The Experts below are selected from a list of 45 Experts worldwide ranked by ideXlab platform

Sten Nilsson - One of the best experts on this subject based on the ideXlab platform.

  • Somatostatin Derivative smsdx targets cellular metabolism in prostate cancer cells after androgen deprivation therapy
    PLOS ONE, 2013
    Co-Authors: Zhaoquan Xing, Zhiqing Fang, Wei Jiao, Zhonghua Xu, Zhenghui Fang, Anders R Holmberg, Sten Nilsson
    Abstract:

    Cancer cell metabolism responsive to androgen deprivation therapy (ADT) may be involved in the development and progression of prostate cancer and the ultimate failure of androgen-deprivation therapy. To investigate the metabolism regulation effects on androgen-independent growth of prostate cancer, an established LNCaP-s cell model that resembles the clinical scenario of castration-resistant prostate cancer (CRPC), was used in this current study. This cell line was cultured from androgen-sensitive LNCaP parental cells, in an androgen-reduced condition, resembling clinical androgen deprivation therapy. To assess the effects of smsDX on the invasiveness of prostate cancer cells we used wound healing assay and Matrigel™ invasion assay. We evaluated differentially expressed proteins of the parental LNCaP cells and LNCaP-s cells after ADT by means of two-dimensional gel electrophoresis (2-DE) followed by MALDI-TOF mass spectrometric analysis. The covered area in the wound and the number of cells invading through a Matrigel chamber were significantly smaller for cells treated with smsDX than they were for control cells treated with vehicle. 56 proteins were found differentially expressed in LNCaP-s cells compared to LNCaP cells, majority of them were down-regulated after ADT treatment. 104 proteins of LNCaP cells and 86 in LNCaP-s cells, separately, were found differentially expressed after treatment with smsDX, When we explored these protein functions within the website UniProtKB/Swiss-Prot, surprisingly, most of the proteins were found to be involved in the cellular metabolism and mitochondrial function regulation. LNCaP-s as potential metastatic androgen-independent cancer cells, its metabolism and mitochondrial functions could be altered by a new Somatostatin Derivative smsDX, the smsDX regulatory effects on metabolism in LNCaP-s deliver more therapeutic information with the treatment of CRPC.

  • Phase I trial on sms-D70 Somatostatin analogue in advanced prostate and renal cell cancer.
    Annals of the New York Academy of Sciences, 2004
    Co-Authors: Timo Joensuu, Anders R Holmberg, Sten Nilsson, Marcela Márquez, Mikko Tenhunen, Tiina Saarto, Heikki Joensuu
    Abstract:

    Plasma concentrations and tolerability of a novel Somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to Somatostatin receptor subtypes 2 and 5, HRPC expressing mainly Somatostatin receptors 1 and 4, a Somatostatin Derivative based on the natural Somatostatin having affinity to all five Somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated Derivative, Somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the Somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 1 3 1 I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

Silvia S Jurisson - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and in vitro evaluation of a rhenium cyclized Somatostatin Derivative series
    Journal of Medicinal Chemistry, 2008
    Co-Authors: Heather M Bigotthennkens, Sulochana Junnotula, Fabio Gallazzi, Michael R Lewis, Silvia S Jurisson
    Abstract:

    The structure–activity relationships of a series of rhenium (Re)-cyclized octreotide Derivatives are described. The effects of changes in the peptide sequence, N-terminus, and C-terminus on metal cyclization, as well as binding to the Somatostatin receptor, were investigated. Each peptide complex was found to have an integrated Re(V) core with a single metal oxo group, two coordination sites filled by the cysteine sulfhydryls, and another by the amide nitrogen of Phe3/Tyr3. The final coordination site was determined by the peptide N-terminus: the N-terminal amine coordinated for N-NH2 peptides and the amide nitrogen of Thr6 for peptides with acetylated N-termini. Re-cyclization of the octreotide Derivatives led to structural perturbations of the Somatostatin receptor-binding sequence relative to the Re−free disulfide analogues, resulting in reduced binding affinities. The findings presented herein demonstrate the importance of understanding the consequences of structural modifications when designing metal...

Anders R Holmberg - One of the best experts on this subject based on the ideXlab platform.

  • Somatostatin Derivative smsdx targets cellular metabolism in prostate cancer cells after androgen deprivation therapy
    PLOS ONE, 2013
    Co-Authors: Zhaoquan Xing, Zhiqing Fang, Wei Jiao, Zhonghua Xu, Zhenghui Fang, Anders R Holmberg, Sten Nilsson
    Abstract:

    Cancer cell metabolism responsive to androgen deprivation therapy (ADT) may be involved in the development and progression of prostate cancer and the ultimate failure of androgen-deprivation therapy. To investigate the metabolism regulation effects on androgen-independent growth of prostate cancer, an established LNCaP-s cell model that resembles the clinical scenario of castration-resistant prostate cancer (CRPC), was used in this current study. This cell line was cultured from androgen-sensitive LNCaP parental cells, in an androgen-reduced condition, resembling clinical androgen deprivation therapy. To assess the effects of smsDX on the invasiveness of prostate cancer cells we used wound healing assay and Matrigel™ invasion assay. We evaluated differentially expressed proteins of the parental LNCaP cells and LNCaP-s cells after ADT by means of two-dimensional gel electrophoresis (2-DE) followed by MALDI-TOF mass spectrometric analysis. The covered area in the wound and the number of cells invading through a Matrigel chamber were significantly smaller for cells treated with smsDX than they were for control cells treated with vehicle. 56 proteins were found differentially expressed in LNCaP-s cells compared to LNCaP cells, majority of them were down-regulated after ADT treatment. 104 proteins of LNCaP cells and 86 in LNCaP-s cells, separately, were found differentially expressed after treatment with smsDX, When we explored these protein functions within the website UniProtKB/Swiss-Prot, surprisingly, most of the proteins were found to be involved in the cellular metabolism and mitochondrial function regulation. LNCaP-s as potential metastatic androgen-independent cancer cells, its metabolism and mitochondrial functions could be altered by a new Somatostatin Derivative smsDX, the smsDX regulatory effects on metabolism in LNCaP-s deliver more therapeutic information with the treatment of CRPC.

  • Phase I trial on sms-D70 Somatostatin analogue in advanced prostate and renal cell cancer.
    Annals of the New York Academy of Sciences, 2004
    Co-Authors: Timo Joensuu, Anders R Holmberg, Sten Nilsson, Marcela Márquez, Mikko Tenhunen, Tiina Saarto, Heikki Joensuu
    Abstract:

    Plasma concentrations and tolerability of a novel Somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to Somatostatin receptor subtypes 2 and 5, HRPC expressing mainly Somatostatin receptors 1 and 4, a Somatostatin Derivative based on the natural Somatostatin having affinity to all five Somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated Derivative, Somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the Somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 1 3 1 I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

Heather M Bigotthennkens - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and in vitro evaluation of a rhenium cyclized Somatostatin Derivative series
    Journal of Medicinal Chemistry, 2008
    Co-Authors: Heather M Bigotthennkens, Sulochana Junnotula, Fabio Gallazzi, Michael R Lewis, Silvia S Jurisson
    Abstract:

    The structure–activity relationships of a series of rhenium (Re)-cyclized octreotide Derivatives are described. The effects of changes in the peptide sequence, N-terminus, and C-terminus on metal cyclization, as well as binding to the Somatostatin receptor, were investigated. Each peptide complex was found to have an integrated Re(V) core with a single metal oxo group, two coordination sites filled by the cysteine sulfhydryls, and another by the amide nitrogen of Phe3/Tyr3. The final coordination site was determined by the peptide N-terminus: the N-terminal amine coordinated for N-NH2 peptides and the amide nitrogen of Thr6 for peptides with acetylated N-termini. Re-cyclization of the octreotide Derivatives led to structural perturbations of the Somatostatin receptor-binding sequence relative to the Re−free disulfide analogues, resulting in reduced binding affinities. The findings presented herein demonstrate the importance of understanding the consequences of structural modifications when designing metal...

V 武切诺维奇 - One of the best experts on this subject based on the ideXlab platform.