Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin
Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resu...
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| Veröffentlicht in: | Anti-cancer drugs 2012-02, Vol.23 (2), p.173-184 |
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| creator | Jones, Barry Komarnitsky, Philip Miller, Glenn T Amedio, John Wallner, Barbara P |
| description | Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague–Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P |
| doi_str_mv | 10.1097/CAD.0b013e32834d73a6 |
| format | Article |
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Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague–Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48–73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62–75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.</description><identifier>ISSN: 0959-4973</identifier><identifier>EISSN: 1473-5741</identifier><identifier>DOI: 10.1097/CAD.0b013e32834d73a6</identifier><identifier>PMID: 22027537</identifier><language>eng</language><publisher>England: Lippincott Williams & Wilkins, Inc</publisher><subject><![CDATA[Administration, Oral ; Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological Availability ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Doxorubicin - administration & dosage ; Doxorubicin - therapeutic use ; Drug Administration Schedule ; Female ; Ifosfamide - administration & dosage ; Ifosfamide - analogs & derivatives ; Ifosfamide - pharmacokinetics ; Ifosfamide - therapeutic use ; Injections, Intravenous ; Leukemia, Experimental - drug therapy ; Lysine - administration & dosage ; Lysine - analogs & derivatives ; Lysine - pharmacokinetics ; Lysine - therapeutic use ; Male ; Mammary Neoplasms, Experimental - drug therapy ; Mice ; Mice, Nude ; Phosphoramide Mustards - administration & dosage ; Phosphoramide Mustards - pharmacokinetics ; Phosphoramide Mustards - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Taxoids - administration & dosage ; Taxoids - therapeutic use ; Xenograft Model Antitumor Assays]]></subject><ispartof>Anti-cancer drugs, 2012-02, Vol.23 (2), p.173-184</ispartof><rights>2012 Lippincott Williams & Wilkins, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3366-decbfb02d38e0d201ae685908035619b09c4a8054dc1916cfd71a6039a51381c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22027537$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jones, Barry</creatorcontrib><creatorcontrib>Komarnitsky, Philip</creatorcontrib><creatorcontrib>Miller, Glenn T</creatorcontrib><creatorcontrib>Amedio, John</creatorcontrib><creatorcontrib>Wallner, Barbara P</creatorcontrib><title>Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin</title><title>Anti-cancer drugs</title><addtitle>Anticancer Drugs</addtitle><description>Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague–Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48–73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62–75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological Availability</subject><subject>Disease-Free Survival</subject><subject>Dose-Response Relationship, Drug</subject><subject>Doxorubicin - administration & dosage</subject><subject>Doxorubicin - therapeutic use</subject><subject>Drug Administration Schedule</subject><subject>Female</subject><subject>Ifosfamide - administration & dosage</subject><subject>Ifosfamide - analogs & derivatives</subject><subject>Ifosfamide - pharmacokinetics</subject><subject>Ifosfamide - therapeutic use</subject><subject>Injections, Intravenous</subject><subject>Leukemia, Experimental - drug therapy</subject><subject>Lysine - administration & dosage</subject><subject>Lysine - analogs & derivatives</subject><subject>Lysine - pharmacokinetics</subject><subject>Lysine - therapeutic use</subject><subject>Male</subject><subject>Mammary Neoplasms, Experimental - drug therapy</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Phosphoramide Mustards - administration & dosage</subject><subject>Phosphoramide Mustards - pharmacokinetics</subject><subject>Phosphoramide Mustards - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Taxoids - administration & dosage</subject><subject>Taxoids - therapeutic use</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0959-4973</issn><issn>1473-5741</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAURS0EotPCHyDkHZumPMdJHLMbDVCQKrGBdfRivygGTzzYzkyH_-B_STsFJBasnvR07r2Lw9gLAVcCtHq9Wb-9gh6EJFm2srJKYvOIrUSlZFGrSjxmK9C1Liqt5Bk7T-krACx_-ZSdlSWUqpZqxX6up-wMToYiR5Pd3uUjDwNPGXvn3Q-yfIfeDSENuHWWuJv43u3DG57MSHb2xGkYyOR0yUNEz3sXcI_O38fz8ZLjZDlN492E_TtxcHnkNhjKeEv-HrLhNsS5d8ZNz9iTAX2i5w_3gn15_-7z5kNx8-n642Z9Uxgpm6awZPqhh9LKlsCWIJCattbQgqwboXvQpsIW6soaoUVjBqsENiA11kK2wsgL9urUu4vh-0wpd1uXDHmPE4U5dboEpWtRqoWsTqSJIaVIQ7eLbovx2Ano7nx0i4_uXx9L7OXDwNxvyf4J_RawAO0JOASfKaZvfj5Q7EZCn8f_d_8CC42cIg</recordid><startdate>201202</startdate><enddate>201202</enddate><creator>Jones, Barry</creator><creator>Komarnitsky, Philip</creator><creator>Miller, Glenn T</creator><creator>Amedio, John</creator><creator>Wallner, Barbara P</creator><general>Lippincott Williams & Wilkins, Inc</general><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>7QO</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>201202</creationdate><title>Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin</title><author>Jones, Barry ; Komarnitsky, Philip ; Miller, Glenn T ; Amedio, John ; Wallner, Barbara P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3366-decbfb02d38e0d201ae685908035619b09c4a8054dc1916cfd71a6039a51381c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biological Availability</topic><topic>Disease-Free Survival</topic><topic>Dose-Response Relationship, Drug</topic><topic>Doxorubicin - administration & dosage</topic><topic>Doxorubicin - therapeutic use</topic><topic>Drug Administration Schedule</topic><topic>Female</topic><topic>Ifosfamide - administration & dosage</topic><topic>Ifosfamide - analogs & derivatives</topic><topic>Ifosfamide - pharmacokinetics</topic><topic>Ifosfamide - therapeutic use</topic><topic>Injections, Intravenous</topic><topic>Leukemia, Experimental - drug therapy</topic><topic>Lysine - administration & dosage</topic><topic>Lysine - analogs & derivatives</topic><topic>Lysine - pharmacokinetics</topic><topic>Lysine - therapeutic use</topic><topic>Male</topic><topic>Mammary Neoplasms, Experimental - drug therapy</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Phosphoramide Mustards - administration & dosage</topic><topic>Phosphoramide Mustards - pharmacokinetics</topic><topic>Phosphoramide Mustards - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Taxoids - administration & dosage</topic><topic>Taxoids - therapeutic use</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jones, Barry</creatorcontrib><creatorcontrib>Komarnitsky, Philip</creatorcontrib><creatorcontrib>Miller, Glenn T</creatorcontrib><creatorcontrib>Amedio, John</creatorcontrib><creatorcontrib>Wallner, Barbara P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Anti-cancer drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jones, Barry</au><au>Komarnitsky, Philip</au><au>Miller, Glenn T</au><au>Amedio, John</au><au>Wallner, Barbara P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin</atitle><jtitle>Anti-cancer drugs</jtitle><addtitle>Anticancer Drugs</addtitle><date>2012-02</date><risdate>2012</risdate><volume>23</volume><issue>2</issue><spage>173</spage><epage>184</epage><pages>173-184</pages><issn>0959-4973</issn><eissn>1473-5741</eissn><abstract>Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague–Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48–73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62–75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.</abstract><cop>England</cop><pub>Lippincott Williams & Wilkins, Inc</pub><pmid>22027537</pmid><doi>10.1097/CAD.0b013e32834d73a6</doi><tpages>12</tpages></addata></record> |
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| ispartof | Anti-cancer drugs, 2012-02, Vol.23 (2), p.173-184 |
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| subjects | Administration, Oral Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological Availability Disease-Free Survival Dose-Response Relationship, Drug Doxorubicin - administration & dosage Doxorubicin - therapeutic use Drug Administration Schedule Female Ifosfamide - administration & dosage Ifosfamide - analogs & derivatives Ifosfamide - pharmacokinetics Ifosfamide - therapeutic use Injections, Intravenous Leukemia, Experimental - drug therapy Lysine - administration & dosage Lysine - analogs & derivatives Lysine - pharmacokinetics Lysine - therapeutic use Male Mammary Neoplasms, Experimental - drug therapy Mice Mice, Nude Phosphoramide Mustards - administration & dosage Phosphoramide Mustards - pharmacokinetics Phosphoramide Mustards - therapeutic use Rats Rats, Sprague-Dawley Taxoids - administration & dosage Taxoids - therapeutic use Xenograft Model Antitumor Assays |
| title | Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin |
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