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

Cancer Res. 2003 Jul 15;63(14):4062-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / pharmacokinetics*
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Antibiotics, Antineoplastic / pharmacology
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Humans
  • Maleimides / pharmacokinetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Melanoma / drug therapy*
  • Melanoma / enzymology*
  • Oligopeptides / pharmacokinetics*
  • Prodrugs / pharmacokinetics*
  • Tumor Cells, Cultured

Substances

  • Albumins
  • Antibiotics, Antineoplastic
  • Maleimides
  • Oligopeptides
  • Prodrugs
  • Doxorubicin
  • Matrix Metalloproteinase 2