Polyamine transport as a target for treatment of Pneumocystis pneumonia.
Liao CP, Phanstiel O, Lasbury ME, Zhang C, Shao S, Durant PJ, Cheng BH, Lee CH.
Polyamine levels are greatly increased in alveolar macrophages (AMs) during Pneumocystis pneumonia (PCP), leading to increased production of H(2)O(2), which causes AMs to undergo apoptosis. One of the mechanisms by which polyamine levels in AMs are elevated is enhanced uptake of exogenous polyamines. In this study, the possibility of targeting polyamine uptake as a treatment for PCP was examined. Four anthracene- and one benzene-polyamine conjugates that are potential polyamine transport inhibitors, including N1-anthracen-9-ylmethyl-butane-1,4-diamine; N-(4-aminobutyl)-N-anthracen-9-ylmethylbutane-1,4-diamine; N-[4-(4-aminobutylamino)butyl]-N-anthracen-9-ylmethylbutane-1,4-diamine; N-(4-amino-butyl)-N'-(10-[[4-(4-amino-butylamino)butylamino]-methyl]anthracen-9-ylmethyl)butane-1,4-diamine (44-Ant-44); and benzene-polyamine conjugate N-(4-amino-butyl)-N'-(4-[[4-(4-amino-butylamino)butylamino]-methyl]benzyl)butane-1,4-diamine (44-Bn-44), were tested. Compounds 44-Ant-44 and 44-Bn-44 were found to have a very low toxicity to AMs in vitro and were evaluated for their therapeutic effect on PCP in vivo. Sprague-Dawley rats infected with P. carinii for 28 days were intranasally instilled with 50 microl of a 1 mM solution of 44-Bn-44 or 44-Ant-44 every 2 days. Twenty-one days after initiation of the treatment, three to five rats from each group were sacrificed and examined for lung pathology, organism burden, and apoptosis of AMs. Both 44-Bn-44 and 44-Ant-44 reduced organism burdens; however, only 44-Ant-44 decreased the severity of the infection with reduced lung inflammation, increased clearance of exudates, increased air space, and decreased apoptosis of AMs. 44-Ant-44 also significantly prolonged the survival of treated animals. These results suggest that polyamine uptake is a potential target for treatment of PCP.