BACKGROUND: Several reports describe the importance of the chaperone HSP27 (HSPB1) in cancer progression, and the demand for drugs that modulate HSPB1-activity is increasing rapidly. We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer. METHODS: Chemistry: Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology: HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancer patients: Pilot study, Dose finding study, Phase II study (NCT00550004). RESULTS: Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancer patients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients. CONCLUSIONS: The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.
RCT Entities:
BACKGROUND: Several reports describe the importance of the chaperone HSP27 (HSPB1) in cancer progression, and the demand for drugs that modulate HSPB1-activity is increasing rapidly. We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer. METHODS: Chemistry: Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology: HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancerpatients: Pilot study, Dose finding study, Phase II study (NCT00550004). RESULTS: Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancerpatients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients. CONCLUSIONS: The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.
Authors: Palma Rocchi; Eliana Beraldi; Susan Ettinger; Ladan Fazli; Robert L Vessella; Colleen Nelson; Martin Gleave Journal: Cancer Res Date: 2005-12-01 Impact factor: 12.701
Authors: Louise E Bird; Jingshan Ren; Alan Wright; Kris D Leslie; Bart Degrève; Jan Balzarini; David K Stammers Journal: J Biol Chem Date: 2003-04-09 Impact factor: 5.157
Authors: Christophe Caillat; Dimitri Topalis; Luigi A Agrofoglio; Sylvie Pochet; Jan Balzarini; Dominique Deville-Bonne; Philippe Meyer Journal: Proc Natl Acad Sci U S A Date: 2008-10-29 Impact factor: 11.205
Authors: Bo Zhong; Snigdha Chennamaneni; Rati Lama; Xin Yi; Werner J Geldenhuys; John J Pink; Afshin Dowlati; Yan Xu; Aimin Zhou; Bin Su Journal: J Med Chem Date: 2013-06-28 Impact factor: 7.446
Authors: Leah N Makley; Oleta T Johnson; Phani Ghanakota; Jennifer N Rauch; Delaney Osborn; Taia S Wu; Tomasz Cierpicki; Heather A Carlson; Jason E Gestwicki Journal: Bioorg Med Chem Date: 2021-01-24 Impact factor: 3.641