title: Improved in vivo antitumor effect of a daunorubicin - GnRH-III bioconjugate modified by apoptosis inducing agent butyric acid on colorectal carcinoma bearing mice.
abstract: Compared to classical chemotherapy, peptide-based drug targeting is a promising therapeutic approach for cancer, which can provide increased selectivity and decreased side effects to anticancer drugs. Among various homing devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety, in particular in the treatment of hormone independent tumors that highly express GnRH receptors (e.g. colon carcinoma). We have previously shown that GnRH-III[(4)Lys(Ac),(8)Lys(Dau = Aoa)] bioconjugate, in which daunorubicin was attached via oxime linkage to the (8)Lys of a GnRH-III derivative, exerted significant in vivo antitumor effect on subcutaneously developed HT-29 colon tumor. In contrast, results of the study reported here indicated that this compound was not active on an orthotopically developed tumor. However, if Lys in position 4 was acylated with butyric acid instead of acetic acid, the resulting bioconjugate GnRH-III[(4)Lys(Bu),(8)Lys(Dau = Aoa)] had significant tumor growth inhibitory effect. Furthermore, it prevented tumor neovascularization, without detectable side effects. Nevertheless, the development of metastases could not be inhibited by the bioconjugate; therefore, its application in combination with a metastasis preventive agent might be necessary in order to achieve complete tumor remission. In spite of this result, the treatment with GnRH-III[(4)Lys(Bu),(8)Lys(Dau = Aoa)] bioconjugate proved to have significant benefits over the administration of free daunorubicin, which was used at the maximum tolerated dose.
authors.affiliation: National Institute of Oncology, Budapest, 1122, Hungary.
authors.forename: Bence
authors.initials: B
authors.lastname: Kapuvári
authors.affiliation: MTA-ELTE, Research Group of Peptide Chemistry, Pázmány P. stny. 1/A, Budapest, 1117, Hungary.
authors.forename: Rózsa
authors.initials: R
authors.lastname: Hegedüs
authors.affiliation: National Institute of Oncology, Budapest, 1122, Hungary.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Schulcz
authors.affiliation: Department of Chemistry and Zukunftskolleg, University of Konstanz, 78457, Constance, Germany.
authors.forename: Marilena
authors.initials: M
authors.lastname: Manea
authors.affiliation: National Institute of Oncology, Budapest, 1122, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Tóvári
authors.affiliation: National Institute of Oncology, Budapest, 1122, Hungary.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gacs
authors.affiliation: National Institute of Oncology, Budapest, 1122, Hungary.
authors.forename: Borbála
authors.initials: B
authors.lastname: Vincze
authors.affiliation: MTA-ELTE, Research Group of Peptide Chemistry, Pázmány P. stny. 1/A, Budapest, 1117, Hungary. gmezo@elte.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Mező
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D020148:Butyric Acid / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003630:Daunorubicin / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D019073:HT29 Cells; D006321:Heart / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C448022:gonadotropin-releasing hormone-III; D020148:Butyric Acid; D007987:Gonadotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid; D003630:Daunorubicin
keywords: Colon cancer; Daunorubicin; GnRH-III; In vivo tumor growth inhibition; Short chain fatty acids; Targeted cancer therapy