Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The methods for treatment of advanced prostate cancer, based on the agonistic analogs of LH-RH were reviewed. New therapeutic approaches utilizing antagonistic analogs of LH-RH such as SB-75 (Cetrorelix) have been described. Analogs of LH-RH chemically linked to various cytotoxic radicals are also being developed. Combinations of LH-RH agonists or antagonists with superactive somatostatin analogues such as Octastatin (RC-160) or with bombesin/GRP antagonists are being investigated in order to delay or prevent the relapse and improve the therapy for prostate cancer.
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PMID:Present status of agonistic and antagonistic analogs of LH-RH in the treatment of advanced prostate cancer. 136 77

Prostate-specific antigen (PSA), a M(r) 34,000 serine protease, is recognized as a useful marker for the detection and prognosis of patients with prostate cancer. Although serum PSA is an excellent prognostic indicator, an increasing number of factors were found to regulate the PSA expression of prostatic cancer cells, which include androgenic steroids, the growth factors (GFs) and the extracellular matrix. The purpose of this study is to define a novel protein factor that may be responsible for regulating PSA expression by androgen-independent (AI) human prostate cancer cells. We have established a LNCaP subline (C4) from a parental LNCaP tumor grown in a castrated host. The C4 subline overexpressed PSA mRNA and protein. Serum-free conditioned medium (CM) isolated from the C4 subline is able to stimulate PSA gene expression in parental LNCaP cells in a concentration-dependent manner. This autocrine PSA-inducing activity was found to be organ specific because CMs from other fibroblast cell lines (such as bone, prostate, kidney, and lung fibroblasts) and the CMs from several prostatic carcinoma cell lines (such as parental LNCaP, PC-3, DU-145) and a bladder transitional carcinoma cell line (WH) fail to exhibit similar activity. The activity of the CM from the C4 subline cannot be substituted by GFs such as TGF-alpha, TGF-beta, bFGF, HGF, KGF, or NGF; neuropeptide (bombesin/GRP); secondary messenger analogue (dibutyryl cAMP); beta 2-adrenergic agonist (isoproterenol); or alpha 1-adrenergic agonist (phenylephrine), indicating that the factor(s) may be a novel prostate-specific autocrine factor (PSAF). Both androgen and PSAF exhibit an additive effect on up-regulating PSA gene expression, suggesting that the signal transduction pathway elicited by PSAF may differ from that mediated by the androgen receptor. Further characterization of PSAF by heat, acid, and trypsin digestion revealed that the PSAF may be a protein factor with a unique amino acid composition. These observations suggest that a novel autocrine pathway mediated by PSAF may be responsible for the overexpression of PSA mRNA and protein in a human prostatic cancer cell line. The potential clinical significance of this factor will be discussed.
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PMID:Autocrine regulation of prostate-specific antigen gene expression in a human prostatic cancer (LNCaP) subline. 768 49

The mammalian gastrin-releasing peptide receptor (GRP-R) belongs to the superfamily of G protein-coupled receptors and mediates actions of the regulatory GRP and bombesin, the amphibian homolog of GRP. Owing to its frequent ectopic expression in some epithelial human malignancies, such as cancers of the colon, lung, and prostate, ligand-specific receptor activation may initiate intracellular signals of cell proliferation, differentiation and migration in this context. Because the underlying molecular mechanisms of aberrant human GRP-R (hGRP-R) expression in tumorigenesis remain unknown, we examined in this study the transcriptional activation of hGRP-R in gastrointestinal and prostate cancer cells, which natively express functional hGRP-R. Using various hGRP-R promoter mutants cloned into a luciferase reporter plasmid, transient transfection studies demonstrated robust transcriptional activation in gastrointestinal and prostate cancer cells. Although our study revealed distinct patterns of transcriptional hGRP-R activation in gastrointestinal and prostate cancer cells, genomic sequences between 97 and 247 bp upstream of the major RNA initiation site appear to be of particular significance for basal transcriptional hGRP-R activation. Based on this study, future examination of transcription factor interaction with the hGRP-R promoter will be important to identify molecular mechanisms of hGRP-R regulation relevant in human cancers that express functional receptor sites
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PMID:Transcriptional activation of the human gastrin-releasing peptide receptor gene in gastrointestinal and prostatic epithelial cancer cells. 1474 12

Bombesin/gastrin-releasing peptide (BN/GRP) antagonists RC-3940-II and RC-3940-Et, and growth hormone-releasing hormone (GHRH) antagonists MZ-J-7-118 and RC-J-29-18 inhibit the growth of human androgen-independent PC-3 and DU-145 prostate cancers in nude mice. Additive inhibitory effects were observed after treatment with both classes of analogs. In the present study, we investigated the effects of these antagonists on intracellular signalling pathways of protein kinase C (PKC), mitogen activated protein kinases (MAPK) and c-fos and c-jun oncogenes that are involved in tumour cell proliferation. In PC-3 tumours, antagonists of BN/GRP and GHRH decreased significantly the expression of PKC isoforms alpha (alpha), eta (eta) and zeta (zeta) and increased that of delta (delta) PKC protein. MAPK was not detectable. In DU-145 tumours, which constitutively express MAPK, all treatments strongly decreased the levels of p42/44 MAPK. Treatment with the antagonists tended to reduce m-RNA for c-jun in both tumour models. In proliferation assays in vitro, inhibitors of PKC and MAPK diminished growth of DU-145 and PC-3 cells. These findings suggest that antagonists of BN/GRP and GHRH inhibit the growth of androgen-independent prostate cancer by affecting intracellular signalling mechanisms of PKC, MAPK and c-jun.
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PMID:Inhibition of human androgen-independent PC-3 and DU-145 prostate cancers by antagonists of bombesin and growth hormone releasing hormone is linked to PKC, MAPK and c-jun intracellular signalling. 1629 Oct 86

Bombesin is a tetradecapeptide neurohormone that binds to gastrin-releasing peptide receptors (GRPR). GRPRs have been found in a variety of cancers including invasive breast and prostate tumors. The peptide MP2346 (DOTA-(Pro(1),Tyr(4))-bombesin(1-14)) was designed to bind to these GRP receptors. This study was undertaken to evaluate radiolabeled MP2346 as a positron emission tomography (PET) imaging agent. MP2346 was radiolabeled, in high radiochemical purity, with the positron-emitting nuclides (64)Cu (t(1/2) = 12.7 h, beta+ = 19.3%, E(avg) = 278 keV) and (86)Y (t(1/2) = 14.7 h, beta+ = 33%, E(avg) = 664 keV). (64)Cu-MP2346 and (86)Y-MP2346 were studied in vitro for cellular internalization by GRPR-expressing PC-3 (human prostate adenocarcinoma) cells. Both (64)Cu- and (86)Y-MP2346 were studied in vivo for tissue distribution in nude mice with PC-3 tumors. Biodistribution in PC3 tumor-bearing mice demonstrated higher tumor uptake, but lower liver retention, in animals injected with (86)Y-MP2346 compared to (64)Cu-MP2346. Receptor-mediated uptake was confirmed by a significant reduction in uptake in the PC-3 tumor and other receptor-rich tissues by coinjection of a blockade. Small animal PET/CT imaging was carried out in mice bearing PC-3 tumors and rats bearing AR42J tumors. It was possible to delineate PC-3 tumors in vivo with (64)Cu-MP2346, but superior (86)Y-MP2346-PET images were obtained due to lower uptake in clearance organs and lower background activity. The (86)Y analogue demonstrated excellent PET image quality in models of prostate cancer for the delineation of the GRPR-rich tumors and warrants further investigation.
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PMID:Molecular imaging of gastrin-releasing peptide receptor-positive tumors in mice using 64Cu- and 86Y-DOTA-(Pro1,Tyr4)-bombesin(1-14). 1737

The discovery of hypothalamic hormones was briefly reviewed. The development of new hormonal methods for the therapy of various cancers based on analogues of hypothalmic hormones is then presented. My group isolated luteininzing hormone-releasing hormone (LH-RH), also known as Gn-RH, from pig hypothalmi, elucidated its amino acid sequence, and synthesized it in 1971. The interest in medical applications of LH-RH led to the synthesis of LH-RH analogues by various groups. LH-RH agonists substituted in positions 6 or 10 including Decapeptyl, Leuprolide and Zoladex are much more active than LH-RH and on continuous administration produce inhibition of pituitary and gonads. Chronic administration of LH-RH agonists is being utilized for the treatment of prostate and breast cancer. Octapeptide analogues of somatostatin have various applications in Oncology. In 1980 we developed a new endocrine therapy for advanced prostate cancer based on agonists of LH-RH, which is now preferred by 70-90% of prostate cancer patients for primary treatment. LH-RH antagonists such as Cetrorelix can be used for therapy of BPH. On the basis of the presence of specific receptors for hypothalamic peptides on human cancers, we developed targeted cytotoxic analogues of LH-RH, somatostatin, and bombesin/GRP linked to doxorubicin or 2-pyrrolinodoxorubicin. These analogues inhibit the growth of experimental human prostate, breast, ovarian and endometrial cancer, renal cell carcinoma, pancreatic, colorectal and gastric cancers, small cell lung carcinoma (SCLC) and non-SCLC, brain tumors, melanomas, and lymphomas. Cytotoxic LH-RH analogues are now in clinical trials. Recently we demonstrated that growth hormone-releasing hormone (GH-RH) also serves as an autocrine growth factor in many cancers. Antagonistic analogues of GH-RH synthesized in our laboratory inhibit the growth of diverse tumors. The discovery of LH-RH and somatostatin has led to clinical use of their analogues in the field of cancer treatment and GH-RH antagonists also show a great promise.
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PMID:New approaches to the therapy of various tumors based on peptide analogues. 1849 Dec 50

The gastrin releasing peptide receptor (GRP-R) is overexpressed on a number of tumors and cancer cell lines including pancreas, prostate, breast, gastrointestinal, and small cell lung cancer (SCLC). Radiolabeled bombesin (BBN) analogues have exhibited high binding affinity and specificity to the GRP-R. A bombesin analogue with an antagonist targeting vector at the C-terminus, DOTA-aminohexanoyl-[D-Phe(6), Leu-NHCH 2CH 2CH3(13), des Met(14)] BBN[6-14] (1, "Bomproamide"), has been synthesized and displays high binding affinity (IC50 = 1.36 +/- 0.09 nM) against (125)I-Tyr (4)-BBN in in vitro competitive assays using PC-3 cells. Maximum internalization of (111)In-1 reached 14% in PC-3 cells after 45 min of incubation. Rapid (0.25 h PI) and high (12.21 +/- 3.2%ID/g) pancreatic uptake of (111)In-1 was observed in healthy CF-1 mice, and 90% of the activity was blocked by coinjection of 100 mug of BBN. Rapid (0.25 h PI) and high uptake (6.90 +/- 1.06%ID/g) was observed in PC-3 prostate cancer xenografts in SCID mice, as well as visualized clearly in a SPECT/CT study. These results support the use of a bombesin construct with an antagonist C-terminal vector as a candidate of choice for specific in vivo imaging of tumors overexpressing GRP-receptors.
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PMID:Design, synthesis, and biological evaluation of an antagonist-bombesin analogue as targeting vector. 1880 68

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

The gastrin-releasing peptide receptor (GRP-r) is over-expressed in various human tumors. Recently, (99m)Tc-EDDA/HYNIC-Lys(3)-bombesin ((99m)Tc-BN) was reported as a radiopharmaceutical with specific cell GRP-r binding and images in breast cancer patients demonstrated distinct radioactivity accumulation in malignant tissue. The HIV Tat-derived peptide has been used to deliver a large variety of cargoes into cells. Therefore, a new hybrid radiopharmaceutical of type (99m)Tc-N(2)S(2)-Tat(49-57)-Lys(3)-bombesin ((99m)Tc-Tat-BN) would increase cell uptake. The aim of this research was to prepare and assess in vitro and in vivo uptake kinetics in cancer cells of (99m)Tc-Tat-BN and to compare its cellular internalization with that of (99m)Tc-BN. Structures of N(2)S(2)-Tat-BN and Tc(O)N(2)S(2)-Tat-BN were calculated by an MM procedure. (99m)Tc-Tat-BN was synthesized and stability studies carried out by HPLC and ITLC-SG analyses in serum and cysteine solutions. In vitro internalization was tested using human prostate cancer PC-3 cells and breast carcinoma cell lines MDA-MB231 and MCF7. Biodistribution was determined in PC-3 tumor-bearing nude mice. Results showed a minimum energy of 271 kcal/mol for N(2)S(2)-Tat-BN and 300 kcal/mol for Tc(O)N(2)S(2)-Tat-BN. (99m)Tc-Tat-BN radiochemical purity was >90%. In vitro studies demonstrated stability in serum and cysteine solutions, specific cell receptor binding and internalization in three cell lines was significantly higher than that of (99m)Tc-BN (p<0.05). The tumor-to-muscle radioactivity ratio was 8.5 for (99m)Tc-Tat-BN and 7 for (99m)Tc-BN. Therefore, this hybrid is potentially useful in breast and prostate cancer imaging.
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PMID:Design, preparation, in vitro and in vivo evaluation of (99m)Tc-N2S2-Tat(49-57)-bombesin: a target-specific hybrid radiopharmaceutical. 1939 5

The aim of the present study is the evaluation of the (99m)Tc complexes of two bombesin-like peptides: Gly1'-Gly2'-Cys3'-Aca-BN[2-14] (BN-1.1) and Gly1'-Gly2'-Cys3'-Aca-BN[7-14] (BN-1.1p). The BN derivatives were synthesized according to the solid phase peptide synthesis method, and characterized by ESI-MS and NMR. (185/187)Re-BN-1.1 and (185/187)Re-BN-1.1p were also identified by ESI-MS and NMR. The (99m)Tc complexes were stable over time in human plasma, while they degraded rapidly in kidney-liver homogenates. The peptides and their (99m)Tc complexes showed high affinity for the human GRP receptors expressed in PC-3 cells. The rate of internalization of these radiolabeled biomolecules was found to be time-dependent. Also, it was found that there was no long-term retention of the radioactive metabolites into the cells. Tissue distribution of the radiopeptides was evaluated in normal mice and in prostate cancer experimental models. Significant uptake of radioactivity was observed in the pancreas of PC-3 tumor-bearing SCID mice. Dynamic studies of both radiopeptides showed satisfactory tumor images.
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PMID:Structural assessment and biological evaluation of two N3S bombesin derivatives. 1952 64


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