Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BW2258U89 is a gastrin releasing peptide (GRP) receptor antagonist which inhibits the proliferation of the neuroendocrine tumor small cell lung cancer (SCLC). Here the biological activity of BW2258U89 and its metabolite were investigated. Using mass spectroscopy (LC-ESI/MS) techniques, three major peaks for BW2258U89 were observed with mass/charge (m/z) ratios of 1081.6, 541.4 and 361.4. After metabolism by mouse plasma enzymes, the major product had a m/z ratio of 1082.5, 541.9 and 361.8 suggesting that BW2258U89 was deamidated. Deamidated (Da) BW2258U89 was synthesized and it inhibited ((125)I-Tyr(4)) BB binding to NCI-H345 SCLC cells with an IC(50)value of 450 nM; BW2258U89 had an IC(50)value of 17 nM. BW2258U89 (1 microM) antagonized the ability of 50 nM BB to elevate cytosolic Ca(2+)in NCI-H345 cells, whereas 1 microM (Da) BW2258U89 did not. One micromolar BW2258U89 antagonized the increase in NCI-H345 c-fos mRNA caused by 10 nM BB, whereas 1 microM (Da) BW2258U89 had little effect. One microM BW2258U89 inhibited NCI-H345 clonal growth significantly whereas 1 microM (Da) BW2258U89 did not. These data suggest that an amidated C-terminal is important for antagonism of SCLC GRP receptors by BW2258U89.
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PMID:The metabolism of BW2258U89, a GRP receptor antagonist. 1098 27

It has been shown that gastrin releasing peptide receptors (GRPRs) are overexpressed in various types of cancer cells. Bombesin is an analogue of the mammalian GRP that binds with high specificity and affinity to GRPRs. Significant research efforts have been lately devoted to the design of radiolabeled 8 or 14 aminoacid bombesin (BN) peptides for the detection (either with gamma or positron emitting radionuclides) and therapy (with beta(-) emitting radionuclides) of cancer. The specific aim of the present study was to further investigate the radiolabeled peptide structure and to determine whether the total absence of a linker or the use of a basic diverse amino acid linker could influence the biodistribution profile of the new compounds for specific targeting of human prostate cancer. Thus, two new derivatives with the structure Gly-Gly-Cys-X-BN[2-14], where linker X is either zero (I) or Orn-Orn-Orn (Orn: ornithine) (II) were designed and synthesized. The corresponding (99m)Tc-BN derivatives were obtained with high radiochemical yield (>98%) and had almost identical retention times in RP-HPLC with the (185/187)Re complexes, which were also characterized by ESI-MS. Metabolic stability was found to be high in human plasma, moderate in PC-3 cells, and rather low in mouse liver and kidney homogenates for both BN derivatives studied. The BN derivative without the spacer was less stable in cell culture and liver homogenates. A satisfactory binding affinity to GRPRs, in the nanomolar range, was obtained for both BN derivatives as well as for their Re complexes, with BN (II) demonstrating the highest one. In vitro internalization/externalization assays indicated that approximately 6% of BN (I) and approximately 25% of BN (II) were internalized into PC-3 cells. In vivo evaluation in normal Swiss mice and in tumor bearing SCID mice showed that BN (II) presented higher tumor and pancreas uptake than BN (I). Small animal SPECT dynamic imaging, carried out after an injection of BN (II) in mice bearing PC-3 tumors, resulted in PC-3 tumor delineation with low background activity. Overall, this study performed for two new N(3)S-X-BN[2-14] derivatives indicated that hydrophilicity and charge strongly affected the in vitro and in vivo binding properties and the biodistribution pattern. This finding is confirmed by SPECT imaging of BN (II), which is under further in vivo evaluation for detecting cancer-positive GRPRs.
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PMID:Spacer site modifications for the improvement of the in vitro and in vivo binding properties of (99m)Tc-N(3)S-X-bombesin[2-14] derivatives. 1934 22