Inhibition of induced chemoresistance by cotreatment with (E)-5-(2-bromovinyl)-2'-deoxyuridine (RP101).
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.
Fahrig
Rudolf
R
RESprotect, Dresden, Germany. fahrig@resprotect.de
Heinrich
Jörg-Christian
JC
Nickel
Bernd
B
Wilfert
Falk
F
Leisser
Christina
C
Krupitza
Georg
G
Praha
Christian
C
Sonntag
Denise
D
Fiedler
Beate
B
Scherthan
Harry
H
Ernst
Heinrich
H
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015180:Electrophoresis, Gel, Two-Dimensional; D005347:Fibroblasts / Q000187:drug effects; D007069:Ifosfamide / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D016685:Mitomycin / Q000008:administration & dosage; D008942:Mitoxantrone / Q000008:administration & dosage; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D012517:Sarcoma, Yoshida / Q000188:drug therapy / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077235:Vinorelbine
D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; C020235:brivudine; D016685:Mitomycin; D014747:Vinblastine; D004317:Doxorubicin; D008942:Mitoxantrone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001973:Bromodeoxyuridine; D002945:Cisplatin; D000077235:Vinorelbine; D007069:Ifosfamide; D008727:Methotrexate