HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Styrene maleic acid copolymer-pirarubicin induces tumor-selective oxidative stress and decreases tumor hypoxia as possible treatment of colorectal cancer liver metastases.

AbstractBACKGROUND:
Pirarubicin, a derivative of doxorubicin, induces tumor destruction via the production of reactive oxygen species (ROS) but is associated with cardiotoxicity. As a macromolecule (conjugated to styrene-maleic acid [SMA]), SMA-pirarubicin is selective to tumors resulting in improved survival with decreased systemic toxicity. Tumor destruction is, however incomplete, and resistant cells at the periphery of the tumor contribute to recurrence. Tumor hypoxia is a major factor in tumor resistance. Understanding the effect of oxidative stress induced by SMA-pirarubicin on the tumor microenvironment may be key to overcoming resistance. This study investigated the pattern of ROS production and tumor hypoxia after treatment with SMA-pirarubicin in a murine model of colorectal liver metastases.
METHODS:
Liver metastases were induced in male, CBA mice using a murine-derived colon cancer cell line. SMA-pirarubicin (maximum tolerated dose, 100 mg/kg) or pirarubicin, (maximum tolerated dose, 10 mg/kg) were administered intravenously 14 days after tumor induction. Systemic oxidative stress in serum, liver, and cardiac tissue was quantified using the thiobarbituric acid reactive substances assay. Flow cytometry and fluorescence microscopy were used to assess ROS production for 48 hours after treatment. Tumor hypoxia was quantified using immunohistochemistry for pimonidazole adducts.
RESULTS:
SMA-pirarubicin (100 mg/kg) induced ROS exclusively in tumors with minimal levels in serum and cardiac tissue. ROS levels were induced in a time-dependent and dose-dependent manner optimal between 4 and 24 hours after drug administration. Although tumor hypoxia was decreased overall, residual tumor cells adjacent to patent vessels were hypoxic.
CONCLUSION:
This study provides insight into the tumor microenvironment after chemotherapy. SMA-pirarubicin inhibits the growth of colorectal liver metastases by inducing ROS, which seems to be largely tumor selective. The temporal pattern of ROS production can be used to improve future dosing regimens. Furthermore, the observation that residual tumor cells are hypoxic clarifies the need for a multimodal approach with agents that can alter the hypoxic state to effect complete tumor destruction.
AuthorsJurstine Daruwalla, Khaled Greish, Cathy Malcontenti-Wilson, Vijayaragavan Muralidharan, Hiroshi Maeda, Chris Christophi
JournalSurgery (Surgery) Vol. 158 Issue 1 Pg. 236-47 (Jul 2015) ISSN: 1532-7361 [Electronic] United States
PMID25999256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Maleates
  • Polystyrenes
  • Reactive Oxygen Species
  • Doxorubicin
  • styrofoam
  • maleic acid
  • pirarubicin
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
  • Cell Hypoxia (drug effects)
  • Colorectal Neoplasms (drug therapy, metabolism, pathology)
  • Disease Models, Animal
  • Doxorubicin (administration & dosage, analogs & derivatives)
  • Liver Neoplasms (drug therapy, metabolism, secondary)
  • Male
  • Maleates (administration & dosage)
  • Mice
  • Mice, Inbred CBA
  • Oxidative Stress (drug effects)
  • Polystyrenes (administration & dosage)
  • Reactive Oxygen Species (metabolism)
  • Tumor Microenvironment (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: