A daidzein-daunomycin conjugate improves the therapeutic response in an animal model of ovarian carcinoma.
The use of daunomycin against neoplasms is limited due to its severe cardiotoxicity. The cytotoxicity of daunomycin can be minimized by linking it to an affinity tag. Since ovarian cancer cells are sensitive to isoflavone action, we synthesized a daidzein daunomycin conjugate. In MLS human ovarian cancer cells, the conjugate was shown to have a larger cytotoxic effect than daunomycin per se at a low concentration. The conjugate was then tested in vivo in mice carrying MLS xenografts. Tumour growth in the groups of conjugate and daunomycin was inhibited by >50% as compared to vehicle treated mice. In contrast to daunomycin treated mice, no weight reduction or death was seen in mice treated with the conjugate. In vivo imaging of the fluorescence signal generated by daunomycin indicated uptake of both conjugate and daunomycin by the tumour. Tumour fluorescence was, however, higher in the conjugate treated mice than in the daunomycin treated mice, thus suggesting specific delivery of the drug to the tumour. Histological examination of myocardial tissue indicated that only the daunomycin, but not conjugate treated mice showed cardiac damage. These results indicate that targeting of daunomycin via carboxymethyldaidzein retains daunomycin's cytotoxic effects while averting its toxicity in an ovarian xenograft.
Somjen
Dalia
D
Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Israel.
Katzburg
Sara
S
Nevo
Nava
N
Gayer
Batya
B
Hodge
Richard P
RP
Renevey
Misty D
MD
Kalchenko
Vyacheslav
V
Meshorer
Asher
A
Stern
Naftali
N
Kohen
Fortune
F
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D048789:Phytoestrogens / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000903:Antibiotics, Antineoplastic; D007529:Isoflavones; D048789:Phytoestrogens; C004742:daidzein; D003630:Daunorubicin