Background
Altretamine is an antineoplastic agent with antiproliferative activity.1 It induces cytotoxicity in an ovarian cancer cell line when used at a concentration of 10 μg/ml, with radiolabeled thymidine uptake equal to 102 and 75% of controls after 48 and 120 hours, respectively.2 Altretamine (100 μg/ml) reduces colony survival in A204 human rhabdomyosarcoma cells in an NADP-dependent manner in the presence of an S-9 hepatic activating mixture.3 In vivo, altretamine (150 mg/kg) reduces tumor growth in a mouse model of M5076 murine reticulum cell sarcoma.1 Altretamine (0.5 mM) inhibits glutathione peroxidase 4 (GPX4) and induces accumulation of lipid-reactive oxygen species (ROS) in U-2932 cells without depleting glutathione (GSH) levels, suggesting it is a class II ferroptosis-inducing compound (FIN).4 It also acts as a chemosterilant in houseflies, preventing hatching and pupation in male and female houseflies when used at a concentration of 0.05%.5 Formulations of altretamine have been used in the treatment of various cancers.
1.Langdon, S.P., Simmonds, R.J., and Stevens, M.F.G.Triazines and related products. Part 26. Synthesis and chemistry of bicyclic analogues of the antitumour drug 2,4,6-tris(dimethylamino)-1,3,5-triazine (hexamethylmelamine)J. Chem. Soc. Perkin 1993-998(1984)
2.D'Incalci, M., Erba, E., Balconi, G., et al.Time dependence of the in vitro cytotoxicity of hexamethylmelamine and its metabolitesBr. J. Cancer41(4)630-635(1980)
3.Miller, K.J., McGovern, R.M., and Ames, M.M.Effect of a hepatic activation system on the antiproliferative activity of hexamethylmelamine against human tumor cell linesCancer Chemother. Pharmacol.15(1)49-53(1985)
4.Woo, J.H., Shimoni, Y., Yang, W.S., et al.Elucidating compound mechanism of action by network perturbation analysisCell162(2)441-451(2015)
5.LaBrecque, G.C., Fye, R.L., DeMilo, A.B., et al.Substituted melamines as chemosterilants of house fliesJ. Econ. Entomol.61(6)1621-1632(1968)
Protocol
Animal experiment: | Mice[1]Balb/c nu/nu 4 week old female mice weighing 18-22 g, receive s.c. injections of 8-10 million MV522 cells. Altretamine is administered i.p. three times a week for 3 weeks, starting on day 10 after tumor implantation. Tumor size is measured in two perpendicular diameters and tumor weight (TW) estimated according to the formula: w = [(width)2 × length/2]. Altretamine is prepared as stock solutions of 1-10 mg/mL in 40% DMSO/normal saline and diluted with 10% DMSO/normal saline as required[1]. |
参考文献: [1]. Kelner MJ, et al. Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model. Cancer Chemother Pharmacol. 2008 Dec;63(1):19-26. |
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