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Berlin Brandenburg

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  • Proceedings of the National Academy of Sciences of the United States of America
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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 06 February 2007, Vol.104(6), pp.1943-6
    Description: Antagonists of growth hormone-releasing hormone (GHRH) are being developed for the treatment of various cancers. In this study, we investigated the effectiveness of treatment with GHRH antagonist JMR-132 alone and in combination with docetaxel chemotherapy in nude mice bearing MX-1 human breast cancers. Specific high-affinity binding sites for GHRH were found on MX-1 tumor membranes using ligand competition assays with (125)I-labeled GHRH antagonist JV-1-42. JMR-132 displaced radiolabeled JV-1-42 with an IC(50) of 0.14 nM, indicating a high affinity of JMR-132 to GHRH receptors. Treatment of nude mice bearing xenografts of MX-1 with JMR-132 at 10 microg per day s.c. for 22 days significantly (P 〈 0.05) inhibited tumor volume by 62.9% and tumor weight by 47.8%. Docetaxel given twice at a dose of 20 mg/kg i.p. significantly reduced tumor volume and weight by 74.1% and 58.6%, respectively. Combination treatment with JMR-132 (10 microg/day) and docetaxel (20 mg/kg i.p.) led to growth arrest of most tumors as shown by an inhibition of tumor volume and weight by 97.7% and 95.6%, respectively (P 〈 0.001). Because no vital cancer cells were detected in some of the excised tumors, a total regression of the tumors was achieved in some cases. Treatment with JMR-132 also strongly reduced the concentration of EGF receptors in MX-1 tumors. Our results demonstrate that GHRH antagonists might provide a therapy for breast cancer and could be combined with docetaxel chemotherapy to enhance the efficacy of treatment.
    Keywords: Antineoplastic Agents -- Pharmacology ; Growth Hormone-Releasing Hormone -- Antagonists & Inhibitors ; Mammary Neoplasms, Experimental -- Prevention & Control ; Taxoids -- Pharmacology
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 26 December 2017, Vol.114(52), pp.13726-13731
    Description: The partitioning of cellular components between the nucleus and cytoplasm is the defining feature of eukaryotic life. The nuclear pore complex (NPC) selectively gates the transport of macromolecules between these compartments, but it is unknown whether surveillance mechanisms exist to reinforce this function. By leveraging in situ cryo-electron tomography to image the native cellular environment of , we observed that nuclear 26S proteasomes crowd around NPCs. Through a combination of subtomogram averaging and nanometer-precision localization, we identified two classes of proteasomes tethered via their Rpn9 subunits to two specific NPC locations: binding sites on the NPC basket that reflect its eightfold symmetry and more abundant binding sites at the inner nuclear membrane that encircle the NPC. These basket-tethered and membrane-tethered proteasomes, which have similar substrate-processing state frequencies as proteasomes elsewhere in the cell, are ideally positioned to regulate transcription and perform quality control of both soluble and membrane proteins transiting the NPC.
    Keywords: Cryo-Electron Tomography ; Focused Ion Beam ; Nuclear Pore Complex ; Proteasome ; Quality Control ; Chlamydomonas Reinhardtii -- Metabolism ; Nuclear Pore -- Metabolism ; Plant Proteins -- Metabolism ; Proteasome Endopeptidase Complex -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 05 July 2006, Vol.103(27), pp.10403-10407
    Description: The aim of this study was to investigate the effect of treatment of experimental ovarian cancers with targeted cytotoxic analogs as single compounds and in combination. Targeted cytotoxic analogs of bombesin (AN-215), somatostatin (AN-238), and luteinizing hormone-releasing hormone (AN-207) consisted of 2-pyrrolinodoxorubicin (AN-201) linked to the respective peptide carrier. AN-238 at 200 nmol/kg significantly inhibited growth of UCI-107, ES-2 and OV-1063 ovarian cancers. AN-215 alone at 200 nmol/kg and its combination with AN-238 at one-half of the dose were also able to inhibit the growth of UCI-107 tumors. A combination of AN-238 with AN-207at 50% of the dose strongly suppressed the proliferation of ES-2 and OV-1063 ovarian tumors. Cytotoxic radical AN-201 was toxic and had no significant effect on tumor growth. In contrast, the toxicity of the conjugated peptide analogs was low. Because ovarian cancers tend to acquire chemoresistance, we used real-time PCR to measure the mRNA expression of multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein after treatment. Low or no induction of multidrug resistance protein 1, multidrug resistance-related protein, and breast cancer resistance protein occurred after treatment with AN-238, AN-215, and the combination of AN-238 with AN-207 or AN-215. These results demonstrate that a therapy with cytotoxic analogs such as single agents and combinations is effective and nontoxic. Our work suggests that cytotoxic peptide analogs of luteinizing hormone-releasing hormone, somatostatin, and bombesin could be used for the therapy of ovarian cancers, considering the lack of induction of chemoresistance.
    Keywords: Antineoplastic Agents -- Pharmacology ; Bombesin -- Therapeutic Use ; Lutein -- Chemistry ; Ovarian Neoplasms -- Drug Therapy ; Somatostatin -- Therapeutic Use
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 5 July 2006, Vol.103(27), pp.10403-10407
    Description: The aim of this study was to investigate the effect of treatment of experimental ovarian cancers with targeted cytotoxic analogs as single compounds and in combination. Targeted cytotoxic analogs of bombesin (AN-215), somatostatin (AN-238), and luteinizing hormone-releasing hormone (AN-207) consisted of 2-pyrrolinodoxorubicin (AN-201) linked to the respective peptide carrier. AN238 at 200 nmol/kg significantly inhibited growth of UCI-107, ES-2 and OV-1063 ovarian cancers. AN-215 alone at 200 nmol/kg and its combination with AN-238 at one-half of the dose were also able to inhibit the growth of UCI-107 tumors. A combination of AN-238 with AN-207at 50% of the dose strongly suppressed the proliferation of ES-2 and OV-1063 ovarian tumors. Cytotoxic radical AN201 was toxic and had no significant effect on tumor growth. In contrast, the toxicity of the conjugated peptide analogs was low. Because ovarian cancers tend to acquire chemoresistance, we used real-time PCR to measure the mRNA expression of multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein after treatment. Low or no induction of multidrug resistance protein 1, multidrug resistance-related protein, and breast cancer resistance protein occurred after treatment with AN-238, AN-215, and the combination of AN-238 with AN-207 or AN-215. These results demonstrate that a therapy with cytotoxic analogs such as single agents and combinations is effective and nontoxic. Our work suggests that cytotoxic peptide analogs of luteinizing hormone-releasing hormone, somatostatin, and bombesin could be used for the therapy of ovarian cancers, considering the lack of induction of chemoresistance.
    ISSN: 00278424
    Source: Archival Journals (JSTOR)
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