Hanaoka Hirofumi, Ohshima Yasuhiro, Suzuki Hiroyuki, Sasaki Ichiro, Watabe Tadashi, Ooe Kazuhiro, Watanabe Shigeki, Ishioka Noriko S
Faculty of Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata 573-1010, Osaka, Japan.
Department of Radiotheranostics, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan.
Cancers (Basel). 2021 Nov 3;13(21):5514. doi: 10.3390/cancers13215514.
L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 (At)-labeled amino acid derivative, 2-At-astato-α-methyl-L-phenylalanine (2-At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2-At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2-At-AAMP by increasing its accumulation in tumors.
L型氨基酸转运体1（LAT1）可能是肿瘤治疗的一个有用靶点，因为它在各种类型的癌症中高表达。我们之前开发了一种砹-211（At）标记的氨基酸衍生物，2-At-砹-α-甲基-L-苯丙氨酸（2-At-AAMP），并证明了其对LAT1阳性癌症的治疗潜力。然而，2-At-AAMP的治疗效果不足，可能是由于其在肿瘤中的滞留率较低。有机阴离子转运体抑制剂丙磺舒的预加载可以延迟一些氨基酸示踪剂从血液中的清除，从而增加它们在肿瘤中的积累。在本研究中，我们评估了丙磺舒预加载对2-At-AAMP在小鼠体内生物分布和治疗效果的影响。在生物分布研究中，丙磺舒预加载后，2-At-AAMP的血液放射性显著增加。因此，丙磺舒处理组中2-At-AAMP在肿瘤中的积累显著高于未加载丙磺舒的组。在一项治疗研究中，丙磺舒联合2-At-AAMP可抑制肿瘤生长，从治疗后第2天到第3天（随访期结束），治疗组的肿瘤体积显著低于未治疗的对照组。这些结果表明，丙磺舒加载可以通过增加2-At-AAMP在肿瘤中的积累来提高其治疗效果。
