title: Conjugates of daidzein-alliinase as a targeted pro-drug enzyme system against ovarian carcinoma.
abstract: Human ovarian cancer cells specifically bind the isoflavone daidzein. A chemical conjugate between daidzein and the garlic enzyme alliinase was prepared. The conjugate specifically bound to ovarian cancer cells and upon addition of the prodrug alliin, it effectively produced cytotoxic allicin molecules which killed the cancer cells. In vivo targeting and antitumor effect was confirmed by NIR and bioluminescence imaging using daidzein-alliinase-CyTE-777 conjugates and luciferase-expressing ovarian cancer cells. Co-localization of the fluorescent conjugate with bioluminescence was observed for intraperitoneal tumors while nonconjugated alliinase did not accumulate. Biodistribution studies with Europium-labeled conjugate revealed a five fold higher uptake in tumors as compared to other tissues. Treatment of tumor bearing mice with daidzein-alliinase and alliin effectively attenuated tumor progression during the first 12 days while a 5-fold increase in bioluminescence was detected in placebo-treated animals. Autopsy revealed only small individual foci of luminescence at the site of tumor cells inoculation. Histological examination of organs and tissues did not reveal any additional foci of carcinoma or signs of toxicity. These results suggest that the targeted alliinase conjugates in the presence of alliin, generated therapeutically effective levels of allicin which were capable of suppressing tumor progression of intraperitoneal ovarian cancer in an animal model.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Appel
authors.forename: Aharon
authors.initials: A
authors.lastname: Rabinkov
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
authors.forename: Fortune
authors.initials: F
authors.lastname: Kohen
authors.forename: David
authors.initials: D
authors.lastname: Mirelman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013437:Carbon-Sulfur Lyases / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004339:Drug Compounding; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014018:Tissue Distribution; D014162:Transfection; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D007529:Isoflavones; D011355:Prodrugs; C004742:daidzein; C006453:alliin; D008156:Luciferases; D013437:Carbon-Sulfur Lyases; C019243:alliin lyase; D003545:Cysteine