title: In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts.
abstract: Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro and in vivo, in vivo data for nemorosone are still missing. Thus, we investigated the growth-inhibitory potential of nemorosone on pancreatic cancer xenografts in NMRI nu/nu mice and determined basic pharmacokinetic parameters. Xenograft tumors were treated with nemorosone and gemcitabine, the current standard of care. Tumor sections were subjected to H&E as well as caspase 3 and Ki-67 staining. Nemorosone plasma kinetics were determined by HPLC and mass spectrometry. Induction of CYP3A4 and other metabolizing enzymes by nemorosone and hyperforin was tested on primary hepatocytes using qRT-PCR. At a dose of 50 mg/kg nemorosone per day, a significant growth-inhibitory effect was observed in pancreatic cancer xenografts. The compound was well tolerated and rapidly absorbed into the bloodstream with a half-life of approximately 30 min. Different metabolites were detected, possibly resembling CYP3A4-independent oxidation products. It is concluded that nemorosone is a potential anti-cancer lead compound with good bioavailability, little side-effects and promising growth-inhibitory effects, thus representing a valuable compound for a combination therapy approach.
authors.affiliation: Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wolf
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Hilger
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hoheisel
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.forename: Frank
authors.initials: F
authors.lastname: Holtrup
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001577:Benzophenones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D006207:Half-Life; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010696:Phloroglucinol / Q000008:administration & dosage / Q000031:analogs & derivatives; D061251:Primary Cell Culture; D013729:Terpenes / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D019394:Ki-67 Antigen; D013729:Terpenes; C437463:nemorosone; D003841:Deoxycytidine; D010696:Phloroglucinol; D051544:Cytochrome P-450 CYP3A; D053148:Caspase 3; C001654:hyperforin; D000093542:Gemcitabine
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