Temozolomide (brand names Temodar and Temodal and Temcad) is an oral alkylating agent used for the treatment of Grade IV astrocytoma an aggressive brain tumor, also known as glioblastoma multiforme as well as for treating melanoma, a form of skin cancer. Temozolomide is also indicated for relapsed Grade III anaplastic astrocytoma and not indicated for, but as of 2011 used to treat oligodendroglioma brain tumors in some countries, replacing the older (and less well tolerated) PCV (Procarbazine-Lomustine-Vincristine) regimen.
The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham, Temozolomide is a prodrug and an imidazotetrazine derivative of the alkylating agent dacarbazine. It has been available in the US since August 1999, and in other countries since the early 2000s.
The therapeutic benefit of temozolomide depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. This methylation damages the DNA and triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage, and therefore diminish the therapeutic efficacy of temozolomide, by expressing a protein O6-alkylguanine DNA alkyltransferase (AGT) encoded in humans by the O-6-methylguanine-DNA methyltransferase (MGMT) gene. In some tumors, epigenetic silencing of the MGMT gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by temozolomide. Conversely, the presence of AGT protein in brain tumors predicts poor response to temozolomide and these patients receive little benefit from chemotherapy with temozolomide.
The most common non-hematological adverse effects associated with temozolomide - nausea and vomiting - are either self-limiting or readily controlled with standard antiemetic therapy. These effects are usually mild to moderate (grade 1 to 2). The incidence of severe nausea and vomiting is around 4% each. Patients who have pre-existing or a history of severe vomiting may require antiemetic therapy before initiating temozolomide treatment. Temozolomide should be administered in the fasting state, at least one hour before a meal. (Capsules must not be opened or chewed, but swallowed whole with a glass of water.) Antiemetic therapy may be administered prior to, or following, administration of temozolomide. Temozolomide is contraindicated in patients with hypersensitivity to its components or to dacarbazine. The use of temozolomide is not recommended in patients with severe myelosuppression.
Temozolomide is genotoxic, teratogenic and fetotoxic and should not be used during pregnancy. Lactating women should discontinue nursing while receiving the drug because of the risk of secretion into breast milk. One study indicated that women that have taken temozolomide without concomitant fertility preservation measures achieve pregnancy to a lesser rate later in life, but the study was too small to show statistical significance in the hypothesis that temozolomide would confer a risk of female infertility. In male patients, temozolomide can have genotoxic effects. Men are advised not to father a child during or up to six months after treatment and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to temozolomide therapy.
Very rarely Temozolomide can cause acute respiratory failure.