Temozolomide is an oral chemotherapeutic drug primarily used in the treatment of astrocytomas, oligodendrogliomas and glioblastomas, often in conjunction with radiotherapy (Stupp protocol).
On this page:
Mechanism of action
Temozolomide is an alkylating agent. It adds a methyl group to the purine bases of DNA (particularly O6-guanine). If unrepaired by MGMT (a DNA repair enzyme), this methylation results in a mismatched pairing of guanine with thymine rather than cytosine during DNA replication. This, in turn, results in subsequent faulty mismatch repair attempts, leading to DNA double-strand breakages that arrest mitosis and eventually lead to cell death 1-6.
Resistance to temozolomide
Tumors abundant in MGMT are resistant to the effects of temozolomide, whereas those with methylated MGMT (which reduces enzyme activity) respond more favourably 1. These, however, are also more likely to demonstrate pseudoprogression.
Similarly, tumor cells with deficient mismatch repair will not develop the lethal double-strand breakages and thus, such a deficiency also confers resistance to temozolomide but can introduce temozolomide-induced hypermutation 1.
Temozolomide-induced hypermutation
When IDH-mutant tumors (particularly low-grade astrocytomas and oligodendrogliomas) treated with temozolomide recur, a subgroup does so with very numerous genome-wide mutations. This is referred to as temozolomide-induced hypermutation and confers poor prognosis. This occurs more commonly in tumors with mismatch repair deficiency 1. The recurrence is more likely to have transformed to a higher grade and disseminated more widely throughout the brain with non-contiguous regions of recurrence 4.
Unable to process the form. Check for errors and try again.