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Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells
The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demons...
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Published in: | Cancer research (Chicago, Ill.) Ill.), 2004, Vol.64 (1), p.252-261 |
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creator | BOULAY, Anne ZUMSTEIN-MECKER, Sabine MARTI, Andreas THOMAS, George LANE, Heidi A STEPHAN, Christine BEUVINK, Iwan ZILBERMANN, Frederic HALLER, Roland TOBLER, Sonja HEUSSER, Christoph O'REILLY, Terence STOLZ, Barbara |
description | The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23-30%, respectively], with 3-5 mg/kg RAD001 administered once weekly (T/C, 14-36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (> or =72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (> or =7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (>95% inactivation with 20 nM RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients. |
doi_str_mv | 10.1158/0008-5472.CAN-3554-2 |
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Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23-30%, respectively], with 3-5 mg/kg RAD001 administered once weekly (T/C, 14-36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (> or =72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (> or =7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (>95% inactivation with 20 nM RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-3554-2</identifier><identifier>PMID: 14729632</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Monitoring - methods ; Everolimus ; Humans ; Immunosuppressive Agents - administration & dosage ; Immunosuppressive Agents - therapeutic use ; Leukocytes, Mononuclear - enzymology ; Male ; MAP Kinase Signaling System - drug effects ; Medical sciences ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - enzymology ; Pancreatic Neoplasms - immunology ; Pharmacology. Drug treatments ; Rats ; Rats, Inbred Lew ; Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors ; Ribosomal Protein S6 Kinases, 90-kDa - blood ; Sirolimus - administration & dosage ; Sirolimus - analogs & derivatives ; Sirolimus - therapeutic use ; Time Factors ; Tumor Cells, Cultured ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2004, Vol.64 (1), p.252-261</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-77db5047b91679c92b6eab6c784f5dcf52847e01ee53f77295ed6c0e5cbccbfb3</citedby><cites>FETCH-LOGICAL-c411t-77db5047b91679c92b6eab6c784f5dcf52847e01ee53f77295ed6c0e5cbccbfb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15422608$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14729632$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>BOULAY, Anne</creatorcontrib><creatorcontrib>ZUMSTEIN-MECKER, Sabine</creatorcontrib><creatorcontrib>MARTI, Andreas</creatorcontrib><creatorcontrib>THOMAS, George</creatorcontrib><creatorcontrib>LANE, Heidi A</creatorcontrib><creatorcontrib>STEPHAN, Christine</creatorcontrib><creatorcontrib>BEUVINK, Iwan</creatorcontrib><creatorcontrib>ZILBERMANN, Frederic</creatorcontrib><creatorcontrib>HALLER, Roland</creatorcontrib><creatorcontrib>TOBLER, Sonja</creatorcontrib><creatorcontrib>HEUSSER, Christoph</creatorcontrib><creatorcontrib>O'REILLY, Terence</creatorcontrib><creatorcontrib>STOLZ, Barbara</creatorcontrib><title>Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23-30%, respectively], with 3-5 mg/kg RAD001 administered once weekly (T/C, 14-36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (> or =72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (> or =7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (>95% inactivation with 20 nM RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Schedule</subject><subject>Drug Monitoring - methods</subject><subject>Everolimus</subject><subject>Humans</subject><subject>Immunosuppressive Agents - administration & dosage</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Leukocytes, Mononuclear - enzymology</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Medical sciences</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - enzymology</subject><subject>Pancreatic Neoplasms - immunology</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors</subject><subject>Ribosomal Protein S6 Kinases, 90-kDa - blood</subject><subject>Sirolimus - administration & dosage</subject><subject>Sirolimus - analogs & derivatives</subject><subject>Sirolimus - therapeutic use</subject><subject>Time Factors</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNpFkduOFCEQhonRuOPqGxjDjd71Ct3Q3XM5GY_JRhMP1wSqCwelYQR6zTyibyXtju4Vh3z1V8FHyFPOrjiX40vG2NhIMbRX-92HppNSNO09suGyG5tBCHmfbP4jF-RRzt_rUXImH5ILXu-2fdduyO9dKK4sc0wUrXWg4USjpS4UTLMrBUOhJaEu87rLcMBp8ZjpL1cOtByQJn3U8wlcoBMmd6OLu0H6afeKMU4hpoRel3_8MUUfwzecar6G8peOYe2XnIk5ztqvTMGa9rmnPyqVkfJK02MNPx4wVcL4GCc6xxDDAh51ooDe58fkgdU-45Pzekm-vnn9Zf-uuf749v1-d92A4Lw0wzAZycRgtrwftrBtTY_a9DCMwsoJrGxHMSDjiLKzQ_0miVMPDCUYAGNNd0le3ObWSX8umIuaXV4n0AHjktXIeH27aCsobkFIMeeEVh2Tm3U6Kc7UqlCtftTqR1WFalWo1rJn5_zFzDjdFZ2dVeD5GdAZtLdJB3D5jpOibXs2dn8AvfuqfA</recordid><startdate>2004</startdate><enddate>2004</enddate><creator>BOULAY, Anne</creator><creator>ZUMSTEIN-MECKER, Sabine</creator><creator>MARTI, Andreas</creator><creator>THOMAS, George</creator><creator>LANE, Heidi A</creator><creator>STEPHAN, Christine</creator><creator>BEUVINK, Iwan</creator><creator>ZILBERMANN, Frederic</creator><creator>HALLER, Roland</creator><creator>TOBLER, Sonja</creator><creator>HEUSSER, Christoph</creator><creator>O'REILLY, Terence</creator><creator>STOLZ, Barbara</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>2004</creationdate><title>Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells</title><author>BOULAY, Anne ; ZUMSTEIN-MECKER, Sabine ; MARTI, Andreas ; THOMAS, George ; LANE, Heidi A ; STEPHAN, Christine ; BEUVINK, Iwan ; ZILBERMANN, Frederic ; HALLER, Roland ; TOBLER, Sonja ; HEUSSER, Christoph ; O'REILLY, Terence ; STOLZ, Barbara</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-77db5047b91679c92b6eab6c784f5dcf52847e01ee53f77295ed6c0e5cbccbfb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Administration Schedule</topic><topic>Drug Monitoring - methods</topic><topic>Everolimus</topic><topic>Humans</topic><topic>Immunosuppressive Agents - administration & dosage</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Leukocytes, Mononuclear - enzymology</topic><topic>Male</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Medical sciences</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - enzymology</topic><topic>Pancreatic Neoplasms - immunology</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Inbred Lew</topic><topic>Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors</topic><topic>Ribosomal Protein S6 Kinases, 90-kDa - blood</topic><topic>Sirolimus - administration & dosage</topic><topic>Sirolimus - analogs & derivatives</topic><topic>Sirolimus - therapeutic use</topic><topic>Time Factors</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BOULAY, Anne</creatorcontrib><creatorcontrib>ZUMSTEIN-MECKER, Sabine</creatorcontrib><creatorcontrib>MARTI, Andreas</creatorcontrib><creatorcontrib>THOMAS, George</creatorcontrib><creatorcontrib>LANE, Heidi A</creatorcontrib><creatorcontrib>STEPHAN, Christine</creatorcontrib><creatorcontrib>BEUVINK, Iwan</creatorcontrib><creatorcontrib>ZILBERMANN, Frederic</creatorcontrib><creatorcontrib>HALLER, Roland</creatorcontrib><creatorcontrib>TOBLER, Sonja</creatorcontrib><creatorcontrib>HEUSSER, Christoph</creatorcontrib><creatorcontrib>O'REILLY, Terence</creatorcontrib><creatorcontrib>STOLZ, Barbara</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BOULAY, Anne</au><au>ZUMSTEIN-MECKER, Sabine</au><au>MARTI, Andreas</au><au>THOMAS, George</au><au>LANE, Heidi A</au><au>STEPHAN, Christine</au><au>BEUVINK, Iwan</au><au>ZILBERMANN, Frederic</au><au>HALLER, Roland</au><au>TOBLER, Sonja</au><au>HEUSSER, Christoph</au><au>O'REILLY, Terence</au><au>STOLZ, Barbara</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2004</date><risdate>2004</risdate><volume>64</volume><issue>1</issue><spage>252</spage><epage>261</epage><pages>252-261</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The orally bioavailable rapamycin derivative RAD001 (everolimus) targets the mammalian target of rapamycin pathway and possesses potent immunosuppressive and anticancer activities. Here, the antitumor activity of RAD001 was evaluated in the CA20948 syngeneic rat pancreatic tumor model. RAD001 demonstrated dose-dependent antitumor activity with daily and weekly administration schedules; statistically significant antitumor effects were observed with 2.5 and 0.5 mg/kg RAD001 administered daily [treated tumor versus control tumor size (T/C), 23% and 23-30%, respectively], with 3-5 mg/kg RAD001 administered once weekly (T/C, 14-36%), or with 5 mg/kg RAD001 administered twice weekly (T/C, 36%). These schedules were well tolerated and exhibited antitumor potency similar to that of the cytotoxic agent 5-fluorouracil (T/C, 23%). Moreover, the efficacy of intermittent treatment schedules suggests a therapeutic window allowing differentiation of antitumor activity from the immunosuppressive properties of this agent. Detailed biochemical profiling of mammalian target of rapamycin signaling in tumors, skin, and peripheral blood mononuclear cells (PBMCs), after a single administration of 5 mg/kg RAD001, indicated that RAD001 treatment blocked phosphorylation of the translational repressor eukaryotic initiation factor 4E-binding protein 1 and inactivated the translational activator ribosomal protein S6 kinase 1 (S6K1). The efficacy of intermittent treatment schedules was associated with prolonged inactivation of S6K1 in tumors and surrogate tissues (> or =72 h). Furthermore, detailed analysis of the dose dependency of weekly treatment schedules demonstrated a correlation between antitumor efficacy and prolonged effects (> or =7 days) on PBMC-derived S6K1 activity. Analysis of human PBMCs revealed that S6K1 also underwent a concentration-dependent inactivation after RAD001 treatment ex vivo (>95% inactivation with 20 nM RAD001). In contrast, human PBMC-derived eukaryotic initiation factor 4E-binding protein 1 was present predominantly in the hypophosphorylated form and was unaffected by RAD001 treatment. Taken together, these results demonstrate a correlation between the antitumor efficacy of intermittent RAD001 treatment schedules and prolonged S6K1 inactivation in PBMCs and suggest that long-term monitoring of PBMC-derived S6K1 activity levels could be used for assessing RAD001 treatment schedules in cancer patients.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>14729632</pmid><doi>10.1158/0008-5472.CAN-3554-2</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antineoplastic agents Biological and medical sciences Disease Models, Animal Dose-Response Relationship, Drug Drug Administration Schedule Drug Monitoring - methods Everolimus Humans Immunosuppressive Agents - administration & dosage Immunosuppressive Agents - therapeutic use Leukocytes, Mononuclear - enzymology Male MAP Kinase Signaling System - drug effects Medical sciences Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - enzymology Pancreatic Neoplasms - immunology Pharmacology. Drug treatments Rats Rats, Inbred Lew Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors Ribosomal Protein S6 Kinases, 90-kDa - blood Sirolimus - administration & dosage Sirolimus - analogs & derivatives Sirolimus - therapeutic use Time Factors Tumor Cells, Cultured Tumors |
title | Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells |
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