Activity of the hypoxia-activated pro-drug TH-302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Int J Cancer. 2014 Jun 1;134(11):2726-34. doi: 10.1002/ijc.28595. Epub 2013 Dec 13.

Abstract

Many chemotherapy drugs have poor therapeutic activity in regions distant from tumor blood vessels because of poor tissue penetration and low cytotoxic activity against slowly-proliferating cells. The hypoxia-activated pro-drug TH-302 may have selective toxicity for hypoxic and neighboring cells in tumors. Here we characterize the spatial distribution and ability of TH-302 to selectively target hypoxic regions and complement the effect of doxorubicin and docetaxel by modifying biomarker distribution. Athymic nude mice bearing human breast MCF-7 or prostate PC-3 tumors were treated with doxorubicin or docetaxel respectively and TH-302 alone or in combination. Biomarkers of drug effect including γH2aX (a marker of DNA damage), cleaved caspase-3 or -6 (markers of apoptosis) and reduction in Ki-67 (a marker of cell proliferation) were quantified in tumor sections in relation to functional blood vessels (recognized by DiOC7) and hypoxia (recognized by EF5) using immunohistochemistry. γH2aX expression at 10 min and cleaved caspase-3 or -6 at 24 hr after doxorubicin or docetaxel decreased with increasing distance from tumor blood vessels, with minimal expression in hypoxic regions; maximum reduction in Ki67 levels was observed in regions closest to vasculature at 24 hr. TH-302 induced maximal cell damage in hypoxic and neighboring regions, but was also active in tumor regions closer to blood vessels. TH-302 given 4 hr before doxorubicin or docetaxel increased DNA damage and apoptosis throughout the tumor compared to chemotherapy alone. When given with doxorubicin or docetaxel, TH-302 complements and enhances anticancer effects in both perivascular and hypoxic regions but also increases toxicity.

Keywords: TH-302; drug distribution; drug penetration; hypoxia-activated pro-drug; pharmacodynamic markers; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / analysis
  • Breast Neoplasms / blood supply*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Hypoxia / drug effects*
  • Docetaxel
  • Doxorubicin / administration & dosage
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Nitroimidazoles / administration & dosage
  • Phosphoramide Mustards / administration & dosage
  • Prodrugs / therapeutic use*
  • Prostatic Neoplasms / blood supply*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Taxoids / administration & dosage
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Nitroimidazoles
  • Phosphoramide Mustards
  • Prodrugs
  • TH 302
  • Taxoids
  • Docetaxel
  • Doxorubicin