Morales Pablo R, Dillehay Dirck L, Moody Steven J, Pallas David C, Pruett Sarah, Allgood Jeremy C, Symolon Holly, Merrill Alfred H
Division of Animal Resources, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Drug Chem Toxicol. 2007;30(3):197-216. doi: 10.1080/01480540701375018.
Safingol [(2S,3S)-2-amino-1,3-octadecanediol] is an unnatural l-threo-stereoisomer of sphinganine that is cytotoxic for cancer cells in culture and is being tested in phase 1 human clinical trials. To determine if safingol can be absorbed orally and if it affects prostate cancer in a mouse strain used in prostate cancer studies, safingol was fed to TRAMP (transgenic adenocarcinoma of mouse prostate) mice for 2 weeks at 0.0125% to 0.1% w/w of the diet. Analysis of safingol and safingol metabolites in blood and tissues by liquid chromatography electrospray ionization tandem mass spectrometry revealed uptake in tissue and extensive conversion of safingol to N-acyl species (comparable to natural "ceramides") and mono-, di-, and tri-N-methyl metabolites that have not been observed previously. Safingol caused significant hepatotoxicity at all dosages, as reflected in elevated liver alanine aminotransferase, and at the highest dose (0.1 %) caused changes in liver histology (appearance of autophagosomal vacuoles) and renal toxicity (based on elevation of blood urea nitrogen) and decreases in packed blood cell volume and body weight. Safingol did not inhibit the prostate pre-neoplastic lesion (prostate intraepithelial neoplasia) in TRAMP mice; however, additional studies at lower dosages for longer time were not pursued due to host toxicity. Safingol and its N-methyl metabolites were cytotoxic to both a human prostate cell line (DU145) and mouse BALB 3T3 cells; therefore, the host and potential antitumor toxicity may be due to multiple molecular species of safingol.
沙芬戈[（2S，3S）-2-氨基-1，3-十八烷二醇]是鞘氨醇的一种非天然L-苏式立体异构体，在体外培养中对癌细胞具有细胞毒性，目前正处于1期人体临床试验阶段。为了确定沙芬戈是否能口服吸收，以及它对用于前列腺癌研究的小鼠品系中的前列腺癌是否有影响，将沙芬戈以0.0125%至0.1%w/w的剂量添加到TRAMP（小鼠前列腺转基因腺癌）小鼠的饮食中，持续喂养2周。通过液相色谱电喷雾电离串联质谱法分析血液和组织中的沙芬戈及其代谢产物，结果显示其在组织中有摄取，并且沙芬戈广泛转化为N-酰基物质（类似于天然的“神经酰胺”）以及之前未观察到的单、二和三N-甲基代谢产物。沙芬戈在所有剂量下均引起显著的肝毒性，表现为肝脏丙氨酸转氨酶升高，在最高剂量（0.1%）时导致肝脏组织学改变（自噬体空泡出现）和肾毒性（基于血尿素氮升高），以及血细胞比容和体重下降。沙芬戈并未抑制TRAMP小鼠的前列腺癌前病变（前列腺上皮内瘤变）；然而，由于宿主毒性，未进行更低剂量、更长时间的进一步研究。沙芬戈及其N-甲基代谢产物对人前列腺细胞系（DU145）和小鼠BALB 3T3细胞均具有细胞毒性；因此，宿主毒性和潜在的抗肿瘤毒性可能归因于沙芬戈的多种分子形式。
