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Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10 viral particles (vp)/mL or 3 × 10 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 10 vp/mL, n = 21; 3 × 10 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.

We report the synthesis and in vitro biological activity of the nonpeptide bradykinin receptor antagonist WIN 64338, [[4-[[2-[[bis(cyclohexylamino) Bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is a nonapeptide released from kininogens by the actions of plasma kallikreins (1) that has been implicated in a variety of physiological and pathological processes, including pain, inflammation, and regulation of blood pressure (2, 3). The effects of bradykinin are mediated through specific G-protein-coupled cell surface receptors (4). These receptors have been tentatively divided into at least three classes, B1, B2, and B3 (5-7), on the basis of pharmacological characterization with selective bradykinin peptide agonists and antagonists. Bradykinin binds to most putative B2 receptors with an affinity in the low nanomolar range under physiological conditions (8).A bradykinin analogue in which D-phenylalanine replaces L-proline in the 7 position of the native ligand was discovered by Vavrek and Stewart (9) and was found to be a bradykinin B2 receptor antagonist. A series of peptide analogues of bradykinin containing this substitution have demonstrated antagonist activity in a variety of tissues (10, 11). The D-Phe7-substituted bradykinin analogues were critical for initial receptor classification; however, they are generally of low potency in various biological assays and demonstrate partial or full agonist activity in certain tissues (12). In addition, these compounds are substrates for carboxypeptidase N (13). Cleavage of the C-terminal arginine by carboxypeptidase N results in compounds that are inactive at the bradykinin B2 receptor but active at the bradykinin B1 receptor (14).The structure and pharmacological activity of a different kind of bradykinin antagonist, DArg0-[Hyp3,Thi5,DTic7, Oic8lbradykinin (HOE-140) [Hyp, (4R)-4-hydroxyprolyl;Thi, 3-(2-thienyl)alanyl; DTic, 1,2,3,4-tetrahydroisoquinolin-2-yl-carbonyl; Oic, (3aS,7aS)-octahydroindol-2-yl-carbonylJ, has recently been described (15,16). In a variety of bradykinin assays, this compound acts as a selective B2 receptor antagonist and is at least two orders of magnitude more potent than any ofthe 18). Although HOE-140 appears to be a competitive antagonist of bradykinin at the B2 receptor in some biological assays, it is reported to be noncompetitive in other systems (19,20).Despite the increases in potency and biological activity observed in second-generation bradykinin receptor antagonists, these compounds are all peptides and therefore subject to metabolism and poor bioavailability (21 [[4-[[2-[[bis(cyclohexylamino) 4693The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.