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Review
. 2018 Jun 15:9:318.
doi: 10.3389/fendo.2018.00318. eCollection 2018.

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions

Luis V Syro  1 , Fabio Rotondo  2 , Mauricio Camargo  3 , Leon D Ortiz  4 , Carlos A Serna  5 , Kalman Kovacs  2
Affiliations
Review

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions

Luis V Syro et al. Front Endocrinol (Lausanne). .

Abstract

Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.

Keywords: DNA repair; O(6)-Methylguanine-DNA Methyltransferase; alkylating agents; chemotherapy; neoplasms; neuroendocrine tumors; pituitary; temozolomide.

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Figures

Figure 1
Figure 1
(A) Sites of alkylation on the various bases in the DNA. Temozolomide produces alkylation on position N7 and O6 in guanine and N3 in adenine (blue arrows). Other alkylating agents act on different sites of alkylation (small gray arrows). (B) Chemical stability, mutagenesis, cytotoxicity, and repair mechanisms in different sites of alkylation. Based on Ref. (8, 9, 16, 19). Abbreviations: BER, base excision repair; DR, direct repair; MMR, mismatch repair; NER, nucleotide excision repair; DNA, deoxyribonucleic acid.
Figure 2
Figure 2
Schematic of mode of action of temozolomide (TMZ). The activation of TMZ in physiologic pH levels within the blood stream into its reactive state that is responsible for methylating DNA. Based on Ref. (8, 19, 23). Abbreviations: MTIC, 5-(3-monomethyl-1-triazeno) imidazole-4-carboxamide; AIC, 5-aminoimidazole-4-carboxamide; MGMT, O6-methylguanine-DNA methyltransferase.
Figure 3
Figure 3
TMZ action and DNA repair mechanisms involved in the prevention and correction of alkylation-induced DNA damage. Based on Ref. (19, 42, 47, 48). Abbreviations: BER, base excision repair; DR, direct repair; MMR, mismatch repair; NER, nucleotide excision repair; MPG, DNA methylpurine-N-glycosylase; MGMT, O6-methylguanine-DNA methyltransferase; TMZ, temozolomide; SSB, single-strand breaks; DSB, double-strand breaks; DNA, deoxyribonucleic acid.
Figure 4
Figure 4
Temozolomide-treated patients. Demographics, clinical presentation, previous surgeries, and radiotherapy comparing aggressive pituitary adenomas and pituitary carcinomas. Data from Ref. (77).
Figure 5
Figure 5
Pathological subtype of tumors, proliferative markers, and O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in aggressive pituitary adenomas and pituitary carcinomas treated with temozolomide. Data from Ref. (77).
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