Temozolomide是可透过血脑屏障的口服活性的 DNA 烷基化剂。它也是促自噬和促凋亡剂，具有抗肿瘤和抗血管生成作用。

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

NSC 362856;TMZ;替莫唑胺;CCRG 81045;TZM

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