The role of temozolomide in the treatment of aggressive pituitary tumors.

Abstract

Pituitary tumors are amongst the most common intracranial neoplasms and are generally benign. However, some pituitary tumors exhibit clinically aggressive behavior that is characterized by tumor recurrence and continued progression despite repeated treatments with conventional surgical, radiation and medical therapies. More recently, temozolomide, a second generation oral alkylating agent, has shown therapeutic promise for aggressive pituitary adenomas and carcinomas with favorable clinical and radiographic responses. Temozolomide causes DNA damage by methylation of the O(6) position of guanine, which results in potent cytotoxic DNA adducts and consequently, tumor cell apoptosis. The degree of MGMT expression appears to be inversely related to therapeutic responsiveness to temozolomide with a significant number of temozolomide-sensitive pituitary tumors exhibiting low MGMT expression. The presence of high MGMT expression appears to mitigate the effectiveness of temozolomide and this has been used as a marker in several studies to predict the efficacy of temozolomide. Recent evidence also suggests that mutations in mismatch repair proteins such as MSH6 could render pituitary tumors resistant to temozolomide. In this article, the authors review the development of temozolomide, its biochemistry and interaction with O(6)-methylguanine-DNA methyltransferase (MGMT), its role in adjuvant treatment of aggressive pituitary neoplasms, and future works that could influence the efficacy of temozolomide therapy.

• Authors: James K Liu, Jimmy Patel, Jean Anderson Eloy
• Journal: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia (J Clin Neurosci) Vol. 22 Issue 6 Pg. 923-9 (Jun 2015) ISSN: 1532-2653 [Electronic] Scotland
• PMID: 25772801 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Alkylating
• Tumor Suppressor Proteins
• Dacarbazine
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes
• Temozolomide

Topics

• Adenoma (drug therapy, genetics, metabolism)
• Animals
• Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
• Apoptosis (drug effects, genetics)
• DNA Damage (drug effects, physiology)
• DNA Modification Methylases (antagonists & inhibitors, biosynthesis)
• DNA Repair Enzymes (antagonists & inhibitors, biosynthesis)
• Dacarbazine (analogs & derivatives, pharmacology, therapeutic use)
• Disease Progression
• Humans
• Mutation (genetics)
• Neoplasm Recurrence, Local (drug therapy, genetics, metabolism)
• Pituitary Neoplasms (drug therapy, genetics, metabolism)
• Temozolomide
• Tumor Suppressor Proteins (antagonists & inhibitors, biosynthesis)