Development of an oxime bond containing daunorubicin-gonadotropin-releasing hormone-III conjugate as a potential anticancer drug.
Here, we report on the synthesis and biological properties of a conjugate in which daunorubicin (Dau) as chemotherapeutic agent was attached through an oxime bond to gonadotropin-releasing hormone-III (GnRH-III) as targeting moiety. In vitro toxicity and the cytostatic effect of the conjugate on MCF-7 human breast and C26 murine colon cancer cell lines were determined, and the results were compared with those obtained for the free daunorubicin, as well as with the doxorubicin containing derivative. In vivo antitumor effect of daunorubicin-GnRH-III was studied on Balb/c female mice transplanted with C26 tumor. Our data indicate that the daunorubicin-GnRH-III conjugate had a lower toxic effect than the free daunorubicin and it was essentially nontoxic up to 15 mg (Dau content)/kg body weight. The treatment of the C26 tumor bearing mice with the conjugate led to tumor growth inhibition and longer survival time in comparison with the controls and with the administration of the free drug. When mice were treated twice with the conjugate (on days 4 and 7 after tumor transplantation), 46% tumor growth inhibition was obtained. In this case, the increase of the median survival time was 38% compared to the controls.
Szabó
Ildikó
I
Hungarian Academy of Sciences, and Institute of Chemistry, Eotvos Lorand University, Budapest, Hungary.
Manea
Marilena
M
Orbán
Erika
E
Csámpai
Antal
A
Bosze
Szilvia
S
Szabó
Rita
R
Tejeda
Miguel
M
Gaál
Dezso
D
Kapuvári
Bence
B
Przybylski
Michael
M
Hudecz
Ferenc
F
Mezo
Gábor
G
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D003630:Daunorubicin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D010091:Oximes / Q000737:chemistry*
D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D010091:Oximes; D007987:Gonadotropin-Releasing Hormone; D002401:Cathepsin B; D003630:Daunorubicin