Temozolomide is a DNA alkylating agent interfering with DNA replication.

The cytotoxic/mutagenic effects of temozolomide are based on the presence of DNA O(6)-methylguanine adducts that generate base/base mismatches with cytosine and with thymine. These adducts lead to cell death, or if the cell survives, provoke somatic point mutations represented by C:G-->T:A transition in DNA helix [1]. The IC50 values for Temozolomide (TMZ) in different cell lines were ranging from 14.1 to 234.6 μM: cell lines with low IC50 values (< 50 μM), which included A172 (14.1 μM) and LN229 cells (14.5 μM), and those with high IC50 values (> 100 μM), which included SF268 (147.2 μM) and SK-N-SH cells (234.6 μM) [2]. TMZ sensitivity of both chemo-sensitive and resistant cells was enhanced significantly under hyperoxia. At the cell line-specific optimum oxygen concentration (D54-R, 80 %; U87-R, 40 %), resistant cells had the same response to TMZ as the parent chemosensitive cells under normoxia via the caspase-dependent pathway [3].

No drug-related death occurred in mice treated with TZM (100 or 200 mg/kg) or with NU1025 ± TZM and that the maximal weight loss was 12%. Intracranial injection of NU1025, immediately before the administration of 100 or 200 mg/kg TZM, significantly increased lifespans with respect to controls or to groups treated with TZM only [4]. Co-administration of AG-014699 with temozolomide resulted in complete tumour regressions in all mice, of which three out of five were sustained throughout the experiment. The MMR-defective D283Med xenografts grew very rapidly (median time to RTV4=7 days) and showed very little response to temozolomide alone (TGD of only 2 days) with no regressions observed in any mice [5].

Cell lines exposed to TMZ (with or without 5-Aza or O6-BG pre-treatment) were grown in 24-well plates under standard culture conditions for 6 days. Cytotoxicity was determined using the sulphorhodamine-B (SRB) method. Briefly, the cells were fixed with 10% trichloroacetic acid for 20 min at 4°C then washed three times with water. After 24 hours, cells were stained for 30 min at room temperature with 0.4% SRB dissolved in 1% acetic acid and then washed three times with 1% acetic acid. The plates were air-dried and the dye solubilized with 300 ml/well of 10 mM Tris base (pH 10.5) for 10 min on a shaker. The optical density of each well was measured spectrophotometrically using a Titertek multiscan colorimeter at 492 nm [2].

TZM was dissolved in dimethyl-sulfoxide (40 mg/mL), diluted in saline (5 mg/mL), and administered intraperitoneally on day 2 after tumor injection at 100 mg/kg or 200 mg/kg, doses commonly used for in vivo preclinical studies.15-17 Because cytotoxicity induced by TZM and PARP inhibitors can be improved by fractionated modality of treatment,9 in selected groups a total dose of 200 mg/kg TZM was divided in 2 doses of 100 mg/kg given on days 2 and 3. NU1025 was dissolved in polyethylene glycol-400 (40% in saline) and was injected intracranially at the maximal deliverable dose (1 mg/mouse, 0.03 mL) or, in selected groups, intraperitoneally (0.3 mL) on day 2 after tumor challenge, 1 hour before TZM administration. Control mice were injected with drug vehicles [4].

85622-93-1

C6H6N6O2

194.154

替莫唑胺;TZM;TMZ;CCRG 81045;NSC 362856;Temozolomide

[1]Tentori L, et al. Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site. Blood. 2002 Mar 15;99(6):2241-4. [2]Marchesi F, et al. Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol Res. 2007 Oct;56(4):275-87. [3]Perazzoli G, et al. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression. PLoS One. 2015 Oct 8;10(10):e0140131. [4]Zhang B, Xu C, Liu J, et al. Nidogen-1 expression is associated with overall survival and temozolomide sensitivity in low-grade glioma patients[J]. Aging (Albany NY). 2021, 13(6): 9085. [5]Herbener V J, Burster T, Goreth A, et al. Considering the Experimental use of Temozolomide in Glioblastoma Research[J]. Biomedicines. 2020, 8(6): 151. [6]Daniel RA, et al. Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly(ADP-ribose) polymerase inhibitor AG-014699. [7]Sun S, et al. Hyperoxia resensitizes chemoresistant human glioblastoma cells to temozolomide. J Neurooncol. 2012 Sep;109(3):467-75.

[1]Li F, Chen S, Yu J, et al. Interplay of m6A and histone modifications contributes to temozolomide resistance in glioblastoma. Clinical and Translational Medicine. 2021, 11(9): e553 [2]Zhang B, Xu C, Liu J, et al. Nidogen-1 expression is associated with overall survival and temozolomide sensitivity in low-grade glioma patients. Aging (Albany NY). 2021 Mar 18;13(6):9085-9107. doi: 10.18632/aging.202789. Epub 2021 Mar 18. [3]Wang Y, Wang X, Wang X, et al. Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide. Journal of Cellular and Molecular Medicine. 2021 [4]Herbener V J, Burster T, Goreth A, et al. Considering the Experimental use of Temozolomide in Glioblastoma Research. Biomedicines. 2020, 8(6): 151 [5]Li J, Sun Y, Sun X, et al. AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide. Scientific reports. 2021, 11(1): 1-12. [6]Jiao W, Zhu S, Shao J, et al. ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair. BioMed Research International. 2022

DMSO:9.7 mg/mL (50 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years