A Prostate-specific Antigen (PSA)-activated Vinblastine Prodrug Selectively Kills PSA-secreting Cells in Vivo
Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains a peptide bo...
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| Veröffentlicht in: | Molecular cancer therapeutics 2002-05, Vol.1 (7), p.451 |
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| creator | DeFeo-Jones, Deborah Brady, Stephen F Feng, Dong-Mei Wong, Bradly K Bolyar, Trina Haskell, Kathleen Kiefer, David M Leander, Karen McAvoy, Elizabeth Lumma, Patricia Pawluczyk, Joseph M Wai, Jenny Motzel, Sherri L Keenan, Kevin Van Zwieten, Matthew Lin, Jiunn H Garsky, Victor M Freidinger, Roger Oliff, Allen Jones, Raymond E |
| description | Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This
report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains
a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate)
is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed,
generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that
were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing
PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate
showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate
is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight
after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted
with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic
metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10–70% mortality with a very slight effect
on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy,
very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment
of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable
vinblastine-conjugate as an experimental therapy for prostate cancer in man. |
| format | Article |
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report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains
a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate)
is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed,
generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that
were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing
PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate
showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate
is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight
after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted
with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic
metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10–70% mortality with a very slight effect
on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy,
very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment
of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable
vinblastine-conjugate as an experimental therapy for prostate cancer in man.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>PMID: 12479263</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic Agents - therapeutic use ; Antineoplastic Agents, Phytogenic - metabolism ; Antineoplastic Agents, Phytogenic - therapeutic use ; Dogs ; Doxorubicin - therapeutic use ; Humans ; Male ; Mice ; Mice, Nude ; Models, Chemical ; Neoplasm Transplantation ; Prodrugs - metabolism ; Prodrugs - therapeutic use ; Prostate-Specific Antigen - metabolism ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - therapy ; Species Specificity ; Tissue Distribution ; Tumor Cells, Cultured ; Vinblastine - metabolism ; Vinblastine - therapeutic use</subject><ispartof>Molecular cancer therapeutics, 2002-05, Vol.1 (7), p.451</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12479263$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DeFeo-Jones, Deborah</creatorcontrib><creatorcontrib>Brady, Stephen F</creatorcontrib><creatorcontrib>Feng, Dong-Mei</creatorcontrib><creatorcontrib>Wong, Bradly K</creatorcontrib><creatorcontrib>Bolyar, Trina</creatorcontrib><creatorcontrib>Haskell, Kathleen</creatorcontrib><creatorcontrib>Kiefer, David M</creatorcontrib><creatorcontrib>Leander, Karen</creatorcontrib><creatorcontrib>McAvoy, Elizabeth</creatorcontrib><creatorcontrib>Lumma, Patricia</creatorcontrib><creatorcontrib>Pawluczyk, Joseph M</creatorcontrib><creatorcontrib>Wai, Jenny</creatorcontrib><creatorcontrib>Motzel, Sherri L</creatorcontrib><creatorcontrib>Keenan, Kevin</creatorcontrib><creatorcontrib>Van Zwieten, Matthew</creatorcontrib><creatorcontrib>Lin, Jiunn H</creatorcontrib><creatorcontrib>Garsky, Victor M</creatorcontrib><creatorcontrib>Freidinger, Roger</creatorcontrib><creatorcontrib>Oliff, Allen</creatorcontrib><creatorcontrib>Jones, Raymond E</creatorcontrib><title>A Prostate-specific Antigen (PSA)-activated Vinblastine Prodrug Selectively Kills PSA-secreting Cells in Vivo</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This
report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains
a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate)
is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed,
generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that
were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing
PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate
showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate
is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight
after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted
with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic
metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10–70% mortality with a very slight effect
on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy,
very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment
of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable
vinblastine-conjugate as an experimental therapy for prostate cancer in man.</description><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antineoplastic Agents, Phytogenic - metabolism</subject><subject>Antineoplastic Agents, Phytogenic - therapeutic use</subject><subject>Dogs</subject><subject>Doxorubicin - therapeutic use</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Models, Chemical</subject><subject>Neoplasm Transplantation</subject><subject>Prodrugs - metabolism</subject><subject>Prodrugs - therapeutic use</subject><subject>Prostate-Specific Antigen - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Prostatic Neoplasms - therapy</subject><subject>Species Specificity</subject><subject>Tissue Distribution</subject><subject>Tumor Cells, Cultured</subject><subject>Vinblastine - metabolism</subject><subject>Vinblastine - therapeutic use</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1j11LwzAUhoMobk7_guRK9CKQj-ajl2XoFAcOpt6WLDltI103km6yf2_n9Ooc3vM8L5wzNGZSGGIky85_d0k0U2KErlL6opSZnLNLNGI80zlXYozWBV7ETeptDyRtwYUqOFx0faihw_eLZfFArOvDfrh7_Bm6VWtTHzo4Wj7uaryEFo4AtAf8Gto24UEiCVyEgavxFI5Z6AZ5v7lGF5VtE9z8zQn6eHp8nz6T-dvsZVrMScMz2hPlLaPaVN6AlNpaXimvhKPSMGm4cnqVZ8xmSjtVUeqd8LLiOZXUG58rK8UE3Z56t7vVGny5jWFt46H8_3sA7k5AE-rmO0Qone0cxAgJbHRNyUpdZpKJHyA2Ysk</recordid><startdate>20020501</startdate><enddate>20020501</enddate><creator>DeFeo-Jones, Deborah</creator><creator>Brady, Stephen F</creator><creator>Feng, Dong-Mei</creator><creator>Wong, Bradly K</creator><creator>Bolyar, Trina</creator><creator>Haskell, Kathleen</creator><creator>Kiefer, David M</creator><creator>Leander, Karen</creator><creator>McAvoy, Elizabeth</creator><creator>Lumma, Patricia</creator><creator>Pawluczyk, Joseph M</creator><creator>Wai, Jenny</creator><creator>Motzel, Sherri L</creator><creator>Keenan, Kevin</creator><creator>Van Zwieten, Matthew</creator><creator>Lin, Jiunn H</creator><creator>Garsky, Victor M</creator><creator>Freidinger, Roger</creator><creator>Oliff, Allen</creator><creator>Jones, Raymond E</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20020501</creationdate><title>A Prostate-specific Antigen (PSA)-activated Vinblastine Prodrug Selectively Kills PSA-secreting Cells in Vivo</title><author>DeFeo-Jones, Deborah ; Brady, Stephen F ; Feng, Dong-Mei ; Wong, Bradly K ; Bolyar, Trina ; Haskell, Kathleen ; Kiefer, David M ; Leander, Karen ; McAvoy, Elizabeth ; Lumma, Patricia ; Pawluczyk, Joseph M ; Wai, Jenny ; Motzel, Sherri L ; Keenan, Kevin ; Van Zwieten, Matthew ; Lin, Jiunn H ; Garsky, Victor M ; Freidinger, Roger ; Oliff, Allen ; Jones, Raymond E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h240t-6da1078fd8e557aa2f6d63c05815826c7b941a467c6f00dc3d5f29050d8d96a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Antineoplastic Agents, Phytogenic - metabolism</topic><topic>Antineoplastic Agents, Phytogenic - therapeutic use</topic><topic>Dogs</topic><topic>Doxorubicin - therapeutic use</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Models, Chemical</topic><topic>Neoplasm Transplantation</topic><topic>Prodrugs - metabolism</topic><topic>Prodrugs - therapeutic use</topic><topic>Prostate-Specific Antigen - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Prostatic Neoplasms - therapy</topic><topic>Species Specificity</topic><topic>Tissue Distribution</topic><topic>Tumor Cells, Cultured</topic><topic>Vinblastine - metabolism</topic><topic>Vinblastine - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DeFeo-Jones, Deborah</creatorcontrib><creatorcontrib>Brady, Stephen F</creatorcontrib><creatorcontrib>Feng, Dong-Mei</creatorcontrib><creatorcontrib>Wong, Bradly K</creatorcontrib><creatorcontrib>Bolyar, Trina</creatorcontrib><creatorcontrib>Haskell, Kathleen</creatorcontrib><creatorcontrib>Kiefer, David M</creatorcontrib><creatorcontrib>Leander, Karen</creatorcontrib><creatorcontrib>McAvoy, Elizabeth</creatorcontrib><creatorcontrib>Lumma, Patricia</creatorcontrib><creatorcontrib>Pawluczyk, Joseph M</creatorcontrib><creatorcontrib>Wai, Jenny</creatorcontrib><creatorcontrib>Motzel, Sherri L</creatorcontrib><creatorcontrib>Keenan, Kevin</creatorcontrib><creatorcontrib>Van Zwieten, Matthew</creatorcontrib><creatorcontrib>Lin, Jiunn H</creatorcontrib><creatorcontrib>Garsky, Victor M</creatorcontrib><creatorcontrib>Freidinger, Roger</creatorcontrib><creatorcontrib>Oliff, Allen</creatorcontrib><creatorcontrib>Jones, Raymond E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DeFeo-Jones, Deborah</au><au>Brady, Stephen F</au><au>Feng, Dong-Mei</au><au>Wong, Bradly K</au><au>Bolyar, Trina</au><au>Haskell, Kathleen</au><au>Kiefer, David M</au><au>Leander, Karen</au><au>McAvoy, Elizabeth</au><au>Lumma, Patricia</au><au>Pawluczyk, Joseph M</au><au>Wai, Jenny</au><au>Motzel, Sherri L</au><au>Keenan, Kevin</au><au>Van Zwieten, Matthew</au><au>Lin, Jiunn H</au><au>Garsky, Victor M</au><au>Freidinger, Roger</au><au>Oliff, Allen</au><au>Jones, Raymond E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Prostate-specific Antigen (PSA)-activated Vinblastine Prodrug Selectively Kills PSA-secreting Cells in Vivo</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2002-05-01</date><risdate>2002</risdate><volume>1</volume><issue>7</issue><spage>451</spage><pages>451-</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This
report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains
a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate)
is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed,
generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that
were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing
PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate
showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate
is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight
after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted
with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic
metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10–70% mortality with a very slight effect
on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy,
very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment
of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable
vinblastine-conjugate as an experimental therapy for prostate cancer in man.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>12479263</pmid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1535-7163 |
| ispartof | Molecular cancer therapeutics, 2002-05, Vol.1 (7), p.451 |
| issn | 1535-7163 1538-8514 |
| language | eng |
| recordid | cdi_pubmed_primary_12479263 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antineoplastic Agents - therapeutic use Antineoplastic Agents, Phytogenic - metabolism Antineoplastic Agents, Phytogenic - therapeutic use Dogs Doxorubicin - therapeutic use Humans Male Mice Mice, Nude Models, Chemical Neoplasm Transplantation Prodrugs - metabolism Prodrugs - therapeutic use Prostate-Specific Antigen - metabolism Prostatic Neoplasms - pathology Prostatic Neoplasms - therapy Species Specificity Tissue Distribution Tumor Cells, Cultured Vinblastine - metabolism Vinblastine - therapeutic use |
| title | A Prostate-specific Antigen (PSA)-activated Vinblastine Prodrug Selectively Kills PSA-secreting Cells in Vivo |
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