Inhibition of Induced Chemoresistance by Cotreatment with (E)-5-(2-Bromovinyl)-2'-Deoxyuridine (RP101)

Rudolf Fahrig, Jörg-Christian Heinrich, Bernd Nickel, Falk Wilfert, Christina Leisser, Georg Krupitza, Christian Praha, Denise Sonntag, Beate Fiedler, Harry Scherthan and Heinrich Ernst

RESprotect, Dresden, Germany D-01307 [R. F., J-C. H., F. W., C. P., D. S.]; Baxter Oncology, Frankfurt am Main, Germany 60314 [B. N.]; Institute of Clinical Pathology, University of Vienna, Vienna, Austria 1097 [C. L., G. K.]; Medical School Hannover, Hannover, Germany 30625 [B. F.]; Max-Planck-Institute for Molecular Genetics, Berlin, Germany 14195 [H. S.]; and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany 30625 [H. E.]

Abstract

  Induced chemoresistance leads to the reduction of apoptotic responses. Although several drugs are in development that circumvent or decrease existing chemoresistance, none has the potential to prevent or reduce its induction. Here, we present data from a drug that could perhaps fill this gap. Cotreatment of chemotherapy with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, RP101) prevented the decrease of apoptotic effects during the course of chemotherapy and reduced nonspecific toxicity. Amplification of chemoresistance genes (Mdr1 and Dhfr) and overexpression of gene products involved in proliferation (DDX1) or DNA repair (UBE2N and APEX) were inhibited, whereas activity of NAD(P)H: quinone oxidoreductase 1 (NQO1) was enhanced. During recovery, when treatment was with BVDU only, microfilamental proteins were up-regulated, and proteins involved in ATP generation or cell survival (STAT3 and JUN-D) were down-regulated. That way, in three different rat tumor models, the antitumor efficiency of chemotherapy was optimized, and toxic side effects were reduced. Because of these beneficial properties of BVDU, a clinical pilot Phase I/II study with five human tumor entities has been started at the University of Dresden (Dresden, Germany). So far, no unwanted side effects have been observed.