Clostridium perfringens enterotoxin as a novel-targeted therapeutic for brain metastasis.

Abstract

Brain metastasis is the most commonly occurring intracranial tumor whose incidence seems to be increasing. With standard therapy, the average survival time of patients is approximately 8 months, and treatment often leads to neurologic dysfunction in long-term survivors, emphasizing the need for novel therapeutics. Clostridium perfringens enterotoxin (CPE) has recently been shown to rapidly and specifically destroy cancer cells expressing CPE receptors claudin-3 and claudin-4. Unfortunately, the utility of CPE is precluded by systemic toxicity because its receptors are expressed in numerous organs. Here, we provide the first preclinical evidence that CPE may be uniquely suited to the local treatment of brain metastasis. By immunohistochemical analysis, claudin-3 and claudin-4 were expressed frequently in metastases from breast (15 of 18), lung (15 of 20), and colon (12 of 14) carcinoma, and infrequently in metastases from renal cell carcinoma (2 of 16) and melanoma (2 of 16). In contrast, expression of claudin-3 and claudin-4 was absent in adjacent normal brain tissue. Further examination of the central nervous system (CNS) revealed low or undetectable levels of claudin-3 and claudin-4 in all regions tested by Western and immunohistochemical analysis. Treatment of breast cancer cell lines (MCF-7, MDA-MB-468, NT2.5-luc) and normal human astrocytes with CPE in vitro resulted in rapid and dose-dependent cytolysis exclusively in breast cancer cells, correlating with claudin-3 and claudin-4 expression. Moreover, intracranial CPE treatment significantly inhibited tumor growth and increased survival in two murine models of breast cancer brain metastasis, without any apparent local or systemic toxicity. These data suggest that CPE therapy may have efficacy against a wide variety of brain metastases without CNS toxicity.

• Authors: Scott L Kominsky, Betty Tyler, Jeffrey Sosnowski, Kelly Brady, Michele Doucet, Delissa Nell, James G Smedley 3rd, Bruce McClane, Henry Brem, Saraswati Sukumar
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 17 Pg. 7977-82 (Sep 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17804705 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CLDN3 protein, human
• CLDN4 protein, human
• Claudin-3
• Claudin-4
• Cldn3 protein, mouse
• Cldn4 protein, mouse
• Enterotoxins
• Membrane Proteins
• enterotoxin, Clostridium

Topics

• Animals
• Apoptosis (drug effects)
• Astrocytes (metabolism)
• Brain Neoplasms (drug therapy, secondary)
• Breast Neoplasms (drug therapy, mortality, pathology)
• Carcinoma (drug therapy, mortality, pathology)
• Claudin-3
• Claudin-4
• Drug Evaluation, Preclinical
• Enterotoxins (therapeutic use)
• Female
• Humans
• Membrane Proteins (metabolism)
• Mice
• Mice, Nude
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays