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Antiangiogenesis targeting tumor microenvironment synergizes glucuronide prodrug antitumor activity

Ting-Yi Juan1, Steve R Roffler, Hsien-San Hou

  • 1Divisions of Urology, Graduate Institute of Life Sciences, Institute of Biomedical Sciences, Academia Sinica, National Yang-Ming University,Taipei,Taiwan.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 9, 2009
PubMed
Abstract

Insights

A novel glucuronide prodrug, 9-aminocamptothecin glucuronide (9ACG), shows potent antitumor activity. Combining 9ACG with antiangiogenesis therapy enhances efficacy, particularly in tumors with inflammatory cell infiltration.

Area of Science:

  • Oncology
  • Pharmacology
  • Immunology

Background:

  • Tumor microenvironment plays a critical role in cancer progression and treatment response.
  • Targeting tumor microenvironment with antiangiogenesis therapy is a promising strategy.
  • Prodrugs offer a way to deliver cytotoxic agents specifically to the tumor site.

Purpose of the Study:

  • To investigate the in vivo antitumor activity of 9-aminocamptothecin glucuronide (9ACG), a novel cell-impermeable glucuronide prodrug.
  • To evaluate the synergistic antitumor effects of 9ACG in combination with antiangiogenesis therapy.
  • To elucidate the role of the tumor microenvironment in mediating the efficacy of 9ACG and combination therapy.

Main Methods:

  • Assessed antitumor effects of 9ACG alone and with antiangiogenic antibody DC101 on human tumor xenografts in mice.
  • Measured tumor growth and mouse survival.
  • Analyzed drug delivery, immune response, and angiogenesis using chromatography and immunohistochemistry.

Main Results:

  • Developed a nontoxic, cell-impermeable prodrug (9ACG) activated by extracellular beta-glucuronidase.
  • 9ACG demonstrated potent antitumor activity in immunocompetent mice but not in immunodeficient mice, indicating immune cell involvement.
  • Antiangiogenic antibody DC101 potentiated 9ACG activity and prolonged survival by enhancing beta-glucuronidase activity and inflammatory cell infiltration.

Conclusions:

  • 9ACG exhibits potential as a monotherapy or in combination with antiangiogenesis treatment.
  • The efficacy of 9ACG is dependent on the infiltration of macrophage or neutrophil inflammatory cells.
  • Targeting the tumor microenvironment is crucial for optimizing prodrug therapy.

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