The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide)
The influence of L-cystein on the toxic and therapeutic responses of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated" cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosph...
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| Veröffentlicht in: | Investigational new drugs 1984-01, Vol.2 (2), p.253-259 |
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| creator | Voelcker, G Laber, P Rockinger, H Wientzek, C Hohorst, H J |
| description | The influence of L-cystein on the toxic and therapeutic responses of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated" cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein. Simultaneous application of double molar amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic activity is not affected by this ratio of L-cystein so that the protector thiol increases the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity in nude mice and the therapeutic efficacy against the human xenograft. The perfusion experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing limb is only tolerated in combination with L-cystein. |
| doi_str_mv | 10.1007/BF00232360 |
| format | Article |
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Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein. Simultaneous application of double molar amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic activity is not affected by this ratio of L-cystein so that the protector thiol increases the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity in nude mice and the therapeutic efficacy against the human xenograft. The perfusion experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing limb is only tolerated in combination with L-cystein.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/BF00232360</identifier><identifier>PMID: 6469518</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Chemotherapy, Cancer, Regional Perfusion ; Cyclophosphamide - administration & dosage ; Cyclophosphamide - analogs & derivatives ; Cyclophosphamide - therapeutic use ; Cyclophosphamide - toxicity ; Cysteine ; Female ; Humans ; Lethal Dose 50 ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Rats ; Rats, Inbred Strains ; Sarcoma, Yoshida - drug therapy ; Structure-Activity Relationship ; Transplantation, Heterologous ; Urinary Bladder Neoplasms - drug therapy</subject><ispartof>Investigational new drugs, 1984-01, Vol.2 (2), p.253-259</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c282t-9b5e694170d8f768cf0aea0f4be1780d6793c1cfdbc915fdafd0e738ec33b3f63</citedby><cites>FETCH-LOGICAL-c282t-9b5e694170d8f768cf0aea0f4be1780d6793c1cfdbc915fdafd0e738ec33b3f63</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/6469518$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Voelcker, G</creatorcontrib><creatorcontrib>Laber, P</creatorcontrib><creatorcontrib>Rockinger, H</creatorcontrib><creatorcontrib>Wientzek, C</creatorcontrib><creatorcontrib>Hohorst, H J</creatorcontrib><title>The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide)</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><description>The influence of L-cystein on the toxic and therapeutic responses of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated" cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein. Simultaneous application of double molar amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic activity is not affected by this ratio of L-cystein so that the protector thiol increases the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity in nude mice and the therapeutic efficacy against the human xenograft. The perfusion experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing limb is only tolerated in combination with L-cystein.</description><subject>Animals</subject><subject>Chemotherapy, Cancer, Regional Perfusion</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>Cyclophosphamide - analogs & derivatives</subject><subject>Cyclophosphamide - therapeutic use</subject><subject>Cyclophosphamide - toxicity</subject><subject>Cysteine</subject><subject>Female</subject><subject>Humans</subject><subject>Lethal Dose 50</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasm Transplantation</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Sarcoma, Yoshida - drug therapy</subject><subject>Structure-Activity Relationship</subject><subject>Transplantation, Heterologous</subject><subject>Urinary Bladder Neoplasms - drug therapy</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1984</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkE1LAzEQhoMotVYv3oXgqRWik2ab7B5V_ALBg3pessmERrabZZOK9R_5L93aouBpeGYeXoaXkGMO5xxAXVzdAkzFVEjYIUM-U4KBzOQuGQKXismiUPvkIMY3ABCFygZk0J-LGc-H5OtljtQ3rl5iY5AGR1O_aLuQ0KTQ9eRDTR-ZWcWEvqGh-RFS-PCG6sauqdMtLlPPHcY2NBHjOicmXfnaf6Klp9ok_64T2lNqVqYO7TzEdq4X3iIdZ2z8zDDNdRPqCYvL2nkb2H9vckj2nK4jHm3niLze3rxc37PHp7uH68v-xWk-TayoZiiLjCuwuVMyNw40anBZhVzlYKUqhOHG2coUfOasdhZQiRyNEJVwUozI2SbXdCHGDl3Zdn6hu1XJoVzXXf7V3csnG7ldVgu0v-q2X_ENcmt-gA</recordid><startdate>19840101</startdate><enddate>19840101</enddate><creator>Voelcker, G</creator><creator>Laber, P</creator><creator>Rockinger, H</creator><creator>Wientzek, C</creator><creator>Hohorst, H J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>19840101</creationdate><title>The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide)</title><author>Voelcker, G ; Laber, P ; Rockinger, H ; Wientzek, C ; Hohorst, H J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c282t-9b5e694170d8f768cf0aea0f4be1780d6793c1cfdbc915fdafd0e738ec33b3f63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1984</creationdate><topic>Animals</topic><topic>Chemotherapy, Cancer, Regional Perfusion</topic><topic>Cyclophosphamide - administration & dosage</topic><topic>Cyclophosphamide - analogs & derivatives</topic><topic>Cyclophosphamide - therapeutic use</topic><topic>Cyclophosphamide - toxicity</topic><topic>Cysteine</topic><topic>Female</topic><topic>Humans</topic><topic>Lethal Dose 50</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Transplantation</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Sarcoma, Yoshida - drug therapy</topic><topic>Structure-Activity Relationship</topic><topic>Transplantation, Heterologous</topic><topic>Urinary Bladder Neoplasms - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Voelcker, G</creatorcontrib><creatorcontrib>Laber, P</creatorcontrib><creatorcontrib>Rockinger, H</creatorcontrib><creatorcontrib>Wientzek, C</creatorcontrib><creatorcontrib>Hohorst, H J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Voelcker, G</au><au>Laber, P</au><au>Rockinger, H</au><au>Wientzek, C</au><au>Hohorst, H J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide)</atitle><jtitle>Investigational new drugs</jtitle><addtitle>Invest New Drugs</addtitle><date>1984-01-01</date><risdate>1984</risdate><volume>2</volume><issue>2</issue><spage>253</spage><epage>259</epage><pages>253-259</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>The influence of L-cystein on the toxic and therapeutic responses of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated" cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein. Simultaneous application of double molar amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic activity is not affected by this ratio of L-cystein so that the protector thiol increases the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity in nude mice and the therapeutic efficacy against the human xenograft. The perfusion experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing limb is only tolerated in combination with L-cystein.</abstract><cop>United States</cop><pmid>6469518</pmid><doi>10.1007/BF00232360</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0167-6997 |
| ispartof | Investigational new drugs, 1984-01, Vol.2 (2), p.253-259 |
| issn | 0167-6997 1573-0646 |
| language | eng |
| recordid | cdi_crossref_primary_10_1007_BF00232360 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Animals Chemotherapy, Cancer, Regional Perfusion Cyclophosphamide - administration & dosage Cyclophosphamide - analogs & derivatives Cyclophosphamide - therapeutic use Cyclophosphamide - toxicity Cysteine Female Humans Lethal Dose 50 Male Mice Mice, Nude Neoplasm Transplantation Rats Rats, Inbred Strains Sarcoma, Yoshida - drug therapy Structure-Activity Relationship Transplantation, Heterologous Urinary Bladder Neoplasms - drug therapy |
| title | The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide) |
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