Targeting cell surface alpha(v)beta(3) integrin increases therapeutic efficacies of a legumain protease-activated auristatin prodrug

Mol Pharm. 2012 Jan 1;9(1):168-75. doi: 10.1021/mp200434n. Epub 2011 Nov 22.

Abstract

Novel monomethylauristatin E (MMAE) prodrug 8 was designed and prepared that bound cell surface glycoprotein integrin αvβ3, and was activated using legumain protease as a catalyst. Upon activation, prodrug 8 strongly induced the death of MDA-MB-435 cells that express integrin αvβ3 on cell surface. Efficacies of prodrug 8 were also determined in vivo using animal models of 4T1 murine breast cancer, D121 Lewis lung carcinoma, and MDA-MB-435 human breast cancer. The results demonstrated that prodrug 8 decreased tumor growth and metastasis effectively. In comparison to the parent cytotoxin, MMAE, and prodrug 3, prodrug 8 was less toxic to mouse white blood cells. The latter caused no loss in weight gain of mice at a dose 3 mg/kg, which is over 30 times in excess to MMAE (0.1 mg/kg). We hypothesize that overexpression and colocalization of integrin αvβ3 and legumain protease on tumor cells, tumor vasculature, and/or tumor microenvironments can be exploited to enhance the efficacy and selectivity of potent cytotoxins, such as MMAE, which is otherwise too toxic to use for therapy.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biotransformation
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cysteine Endopeptidases / metabolism*
  • Drug Design*
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors
  • Integrin alphaVbeta3 / metabolism*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Maximum Tolerated Dose
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism*
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Oligopeptides / adverse effects
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use*
  • Prodrugs / adverse effects
  • Prodrugs / metabolism
  • Prodrugs / pharmacology
  • Prodrugs / therapeutic use*
  • Rats
  • Survival Analysis

Substances

  • Antineoplastic Agents
  • Integrin alphaVbeta3
  • Neoplasm Proteins
  • Oligopeptides
  • Prodrugs
  • Cysteine Endopeptidases
  • asparaginylendopeptidase
  • monomethyl auristatin E