A new approach for the treatment of malignant melanoma: Enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2

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Item Type:	Article
Title:	A new approach for the treatment of malignant melanoma: Enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2
Creators Name:	Mansour, A.M., Drevs, J., Esser, N., Hamada, F.M., Badary, O.A., Unger, C., Fichtner, I. and Kratz, F.
Abstract:	The progression of malignant melanoma is characterized by overexpression of a number of matrix metalloproteinases (MMPs), especially MMP-2, which play a critical role in the degradation of basement membranes and the extracellular matrix. Consequently, we assessed a drug targeting strategy in which the protease activity of MMP-2 is exploited to release an anticancer agent from a macromolecular carrier, i.e., circulating albumin. For this purpose, a water-soluble maleimide derivative of doxorubicin (1) incorporating a MMP-2 specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln) was developed that binds rapidly and selectively to the cysteine-34 position of circulating albumin. The albumin-bound form of 1 was efficiently and specifically cleaved by MMP-2 liberating a doxorubicin tetrapeptide (Ile-Ala-Gly-Gln-DOXO) and subsequently doxorubicin. In vivo, 1 was superior to the parent compound doxorubicin in the A375 human melanoma xenograft, which is characterized by a high expression of MMP-2.
Keywords:	Albumins, Antineoplastic Antibiotics, Cultured Tumor Cells, Doxorubicin, Maleimides, Matrix Metalloproteinase 2, Melanoma, Oligopeptides, Prodrugs
Source:	Cancer Research
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Volume:	63
Number:	14
Page Range:	4062-4066
Date:	15 July 2003
Official Publication:	http://cancerres.aacrjournals.org/cgi/content/abstract/63/14/4062
PubMed:	View item in PubMed

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