title: Development of (99m)Tc-EC-tyrosine for early detection of breast cancer tumor response to the anticancer drug melphalan.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. fanlin.kong@mdanderson.org
authors.forename: Fan-Lin
authors.initials: FL
authors.lastname: Kong
authors.forename: Yinhan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Young
authors.forename: Dong-Fang
authors.initials: DF
authors.lastname: Yu
authors.forename: David J
authors.initials: DJ
authors.lastname: Yang
mesh_terms: D027241:Amino Acid Transport System y+L / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry*; D003545:Cysteine / Q000138:chemical synthesis / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008558:Melphalan / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D011877:Radionuclide Imaging; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D016896:Treatment Outcome; D014443:Tyrosine / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D027241:Amino Acid Transport System y+L; D002614:Chelating Agents; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D015609:Organotechnetium Compounds; C115131:SLC43A1 protein, human; D014443:Tyrosine; D003545:Cysteine; D008558:Melphalan