COX Inhibitors Markedly enhance Tumor Radiosensitization of Cultured Human Cancer Cells under Acidic Microenvironment

Ryan Smith, MD
University of Pennsylvania Cancer Center
Last Modified: November 6, 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.

Materials and 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.

Clinical/Scientific Implications
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.

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