Disease relevance of NSC 353451

• In concentrations of 1 to 500 micrograms/ml, mitozolomide completely inhibited the colony-forming ability in soft agar of cell suspensions from sarcomas, melanomas, lung and colon cancers, and a mammary carcinoma [1].
• When tested against the TLX5 lymphoma in vitro the ID50 values for dimethylmitozolomide, methylmitozolomide, and mitozolomide were 14.6, 3.0, and 2.3 microM, respectively [2].
• The results indicate that clinical responses to mitozolomide may be anticipated in sarcoma, melanoma, small cell lung cancer, and possibly in colon cancer [1].
• We have therefore successfully conferred a protective advantage against mitozolomide toxicity to cells by rAAV-mediated hAT expression [3].
• Phase II evaluation of mitozolomide in ovarian cancer [4].

High impact information on NSC 353451

• The in vitro cytotoxicity, stability, and metabolism of the 8-(N,N-dimethylcarboxamide) and 8-(N-methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism [2].
• Cell survival analysis following exposure to the chloroethylating agent mitozolomide revealed that expression of hAT at levels two- to fourfold higher than background conferred significant resistance (p < 0.001) to the toxic effects of this drug [3].
• These clones were assayed for cell survival following exposure to mitozolomide [3].
• However, whilst hAT-mediated protection was ablated by 20 microM O6-beG, the hATPA/GA protein provided protection against mitozolomide under the same conditions [5].
• MGMT antisense oligonucleotide enhanced the sensitivity of cells to the tumor therapeutic drug mitozolomide, as measured by sister chromatid exchange formation [6].

Chemical compound and disease context of NSC 353451

• A colony-forming assay was used to demonstrate significant protection (P < 0.001) against mitozolomide or temozolomide toxicity in K562 clones expressing either hAT mutant, as determined from an in vitro assay of activity [7].

Biological context of NSC 353451

• The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described [8].
• Chinese hamster V79 lung fibroblasts are sensitive to the toxic effects of chloroethylating agents such as mitozolomide (Mz) and express very low levels (less than 2 fmol/mg) of the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase (ATase) [9].
• Only in one out of 16 primary cultures of human ovarian cancers was mitozolomide able to induce cell cycle perturbation, suggesting that ovarian carcinoma cells may not be sensitive to this drug [10].
• Two cell lines were chosen to study macromolecular alkylation, GM892A and Raji, the latter being 10-20-fold less sensitive to mitozolomide and CCRG 81045 than the former, but only one-and-a-half-fold less sensitive to CCRG 82019 [11].
• Thus DNA interstrand crosslinking produced by mitozolomide and MCTIC appears to correlate with the Mer phenotype [12].

Anatomical context of NSC 353451

• In the testis cell lines ATase activity (molecules/cell) was related to IC50s for mitozolomide (R = 0.97) but not MNU (R = 0.78) [13].
• In addition mitozolomide and MCTIC induced DNA interstrand crosslinks in the BE but not the HT-29 cell line [12].
• In conjunction with autologous bone marrow rescue, high-dose mitozolomide was given i.v. to 16 patients with refractory malignancies at doses ranging from 100 to 400 mg/m2 over 1 h [14].
• Furthermore, as a result of transgene expression, the number of micronucleated polychromatic erythrocytes induced by mitozolomide was significantly reduced (P < .05) by 40% relative to mock-transduced controls, indicating the potential of this approach to reduce the frequency of mutation associated with chemotherapy exposure [15].

Associations of NSC 353451 with other chemical compounds

• PURPOSE: To investigate the effect of temozolomide, a 3-methyl derivative of mitozolomide in combination with X-rays in human glioma-derived cell lines [16].
• Flow cytometry showed an interesting difference: at the high concentration mitozolomide induced an accumulation of cells in S middle and S late-G2-M phase of the cell cycle whereas BCNU caused only a block in S late-G2-M [10].
• Pretreatment of HT-29 cells (Mer+) with the DNA methylating agent MNNG allows mitozolomide or MCTIC to produce DNA interstrand crosslinks [12].
• Acute administration of TNF produced hypoglycaemia that was more severe than observed with either mitozolomide or in pair-fed controls, a reduction in the circulatory level of free fatty acids (FFA) and an increase in plasma triglycerides, while mitozolomide and pair-feeding had no effect on the level of blood glucose or plasma triglycerides [17].
• The results suggest that, unlike temozolomide, mitozolomide, and BCNU, the cytotoxicity of the tetrazepinones does not correlate with the alkylation of the O6 position of guanine and that the mechanism of MGMT inactivation by tetrazepinones may differ from that of hitherto known inhibitors [18].

Gene context of NSC 353451

• A comparison has been made of the weight loss produced by tumour necrosis factor (TNF) (cachectin) with that produced by a restricted food and water intake (pair-fed controls), and by mitozolomide, a drug which in toxic doses induces weight loss with a similar decrease in nutrient and water intake [17].
• Similarly, mitozolomide (25-100 microM) induced a stronger S-phase arrest in the SF-126 cells than in the SF-188 cells [18].
• The in vivo antitumor activity of etoposide and mitozolomide was assessed in nude mice bearing a xenograft (CC3) of human gestational choriocarcinoma [19].
• Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA [20].
• Inhibition of EMT6 mouse mammary-tumour esterases was seen for mitozolomide and temozolomide, and activity against purified porcine carboxylesterase was demonstrated [21].

Analytical, diagnostic and therapeutic context of NSC 353451

• The chemosensitivity of human tumor xenografts to mitozolomide, 8-carbamoyl-3-(2-chloroethyl)imidazo[5-1-d]-1,2,3,5-tetrazin-4(3H) -one, was studied in 3 different assay systems [1].
• When a panel of tumors of the different histological types was tested for its sensitivity to mitozolomide in vitro, in the 6-day subrenal capsule assay in conventional mice, and, in some cases, as s.c. growing tumors in nude mice, good agreement between the different assay systems was seen [1].
• Twenty-two patients with advanced colorectal cancer (CRC) (12 without prior chemotherapy) and fourteen with pretreated breast cancer (BC) were given mitozolomide (MTZ), IV infusion, every six weeks [22].
• The cytotoxic drug mitozolomide has been found to cause unpredictably severe thrombocytopenia during phase I and II clinical trials [23].
• Antitumour imidazotetrazines. VII. Quantitative analysis of mitozolomide in biological fluids by high-performance liquid chromatography [24].

References