1.Glufosfamide as a new oxazaphosphorine anticancer agent.
Mazur L1, Opydo-Chanek M, Stojak M. Anticancer Drugs. 2011 Jul;22(6):488-93. doi: 10.1097/CAD.0b013e328345e1e0.
Glufosfamide (β-D-glucose-isophosphoramide mustard, D-19575) belongs to the oxazaphosphorine class. Glufosfamide is a novel glucose conjugate of ifosfamide in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to the β-D-glucose molecule. Glufosfamide represents an attractive new agent for cancer therapy. Its mode of action on normal and pathological cells is still under experimental and clinical investigations. An assessment of the anticancer potential of glufosfamide is of key importance in therapy. The researchers reviewed the current knowledge available on glufosfamide tested in the preclinical studies/clinical trials, based on a collection of the original papers and conference abstracts published and relevant articles searched in the SCOPUS and MEDLINE database and websites.
2.In vitro cytotoxicity testing of new generation oxazaphosphorines against human histiocytic lymphoma cells.
Opydo-Chanek M1, Mazur L, Stojak M. Indian J Exp Biol. 2013 Aug;51(8):615-22.
Oxazaphosphorines belong to a group of alkylating agents. Mafosfamide cyclohexylamine salt (D-17272), 4-hydro-peroxy-cyclophosphamide (D-18864) and glufosfamide (D-19575, beta-D-glucose-isophosphoramide mustard) are new generation oxazaphosphorines. The objective of the present study was to compare the cytotoxic action of these oxazaphosphorine compounds against human histiocytic lymphoma U937 cells. The chemical structures of the oxazaphosphorines were responsible for the different responses of U937 cells. The cytotoxic effects of D-17272, D-18864, and D-19575 on U937 cells depended on the agent tested, its dose, and the time intervals after the oxazaphosphorine application. Among the oxazaphosphorine agents, D-18864 appeared to be the most cytotoxic, and D-19575 was characterized by the lowest cytotoxicity. The in vitro cytotoxic activities of the oxazaphosphorines were strongly associated with their cell death inducing potential.
3.Possible contribution of beta-glucosidase and caspases in the cytotoxicity of glufosfamide in colon cancer cells.
Arafa HM1. Eur J Pharmacol. 2009 Aug 15;616(1-3):58-63. doi: 10.1016/j.ejphar.2009.06.024. Epub 2009 Jun 21.
Glycoconjugates represent a recent trend in cancer chemotherapy that adopts the concept of selective prodrug/drug targeting of tumor cells by binding to specific transmembrane glucose transporters. Following preferential uptake of sugar conjugates into cancer cells, they are presumably subject to enzymatic cleavage by specific beta-glycosidases to liberate the free active cytotoxic aglycones that act selectively on cancer cells and spare other noncancerous ones. In this sense, the role of beta-glucosidase and caspases in the bioactivation and cytotoxicity of glufosfamide has been addressed in the current study. The cytotoxicity of glufosfamide has been investigated over 24-96 h in a panel of human colon cancer cells namely, Caco-2, HT29 and T84 using a tetrazole dye; 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT assay technique. Apoptosis was assessed by fluorometric assay of caspase-3 and caspase-9 activities. Enzymatic cleavage of glufosfamide was accomplished using a host of hydrolytic enzymes and cleavage kinetics was determined using HPLC.
4.In vitro effects of new generation oxazaphosphorines on human promyelocytic leukemia cells.
Mazur L1, Opydo-Chanek M, Stojak M, Niemeyer U. Folia Biol (Krakow). 2013;61(1-2):31-40.
Mafosfamide cyclohexylamine salt (D-17272), 4-hydro-peroxy-cyclophosphamide (D-18864) and glufosfamide (D-19575, beta-D-glucose-isophosphoramide mustard) are new generation oxazaphosphorine agents. The present investigation was undertaken to determine the activity of these three oxazaphosphorines in human promyelocytic leukemia HL-60 cells. The research was conducted using the spectrophotometric MTT assay and the electronic Beckman Coulter and microscopy methods. Functional and morphological changes were observed after exposure of HL-60 cells to the oxazaphosphorine agents. The various patterns of temporary alterations in cell viability, size and count, and also in the frequency of leukemic cells undergoing mitotic catastrophe, apoptosis and necrosis, were shown. Different leukemic cell responses to the action of the three oxazaphosphorines were evaluated. These are the first data comparing the in vitro activity of D-17272, D-18864 and D-19575 against human promyelocytic leukemia cells.