Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

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 (211At)-labeled amino acid derivative, 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-211At-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 2-211At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-211At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-211At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-211At-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 2-211At-AAMP by increasing its accumulation in tumors.

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Molecular characterization of human and rat organic anion transporter OATP-D

AJP Renal Physiology ◽

10.1152/ajprenal.00402.2002 ◽

2003 ◽

Vol 285 (6) ◽

pp. F1188-F1197 ◽

Cited By ~ 54

Author(s):

Hisanobu Adachi ◽

Takehiro Suzuki ◽

Michiaki Abe ◽

Naoki Asano ◽

Hiroya Mizutamari ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Amino Acid Sequence ◽

Sequence Homology ◽

Organic Anion ◽

Organic Anion Transporter ◽

Prostaglandin E ◽

Amino Acid Sequence Homology ◽

Phylogenetic Tree Analysis ◽

Anion Transporter

We have isolated and characterized a novel human and rat organic anion transporter subtype, OATP-D. The isolated cDNA from human brain encodes a polypeptide of 710 amino acids ( Mr 76,534) with 12 predicted transmembrane domains. The rat clone encodes 710 amino acids ( Mr 76,821) with 97.6% amino acid sequence homology with human OATP-D. Human and rat OATP-D have moderate amino acid sequence homology with LST-1/rlst-1, the rat oatp family, the prostaglandin transporter, and moat1/MOAT1/KIAA0880/OATP-B. Phylogenetic tree analysis revealed that OATP-D is branched in a different position from all known organic anion transporters. OATP-D transports prostaglandin E1 ( Km 48.5 nM), prostaglandin E2 ( Km 55.5 nM), and prostaglandin F2α, suggesting that, functionally, OATP-D encodes a protein that has similar characteristics to those of the prostaglandin transporter. Rat OATP-D also transports prostaglandins. The expression pattern of OATP-D mRNA was abundant mainly in the heart, testis, brain, and some cancer cells. Immunohistochemical analysis further revealed that rat OATP-D is widely expressed in the vascular, renal, and reproductive system at the protein level. These results suggest that OATP-D plays an important role in translocating prostaglandins in specialized tissues and cells.

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Structure activity relations of aromatic amino acid derivatives to interact with organic anion transporter OAT1 reveal critical moieties for renal accumulation of tumor imaging probes

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_po1-8-40 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. PO1-8-40

Author(s):

Chunhuan Jin ◽

Ryuichi Ohgaki ◽

Hideyuki Tominaga ◽

Suguru Okuda ◽

Shushi Nagamori ◽

...

Keyword(s):

Amino Acid ◽

Aromatic Amino Acid ◽

Tumor Imaging ◽

Organic Anion ◽

Organic Anion Transporter ◽

Amino Acid Derivatives ◽

Structure Activity ◽

Anion Transporter ◽

Structure Activity Relations ◽

Imaging Probes

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Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.272.1.g16 ◽

1997 ◽

Vol 272 (1) ◽

pp. G16-G22 ◽

Cited By ~ 24

Author(s):

K. Ito ◽

H. Suzuki ◽

T. Hirohashi ◽

K. Kume ◽

T. Shimizu ◽

...

Keyword(s):

Amino Acid ◽

Stop Codon ◽

Organic Anion ◽

Amino Acid Level ◽

Premature Stop Codon ◽

Autosomal Recessive Inheritance ◽

Organic Anions ◽

Organic Anion Transporter ◽

Sprague Dawley ◽

Anion Transporter

Several organic anions are excreted into the bile via a canalicular multispecific organic anion transporter (cMOAT), which is hereditarily defective in mutant rats, such as the Eisai hyperbilirubinemic rat (EHBR) and TR- rat. In the present study, we cloned cMOAT from the Sprague-Dawley rat liver cDNA library based on the homology with human multidrug resistance-associated protein (hMRP). cMOAT was encoded by 4,623-base pair (bp) cDNA with a homology of 53.0 and 46.3% with hMRP at the cDNA and deduced amino acid level, respectively. The deduced amino acid sequence was the same as that cloned in Wistar rats (C. C. Paulusma, P. J. Bosma, G. J. Zaman, C. T. Bakker, M. Otter, G. L. Sceffer, P. Borst, and R. P. Oude Elferink. Science Wash. DC 271: 1126, 1996) except for four amino acid substitutions. By screening the library, three kinds of cDNA species for cMOAT with the same open reading frame and different 3'-untranslated region lengths (0.2, 1.5, and 3.5 kbp) were isolated. The Northern blot analysis of poly(A)+ RNA from the liver revealed that the expression of plural bands (approximately 5, 6, and 8 kb) was defective in EHBR, and this may be due to the presence of these cDNA species. Expression of cMOAT was observed almost exclusively in the liver and to a lesser extent in the duodenum, kidney, and jejunum. Reverse transcription-polymerase chain reaction (RT-PCR) and subsequent sequence analysis of EHBR liver, kidney, duodenum, and jejunum revealed that 1-bp replacement from G to A at nucleotide 2564 resulted in the introduction of the premature stop codon in all tissues examined. This mutation was different from that observed in TR (C. C. Paulusma, P. J. Bosma, G. J. Zaman, C. T. Bakker, M. Otter, G. L. Sceffer, P. Borst, and R. P. Oude Elferink. Science Wash. DC 271: 1126, 1996). Because EHBR and TR- are allelic mutants and both strains exhibit an autosomal recessive inheritance in the biliary excretion of organic anions it was concluded that the impaired expression of this particular protein is related to the pathogenesis of hyperbilirubinemia in the mutant animals.

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