| Candidate ID: | R0309 |
| Source ID: | DB00853 |
| Source Type: | approved; investigational |
| Compound Type: |
small molecule
|
| Compound Name: |
Temozolomide
|
| Synonyms: |
3-methyl-4-oxo-3,4-dihydroimidazo(5,1-d)(1,2,3,5)tetrazine-8-carboxamide; 3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide; 3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-as-tetrazine-8-carboxamide; 8-carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one; Methazolastone; Temozolomide
|
| Molecular Formula: |
C6H6N6O2
|
| SMILES: |
CN1N=NC2=C(N=CN2C1=O)C(N)=O
|
| Structure: |
|
| DrugBank Description: |
Refractory anaplastic astrocytoma (WHO grade III) and Glioblastoma multiforme (WHO grade IV) are primary malignant brain tumours with poor prognosis and limited treatment options. Despite considerable genetic heterogeneity, these tumours often have impaired DNA repair systems, rendering them initially sensitive to alkylating agents, although they invariably develop resistance to these agents over time. Temozolomide is an imidazotetrazine prodrug that is stable at acidic pH but undergoes spontaneous nonenzymatic hydrolysis at neutral or slightly basic pH; these properties allow for both oral and intravenous administration. Following initial hydrolysis, further reactions liberate a highly reactive methyl diazonium cation capable of methylating various residues on adenosine and guanine bases leading to DNA lesions and eventual apoptosis. Temozomolide as an adjunct to radiotherapy followed by maintenance dosing remains the standard of care for both Glioblastoma and refractory anaplastic astrocytoma.
Temozolomide was granted FDA approval on August 11, 1999, as an oral capsule and subsequently on February 27, 2009, as an intravenous injection. It is currently marketed under the trademark TEMODAR® by Merck.
|
| CAS Number: |
85622-93-1
|
| Molecular Weight: |
194.1508
|
| DrugBank Indication: |
Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.
|
| DrugBank Pharmacology: |
Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH _in vivo_ to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10<sup>9</sup>/L and a platelet count of ≥100 x 10<sup>9</sup>/L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively.
|
| DrugBank MoA: |
Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue.
The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure.
More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T<sub>reg</sub> cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future.
|
| Targets: |
DNA cross-linking/alkylation
|
| Inclusion Criteria: |
Therapeutic strategy associated
|
