Dose Effect of Rhenium (I)-diselenoether as Anticancer Drug in Resistant Breast Tumor-bearing Mice After Repeated Administrations

Abstract

Abstract. Rhenium (I)-diselenoether has shown promising antiproliferative efficacy in both in vitro and in vivo models. However, the maximal tolerated dose and dose-effect relationships have not been fully addressed for this compound. Here, we evaluated the tolerance and efficacy of three dose-levels (namely 10, 40 and 100 mg/kg) intraperitoneally administered daily over 28 days in mice bearing the resistant MDA-MB231 breast cancer cell line.The upper dose was found to be toxic and was reduced to 60 mg/kg. The 10 mg/kg dose well tolerated, whereas 40 mg/kg was associated with 10% mortality (LD 10 ). Both 10 and 40 mg/kg dosing achieved a significantly similar regression of tumor growth compared with untreated animals. This study suggests that 10 mg/kg daily is the recommended dose for rhenium (I) diselenoether.Rhenium(I)-diselenoether has been proposed as an anticancer agent (1-6). This compound features a central atom of rhenium bound to 3,7-diselenanonanedioic acid ligand in which the two selenium atoms secure a tight complexation of the Re, while the carboxylic group, as sodium salt, allows water solubility. This amphiphilic complex is a hydrophilic drug, soluble in water, easy to administer and lipophilic with a good distribution in tissues after oral administration (2).Re is a heavy transition metal (atomic number 75, atomic mass 186.21 g/mol), with the widest range of oxidation states of any element (−3, −1, +1, +2, +3, +4, +5, +6 +7), providing it with unique properties. It was demonstrated with Re-diselenoether drug that Re formed DNA adducts with one or two guanine bases (3), like cisplatin, but with an octahedral configuration and not a square-planar one. The uptake of Re in the nucleus of malignant cells has also been demonstrated after exposure to Re-diselenoether complex (2). Other Re-based drugs have also shown a high activity against a variety of tumor cell lines, with a good selectivity for cancer cells (7,8). One common mechanism of action could be related to the binding of Re with guanine and adenine bases of DNA (9-12). In contrast with cisplatin, the binding with the DNA bases is reversible (13). Re also binds with proteins (14,15). However, other properties of Re compounds have been identified, like the inhibition of some cysteine proteases (16). We hypothesize that the Re atom could be used either for oxidation or reduction of cell components due to its great number of oxidation states. Re cluster compounds were screened for their biological activities as antioxidants (17) and proposed to protect erythrocytes from hemolytic anemia (18). These Re compounds affected the peroxidation level, the activity of superoxide dismutase, the antioxidant factor and the index of resistance of erythrocytes to hemolysis as a function of the concentration range in the pre-incubation medium of erythrocytes (19,20 (22) and with dichlorotetra-μ-isobutyratodirhenium (III) complex (23) and the cluster Re compound with gamma-aminobutyric acid ligand (24). This synergism was however not observed with the Re (I)-di...

Negative Impact of Total Body Irradiation on the Antitumor Activity of Rhenium-(I)-diselenoether

“…The results of this study are unexpected as they did not confirm the antitumor activity of the Re-diselenoether compound reported in two previous studies (5,6), with the same experimental model of MDA-MB231-transplanted tumors in nude mice treated with the same dose of 10 mg/kg/d of Re-diselenoether. Differences in the experimental conditions may partly explain the difference of results between three experiments.…”

“…In the first published study, the Rediselenoether complex induced remarkable activity with a nearly complete regression of the tumors at the site of the primary tumor and a statistically significantly decrease in the number of pulmonary metastases (5). In the second study (6), there was a significant antitumor activity of the Rediselenoether complex, but not a complete regression of the tumors at the dose of 10 mg/kg/day. However, in these two experiments, the Re-diselenoether complex was active as an anticancer agent at a non-toxic daily dose of 10 mg/kg/d for 4 weeks.…”

“…The plasma Se level is reduced in patients with cancer (6). Radiotherapy induces a much greater decrease of plasma Se level in patients with cancer.…”

“…Se nanoparticles have been shown to be able to potentiate radiotherapy, and again at doses increasing the production of ROS in the cancer cells (21). Cancer cells already have a pro-oxidant status compared with normal cells and it is by further increasing the production of ROS that chemotherapeutic agents usually kill them (6). In our study, the Re-diselenoether compound may have induced an antioxidant status, not only in healthy cells, thereby protecting them, but also in cancer cells.…”

“…The anticancer activity of Re-diselenother has been demonstrated in experimental models of resistant triplenegative breast tumors (MDA-MB231), in malignant cells in culture, as well as after oral (5) or intraperitoneal administration (6) to tumor-bearing mice, at a daily dose of 10 mg/kg/day for 4 weeks, which was safe for the animals. The Re-diseleno ether compound we used, constituted an original chemical combination, and we aimed to complete the investigation of its biological role in an experimental model of cancer.…”