WR-151327 increases resistance to Klebsiella pneumoniae infection in mixed-field- and gamma-photon-irradiated mice

Purpose : To determine the efficacy of WR-151327 (WR) [S3-(3-methylaminopropylamino) propylphosphorothioic acid; (CH 3 -HN-(CH 2) 3 -NH-(CH 2) 3 -S-PO 3 H 2) ] in increasing resistance to bacterial infection after a sublethal dose of gamma-photons or mixed-field neutrons plus gamma-photons. Materials and methods : B6D2F1/J female mice received 200mg/kg WR i.p. or saline vehicle 20-30min before or after sham (0Gy) or 7.0Gy 60 Co gamma-photon irradiation. WR or saline vehicle was given only before 3.5Gy TRIGA-reactor-produced mixed-field [n/(n+gamma)=0.67] irradiation. Four days after drug treatment or drug treatment and irradiation, graded doses of Klebsiella pneumoniae were injected s.c. into mice, and 30-day survival was recorded. To assess haemopoietic changes other unirradiated and irradiated mice not injected with bacteria were given WR or saline. Peripheral blood (PB) and femoral bone marrow (BM) cells were measured 1, 3 or 4, 7, 10 and 14 or 15 days later. Results : WR pretreatment increased resistance to infection in irradiated but not in unirradiated mice. Bacterial CFU-LD 50/30 values for 0Gy saline-treated mice were 1.20 X 10 6 ; for 0Gy WR-treated mice 1.16 X 10 6 ; for gamma-photon-irradiated saline-treated mice 3.02 X 10 1 ; for gamma-photon-irradiated WR-treated mice 1.24 X10 4 ; for mixed-field-irradiated saline-treated mice 1.94 X10 2 ; and for mixed-field-irradiated WR-treated mice 6.13 X10 3. WR-induced resistance to infection paralleled increased numbers of PB white cells, neutrophils, platelets, femoral BM cells and granulocyte macrophage colony-forming cells (GM-CFC) in irradiated mice not given bacteria. Conclusions : These studies quantify the resistance to bacterial infection in mice treated with WR before sublethal irradiation. The findings suggest that WR treatment increases resistance to infection in immunocompromised hosts.