Abstract | BACKGROUND: 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.
|
Authors | Jurstine Daruwalla, Khaled Greish, Cathy Malcontenti-Wilson, Vijayaragavan Muralidharan, Hiroshi Maeda, Chris Christophi |
Journal | Surgery
(Surgery)
Vol. 158
Issue 1
Pg. 236-47
(Jul 2015)
ISSN: 1532-7361 [Electronic] United States |
PMID | 25999256
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 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)
|