Morgan Lee Roy, Struck Robert F, Waud William R, LeBlanc Blaise, Rodgers Andrew H, Jursic Branko S
DEKK-TEC Inc, New Orleans, LA, USA.
Cancer Chemother Pharmacol. 2009 Sep;64(4):829-35. doi: 10.1007/s00280-009-0933-9. Epub 2009 Mar 3.
The purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic metabolite of penclomedine (PEN) seen in patients. DM-PEN has been observed to be an active antitumor agent in mouse human xenograft tumor models and non-neurotoxic in a rat model, however, activity in intracranially implanted human glioma xenograft models have not been reported. The major goal was to identify derivatives that are active in brain tumors.
Derivatives were prepared from DM-PEN and evaluated in vivo against human U251 glioblastoma, D54 glioblastoma and MX-1 breast tumor xenografts and mammary tumor 16/C that were implanted in the mammary fat pad or intracranially (IC).
Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.
The activity of the carbonates and carbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.
本研究的目的是合成一系列4-去甲基喷氯米定（DM-PEN）的碳酸酯和氨基甲酸酯衍生物，DM-PEN是患者体内所见喷氯米定（PEN）的主要血浆无毒代谢物。已观察到DM-PEN在小鼠人异种移植肿瘤模型中是一种活性抗肿瘤剂，在大鼠模型中无神经毒性，然而，其在颅内植入的人胶质瘤异种移植模型中的活性尚未见报道。主要目标是鉴定在脑肿瘤中具有活性的衍生物。
从DM-PEN制备衍生物，并在体内针对植入乳腺脂肪垫或颅内（IC）的人U251胶质母细胞瘤、D54胶质母细胞瘤和MX-1乳腺肿瘤异种移植物以及乳腺肿瘤16/C进行评估。
发现碳酸酯和氨基甲酸酯衍生物在对抗颅内生长的人胶质母细胞瘤异种移植物方面优于DM-PEN。
碳酸酯和氨基甲酸酯在体内对人肿瘤异种移植物的活性表明，DM-PEN的这两个系列衍生物值得考虑用于临床开发。
