RATIONALE AND OBJECTIVES: Radiolabeled tyrosine analogues that have been successfully used in tumor imaging accumulate in tumor cells via an upregulated L-type amino acid transporter system. The anticancer drug melphalan is an L-type amino acid transporter substrate. Therefore, radiolabeled tyrosine analogues may have great potential in evaluating treatment responses to melphalan. In this study, a (99m)Tc-labeled tyrosine analogue, (99m)Tc tyrosine using N,N'-ethylene-di-L-cysteine (EC) as a chelator, was developed and its potential for noninvasively assessing tumors' early response to melphalan determined. MATERIALS AND METHODS: EC-tyrosine was synthesized in a three-step procedure and labeled with (99m)Tc. To assess cellular uptake kinetics, the percentage uptake of (99m)Tc-EC-tyrosine in the rat breast cancer cell line 13762 was measured. Planar imaging was performed in rats with 13762 cell-derived tumors. To determine the transport mechanisms of (99m)Tc-EC-tyrosine, a competitive inhibition study using L-tyrosine as an inhibitor was performed in vitro and in vivo. To assess tumors' response to melphalan, tumor-bearing rats were treated with different doses of melphalan, and planar imaging was performed 0 and 3 days after treatment. Immunohistochemical analyses were conducted to determine expressions of L-type amino acid transporter 1 and cellular proliferation marker Ki-67. RESULTS: L-tyrosine significantly inhibited (99m)Tc-EC-tyrosine uptake in vitro and in vivo. Tumor volume decreased in a dose-dependent manner with melphalan, and tumor/muscle ratios of (99m)Tc-EC-tyrosine were significantly reduced in treated groups. Immunohistochemical data indicated that about 70% of tumor cells in the melphalan-treated groups underwent apoptosis, and the changes in tumor/muscle ratios reflected the decreased percentage of viable cells in treated tumors. CONCLUSIONS: These findings suggest that (99m)Tc-EC-tyrosine has great potential for monitoring tumor response to melphalan in breast tumor-bearing rats. Published by Elsevier Inc.
RATIONALE AND OBJECTIVES: Radiolabeled tyrosine analogues that have been successfully used in tumor imaging accumulate in tumor cells via an upregulated L-type amino acid transporter system. The anticancer drug melphalan is an L-type amino acid transporter substrate. Therefore, radiolabeled tyrosine analogues may have great potential in evaluating treatment responses to melphalan. In this study, a (99m)Tc-labeled tyrosine analogue, (99m)Tc tyrosine using N,N'-ethylene-di-L-cysteine (EC) as a chelator, was developed and its potential for noninvasively assessing tumors' early response to melphalan determined. MATERIALS AND METHODS:EC-tyrosine was synthesized in a three-step procedure and labeled with (99m)Tc. To assess cellular uptake kinetics, the percentage uptake of (99m)Tc-EC-tyrosine in the ratbreast cancer cell line 13762 was measured. Planar imaging was performed in rats with 13762 cell-derived tumors. To determine the transport mechanisms of (99m)Tc-EC-tyrosine, a competitive inhibition study using L-tyrosine as an inhibitor was performed in vitro and in vivo. To assess tumors' response to melphalan, tumor-bearing rats were treated with different doses of melphalan, and planar imaging was performed 0 and 3 days after treatment. Immunohistochemical analyses were conducted to determine expressions of L-type amino acid transporter 1 and cellular proliferation marker Ki-67. RESULTS:L-tyrosine significantly inhibited (99m)Tc-EC-tyrosine uptake in vitro and in vivo. Tumor volume decreased in a dose-dependent manner with melphalan, and tumor/muscle ratios of (99m)Tc-EC-tyrosine were significantly reduced in treated groups. Immunohistochemical data indicated that about 70% of tumor cells in the melphalan-treated groups underwent apoptosis, and the changes in tumor/muscle ratios reflected the decreased percentage of viable cells in treated tumors. CONCLUSIONS: These findings suggest that (99m)Tc-EC-tyrosine has great potential for monitoring tumor response to melphalan in breast tumor-bearing rats. Published by Elsevier Inc.
Authors: Liziane O F Monteiro; Renata S Fernandes; Luciano C Castro; Valbert N Cardoso; Mônica C Oliveira; Danyelle M Townsend; Alice Ferretti; Domenico Rubello; Elaine A Leite; André L B de Barros Journal: Biomed Pharmacother Date: 2017-03-24 Impact factor: 6.529
Authors: F N Carlesso; L L Fuscaldi; R S Araújo; C S Teixeira; M C Oliveira; S O A Fernandes; G D Cassali; D C Reis; A L B Barros; V N Cardoso Journal: Braz J Med Biol Res Date: 2015-05-19 Impact factor: 2.590