COX Inhibitors Markedly enhance Tumor Radiosensitization of Cultured Human Cancer Cells under Acidic Microenvironment
Ryan Smith, MD
University of Pennsylvania Cancer Center
Ultima Vez Modificado: 6 de noviembre del 2001
Presenter: T.R. Shah
Presenter's Affiliation: Henry Ford Hospital
Type of Session: Scientific
Background Prostaglandins are synthesized by COX enzymes. These prostaglandins have been implicated in carcinogenesis, angiogenesis, invasiveness, and metastatic potential, as well as resistance to treatment.
COX inhibitors may stop the production of these prostaglandins, therefore, nullifying their effect. The hypothesis is that the enhancement of radiation response by COX inhibitors should enhance sensitivity.
This study was designed to investigate this hypothesis an to attempt to determine what microenvironment of tumor tissue would influence the sensitization effect by these COX inhibitors.
Methods Two cell lines (human colon cancer, HT-29) and human glioma (U-251) were studied.
The COX-1 inhibitor used was ibuprofen and the COX-2 inhibitor used was SC-236.
Radiation delivered varied from 2-8 Gy in a single fraction.
Culture medium was varied from a pH of 6.5 to a pH of 7.4.
The quantitative cytotoxicity and radiation cell survival curves were evaluated as endpoints.
Results There was a demonstrated cytotoxicity and radiosensitization of the HT-29 cell line with ibuprofen (the COX-1 inhibitor). This increased as a function of drug concentration (>1.5 mM). Cytotoxicity and radiosensitization was also more pronounced as a function of exposure time. There was a much greater cytotoxicity and radiosensitization with ibuprofen at pH of 6.5 compared to pH of 7.4.
There was also a significant cytotoxicity of the HT-29 cell line when exposed to SC-236 (COX-2 inhibitor). There was no radiosensitization effect seen, even when the pH was decreased to 6.5.
There was no radiation enhancement in the U-251 cell line with COX-2 inhibitors.
Author's Conclusions Significant radiation-induced cytotoxicity was seen with the COX-1 inhibitor, especially with higher drug concentration and lower pH.
The optimal environment for cell killing in this experiment was with 1.5 mM concentrationat pH of 6.5, with a modifying factor of 1.8.
COX-2 inhibitor induced cytotoxicity was also seen, though radiosensitization was not seen.
This demonstrates, in vivo, that COX inhibitors may be an effective radiosensitizer for cancer treatment. However, data showed pH and drug together, therefore, it is not known the relative effect of each.
A hypothesis was made that the increase efficacy at lower pH levels may be explained by increased uptake in an acidic environment.
Oncolink's ASTRO Coverage made possible by an unrestricted Educational Grant from Bristol-Myers Squibb Oncology and Pharmacia Oncology.
Serum Amino Acids Are Potential Biomarkers for Renal Cell Cancer
Sep 26, 2011 - The levels of certain serum amino acids are significantly different in patients with renal cell carcinoma and show potential as biomarkers with predictive value for tumor recurrence and overall survival, according to a study published in the October issue of The Journal of Urology.
Frequently Asked Questions
National Cancer Institute
I Wish You Knew
How cancer patients have changed my life
Blogs and Web Chats
OncoLink Blogs give our readers a chance to react to and comment on key cancer news topics and provides a forum for OncoLink Experts and readers to share opinions and learn from each other.
Frente a un nuevo diagnóstico de cáncer o de cambiar el curso de su tratamiento actual? Deje que nuestro personal de enfermería cáncer que ayudan a pasar!