MMS350: A Novel Bifunctional Sulfoxide With Radiation Protection and Mitigation Properties

Abstract

New small molecules for radiation protection and mitigation, applied in either radiation counterterrorism or clinical radiation therapy, must demonstrate safety and effectiveness in both animal models and in humans. MMS350 is a novel water soluble oxetane-substituted sulfoxide which has been developed as a more selective and more potent alternative to dimethyl sulfoxide (DMSO) which is a radioprotector in mice. We evaluated MMS350 as a radioprotector or mitigator. Irradiation survival curves were first performed on bone marrow stromal cells derived from C57BL/6NHsd mice. MMS350 was dissolved in tissue culture medium and administered at a final concentration of 100 μM one hour before irradiation or immediately after irradiation. Cells were irradiated to doses from 0 to 8 Gy , then plated in 4 well tissue culture plates, incubated at 37°C in a high humidity CO2 incubator for 7 days, stained with crystal violet, and colonies of greater than 50 cells counted. The data was analyzed using linear quadratic or single-hit, multiple-target models. To determine if MMS350 was a radiation mitigator in vivo, C57BL/6NTac mice were irradiated to the LD50/30 total body irradiation dose of 9.5 Gy and injected IP with 20 mg/kg of MMS350 dissolved in phosphate buffered saline (PBS) at either 4 or 24 hr after irradiation. MMS350 was protective when administered before irradiation, as shown by the increased shoulder on the survival curve with a ñ of 15.8 ± 2.9 compared to 5.8 ± 1.1 (p = 0.0039) for control irradiated cells. MMS350 was also mitigative when given after irradiation, as shown by the increase in the D0 to 2.4 ± 0.3 compared to 1.9 ± 0.1 (p = 0.0444) for the control irradiated cells. MMS350 was also an effective radiation protector and mitigator of human umbilical cord blood clonagenic multilineage progenitor cells in vitro. Results of in vivo survival curves demonstrated that mice injected with MMS350 at either 4 or 24 hr after irradiation had an increased survival compared to control irradiated mice (p = 0.0092 and 0.0097, respectively). Fifty percent of the control irradiated mice were dead at day 13 after irradiation while 50% of the MMS350 mice survived to day 40. These results demonstrate that MMS350 has a potential for both radiation protection and mitigation of normal tissues in humans.