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Updated: Aug 30, 2026
Modeling Chemotherapy Resistant Leukemia In Vitro
Published on: February 9, 2016
Inhibition of induced chemoresistance by cotreatment with (E)-5-(2-bromovinyl)-2'-deoxyuridine (RP101)
Rudolf Fahrig1, Jörg-Christian Heinrich, Bernd Nickel
1RESprotect, Dresden, Germany. fahrig@resprotect.de
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.
Insights
This study introduces (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) as a novel drug that prevents chemoresistance induction. BVDU enhances chemotherapy efficacy and reduces toxicity in preclinical models, with a human trial underway.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Chemoresistance diminishes treatment efficacy by reducing apoptosis.
- Current therapies address existing resistance but not its induction.
- A need exists for agents that prevent chemoresistance development.
Purpose of the Study:
- To evaluate (E)-5-(2-bromovinyl)-2 -deoxyuridine (BVDU, RP101) for preventing chemoresistance induction.
- To assess BVDU's impact on chemotherapy efficacy and toxicity.
- To investigate BVDU's molecular mechanisms in tumor models.
Main Methods:
- Cotreatment of chemotherapy with BVDU in rat tumor models.
- Analysis of chemoresistance gene amplification (Mdr1, Dhfr).
- Assessment of proliferation (DDX1), DNA repair (UBE2N, APEX), and NQO1 activity.
Main Results:
- BVDU prevented the decrease in apoptosis during chemotherapy.
- Chemoresistance gene amplification and overexpression of proliferation/DNA repair proteins were inhibited.
- BVDU enhanced antitumor efficiency and reduced nonspecific toxicity in rat models.
- BVDU treatment modulated microfilamental proteins and proteins involved in ATP generation and cell survival during recovery.
Conclusions:
- BVDU demonstrates potential in preventing chemoresistance induction.
- BVDU optimizes chemotherapy effectiveness while minimizing side effects.
- A Phase I/II clinical trial in humans has commenced with no observed adverse effects.
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