of 700 mg/m2 experienced a maximum tumor volume reduction of 22.5%. The MTD was estimated to be 900 mg/m2. A dose of 800 mg/m2 is recommended for further phase II studies. The pharmacokinetic/pharmacodynamic properties of E7070 seemed to be influenced by CYP2C19 genotype. The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in monotherapy or in combination chemotherapy.