BVDU co-treatment sensitizes for chemotherapy-induced apoptosis and inhibits chemoresistance

Rudolf Fahrig¹, Jörg-Christian Heinrich¹, Christina Leisser², Georg Krupitza², Falk Wilfert¹, Christian Praha¹, Denise Sonntag¹, Bernd Nickel³, Beate Fiedler⁴, Harry Scherthan⁵ & Heinrich Ernst⁶

During the implementation of a long-term screening program for inhibitors of induced chemoresistance, the pyrimidine nucleoside analog (E)-5-(2-bromovinyl)-2´-deoxyuridine (BVDU) was the only substance of clinical relevance we identified. BVDU co-treatment enhanced apoptosis and inhibited chemoresistance. This might have been due to the following effects of BVDU: 1) Inhibition of survival pathways and DNA repair associated enzymes. BVDU cotreatment might have promoted apoptosis by blocking the anti-apoptotic survival pathways that involve the oncogenes STAT3, JUN-D, and DDX1. Moreover, BVDU reduced the expression of the repair enzymes UBE2N and APEX to about 30% of control. 2) Induction of DT-diaphoras  activity, an activator of quinone-type anticancer drugs. 3) Suppression of chemotherapy-induced Mdr1 or Dhfr gene amplification, 4) Reduced expression of ATP-generating enzymes in the recovery phase, when the cytostatic drug was omitted, but BVDU still present. The expression of nine genes increased, and that of five genes decreased. Gene products linked to microfilament formation, differentiation, and signal transduction were affected, too.

  In rats, co-treatment of doxorubicin (DOX), glufosfamide, or cisplatin with BVDU inhibited the growth of implanted AH13r sarcomas as well as that of dimethylbenzanthrazene (DMBA)-induced and DOX-treated fibrosarcomas and mammary adenocarcinomas. In these experiments, treatment with DOX for 50 days caused Mdr1 gene amplification and overexpression in DMBAinduced rat tumors. Co-treatment with BVDU inhibited this cytostatic drug-induced effect. In the experiments with AH13r sarcomas treate  for only 20 days, no gene amplification could be observed. In in vivo experiments, BVDU reduced the non-specific toxicity of DOX, and to a lesser extent that of cisplatin and glufosfamide.