دورية أكاديمية
Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers
| العنوان: | Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers |
|---|---|
| المؤلفون: | Landowski, Christopher, Dahan, Arik, Wolk, Omri, Yang, Peihua, Mittal, Sachin, Wu, Zhiqian, Landowski, Christopher P., Amidon, Gordon L. |
| المصدر: | Landowski , C , Dahan , A , Wolk , O , Yang , P , Mittal , S , Wu , Z , Landowski , C P & Amidon , G L 2014 , ' Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers ' , Molecular Pharmaceutics , vol. 11 , no. 12 , pp. 4385-94 . https://doi.org/10.1021/mp500483vTest |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being |
| الوصف: | The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://cris.vtt.fi/en/publications/0c157a96-1284-441c-a0b5-419847d35c49Test |
| DOI: | 10.1021/mp500483v |
| الإتاحة: | https://doi.org/10.1021/mp500483vTest https://cris.vtt.fi/en/publications/0c157a96-1284-441c-a0b5-419847d35c49Test |
| حقوق: | info:eu-repo/semantics/closedAccess |
| رقم الانضمام: | edsbas.D6D19661 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/mp500483v |
|---|