A phase II trial of biochemical modulation using N‐ phosphonacetyl‐L‐aspartate, high‐dose methotrexate, high‐dose 5‐fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site
Background. 5‐Fluorouracil (5‐FU) has modest activity as a single agent in a number of human adenocarcinomas. The technique of biochemical modulation has been used preclinically to increase the activity of 5‐FU. Methods. With doses based on a Phase I study, the authors performed a Phase II trial in...
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| Veröffentlicht in: | Cancer 1992-10, Vol.70 (7), p.1988-1992 |
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| container_end_page | 1992 |
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| container_issue | 7 |
| container_start_page | 1988 |
| container_title | Cancer |
| container_volume | 70 |
| creator | Kelsen, David Martin, Daniel S. Colofiore, Joseph Sawyer, Robert Coif, Daniel |
| description | Background. 5‐Fluorouracil (5‐FU) has modest activity as a single agent in a number of human adenocarcinomas. The technique of biochemical modulation has been used preclinically to increase the activity of 5‐FU.
Methods. With doses based on a Phase I study, the authors performed a Phase II trial in patients with advanced metastatic adenocarcinoma of an unknown primary site using N‐phosphonacetyl‐I‐aspartate (PALA), methotrexate (MTX), 5‐FU, and leucovorin. In some patients, 5‐phosphoriosyl‐l‐pyrophosphate (PRPP) and uridine triphosphate (UTP) metabolite pools were assayed before and after PALA and MTX to assess metabolite pool shifts.
Results. Twenty‐one patients were treated in this Phase I1 trial. Toxicity was tolerable. Biopsy specimens of tumor tissue showed increases in PRPP and decreases in UTP levels in two of three and three of four patients, respectively. However, only one objective response was seen, which is not different from that expected with 5‐FU alone.
Conclusions. Expected PRPP and UTP metabolite pool shifts were seen when biochemical modulation was performed with these drugs according to this schedule. Because toxicity was mild, more intense dose schedules of 5‐FU are planned for future studies. Cancer 1992; 70:1988–1992. |
| doi_str_mv | 10.1002/1097-0142(19921001)70:7<1988::AID-CNCR2820700730>3.0.CO;2-K |
| format | Article |
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Methods. With doses based on a Phase I study, the authors performed a Phase II trial in patients with advanced metastatic adenocarcinoma of an unknown primary site using N‐phosphonacetyl‐I‐aspartate (PALA), methotrexate (MTX), 5‐FU, and leucovorin. In some patients, 5‐phosphoriosyl‐l‐pyrophosphate (PRPP) and uridine triphosphate (UTP) metabolite pools were assayed before and after PALA and MTX to assess metabolite pool shifts.
Results. Twenty‐one patients were treated in this Phase I1 trial. Toxicity was tolerable. Biopsy specimens of tumor tissue showed increases in PRPP and decreases in UTP levels in two of three and three of four patients, respectively. However, only one objective response was seen, which is not different from that expected with 5‐FU alone.
Conclusions. Expected PRPP and UTP metabolite pool shifts were seen when biochemical modulation was performed with these drugs according to this schedule. Because toxicity was mild, more intense dose schedules of 5‐FU are planned for future studies. Cancer 1992; 70:1988–1992.</description><identifier>ISSN: 0008-543X</identifier><identifier>EISSN: 1097-0142</identifier><identifier>DOI: 10.1002/1097-0142(19921001)70:7<1988::AID-CNCR2820700730>3.0.CO;2-K</identifier><identifier>PMID: 1381991</identifier><identifier>CODEN: CANCAR</identifier><language>eng</language><publisher>New York: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject><![CDATA[5‐fluoroura‐cil ; Adenocarcinoma - drug therapy ; Adenocarcinoma - metabolism ; Adenocarcinoma - secondary ; adenocarcinoma of unknown primary site ; Adult ; Antimetabolites, Antineoplastic - administration & dosage ; Antineoplastic agents ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Aspartic Acid - administration & dosage ; Aspartic Acid - analogs & derivatives ; biochemical modulation ; Biological and medical sciences ; Chemotherapy ; Drug Evaluation ; Female ; Fluorouracil - administration & dosage ; Humans ; Leucovorin - administration & dosage ; Life Sciences & Biomedicine ; Male ; Medical sciences ; Methotrexate - administration & dosage ; Middle Aged ; Neoplasms, Unknown Primary - drug therapy ; Neoplasms, Unknown Primary - metabolism ; Oncology ; PALA ; Pharmacology. Drug treatments ; Phosphonoacetic Acid - administration & dosage ; Phosphonoacetic Acid - analogs & derivatives ; Phosphoribosyl Pyrophosphate - metabolism ; Science & Technology ; Uridine Triphosphate - metabolism]]></subject><ispartof>Cancer, 1992-10, Vol.70 (7), p.1988-1992</ispartof><rights>Copyright © 1992 American Cancer Society</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>8</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wosA1992JP69200029</woscitedreferencesoriginalsourcerecordid><cites>FETCH-LOGICAL-c4980-7bc30615a07d9087ca78e9e1959b510fce6e4b2503d8f835db79f1ea590580523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27201,27933,27934</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4888008$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1381991$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kelsen, David</creatorcontrib><creatorcontrib>Martin, Daniel S.</creatorcontrib><creatorcontrib>Colofiore, Joseph</creatorcontrib><creatorcontrib>Sawyer, Robert</creatorcontrib><creatorcontrib>Coif, Daniel</creatorcontrib><title>A phase II trial of biochemical modulation using N‐ phosphonacetyl‐L‐aspartate, high‐dose methotrexate, high‐dose 5‐fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site</title><title>Cancer</title><addtitle>CANCER</addtitle><addtitle>Cancer</addtitle><description>Background. 5‐Fluorouracil (5‐FU) has modest activity as a single agent in a number of human adenocarcinomas. The technique of biochemical modulation has been used preclinically to increase the activity of 5‐FU.
Methods. With doses based on a Phase I study, the authors performed a Phase II trial in patients with advanced metastatic adenocarcinoma of an unknown primary site using N‐phosphonacetyl‐I‐aspartate (PALA), methotrexate (MTX), 5‐FU, and leucovorin. In some patients, 5‐phosphoriosyl‐l‐pyrophosphate (PRPP) and uridine triphosphate (UTP) metabolite pools were assayed before and after PALA and MTX to assess metabolite pool shifts.
Results. Twenty‐one patients were treated in this Phase I1 trial. Toxicity was tolerable. Biopsy specimens of tumor tissue showed increases in PRPP and decreases in UTP levels in two of three and three of four patients, respectively. However, only one objective response was seen, which is not different from that expected with 5‐FU alone.
Conclusions. Expected PRPP and UTP metabolite pool shifts were seen when biochemical modulation was performed with these drugs according to this schedule. Because toxicity was mild, more intense dose schedules of 5‐FU are planned for future studies. Cancer 1992; 70:1988–1992.</description><subject>5‐fluoroura‐cil</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - secondary</subject><subject>adenocarcinoma of unknown primary site</subject><subject>Adult</subject><subject>Antimetabolites, Antineoplastic - administration & dosage</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Aspartic Acid - administration & dosage</subject><subject>Aspartic Acid - analogs & derivatives</subject><subject>biochemical modulation</subject><subject>Biological and medical sciences</subject><subject>Chemotherapy</subject><subject>Drug Evaluation</subject><subject>Female</subject><subject>Fluorouracil - administration & dosage</subject><subject>Humans</subject><subject>Leucovorin - administration & dosage</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Methotrexate - administration & dosage</subject><subject>Middle Aged</subject><subject>Neoplasms, Unknown Primary - drug therapy</subject><subject>Neoplasms, Unknown Primary - metabolism</subject><subject>Oncology</subject><subject>PALA</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphonoacetic Acid - administration & dosage</subject><subject>Phosphonoacetic Acid - analogs & derivatives</subject><subject>Phosphoribosyl Pyrophosphate - metabolism</subject><subject>Science & Technology</subject><subject>Uridine Triphosphate - metabolism</subject><issn>0008-543X</issn><issn>1097-0142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EZCTM</sourceid><sourceid>EIF</sourceid><recordid>eNqVkt-K1DAUxoso67r6CEIuvFDcjifpdJKMIgz137jDjoiC4EVI03Qn2iZDkzrOnY_gw_kEPompM46oIAoJac75ztfD-SVJCgwjDEDuYeA0BTwmtzHnJIbwHQpT-gBzxqbT2fxRWpwXLwkjQAFoBg-zEYyK5X2Snl1Kjg_Vl5NjAGBpPs7eXE2uef8uXinJs6PkCGcseuPj5MsMrVfSazSfo9AZ2SBXo9I4tdKtUfHauqpvZDDOot4be4HOv376HGucj9tKpcO2iZFF3NKvZRdk0KdoZS5WMVK56NzqsHKh0x__yOTxo25617m-k8o0p0jaCjW6V-6D64xFca3jv7UNHm1MWCFZaeuU7JSxrpVDr719b90m6jrTym6LvAn6enKllo3XN_bnSfL6yeNXxbN0sXw6L2aLVI05g5SWKoMJziXQigOjSlKmucY852WOoVZ6osclySGrWM2yvCopr7GWOYecQU6yk-Ttzld1zvtO12LfhcAgBpRigCEGGOIHSkFBUDGgFCKiFL-iFJkAUSwFEWfR_ebOfd2Xra5-eu_YxfytfV76SKrupFXGH2RjxljEH2V3d7KNLl3tVZym0gfVbOjr-YsJJ_FxEB7V7N_VhQnfX0bhehtiab0vNY3e_t8o_jqJ3zLZN6O79Jo</recordid><startdate>19921001</startdate><enddate>19921001</enddate><creator>Kelsen, David</creator><creator>Martin, Daniel S.</creator><creator>Colofiore, Joseph</creator><creator>Sawyer, Robert</creator><creator>Coif, Daniel</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>Wiley-Liss</general><scope>BLEPL</scope><scope>DTL</scope><scope>EZCTM</scope><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></search><sort><creationdate>19921001</creationdate><title>A phase II trial of biochemical modulation using N‐ phosphonacetyl‐L‐aspartate, high‐dose methotrexate, high‐dose 5‐fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site</title><author>Kelsen, David ; Martin, Daniel S. ; Colofiore, Joseph ; Sawyer, Robert ; Coif, Daniel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4980-7bc30615a07d9087ca78e9e1959b510fce6e4b2503d8f835db79f1ea590580523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>5‐fluoroura‐cil</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - metabolism</topic><topic>Adenocarcinoma - secondary</topic><topic>adenocarcinoma of unknown primary site</topic><topic>Adult</topic><topic>Antimetabolites, Antineoplastic - administration & dosage</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Aspartic Acid - administration & dosage</topic><topic>Aspartic Acid - analogs & derivatives</topic><topic>biochemical modulation</topic><topic>Biological and medical sciences</topic><topic>Chemotherapy</topic><topic>Drug Evaluation</topic><topic>Female</topic><topic>Fluorouracil - administration & dosage</topic><topic>Humans</topic><topic>Leucovorin - administration & dosage</topic><topic>Life Sciences & Biomedicine</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Methotrexate - administration & dosage</topic><topic>Middle Aged</topic><topic>Neoplasms, Unknown Primary - drug therapy</topic><topic>Neoplasms, Unknown Primary - metabolism</topic><topic>Oncology</topic><topic>PALA</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphonoacetic Acid - administration & dosage</topic><topic>Phosphonoacetic Acid - analogs & derivatives</topic><topic>Phosphoribosyl Pyrophosphate - metabolism</topic><topic>Science & Technology</topic><topic>Uridine Triphosphate - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kelsen, David</creatorcontrib><creatorcontrib>Martin, Daniel S.</creatorcontrib><creatorcontrib>Colofiore, Joseph</creatorcontrib><creatorcontrib>Sawyer, Robert</creatorcontrib><creatorcontrib>Coif, Daniel</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 1992</collection><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><jtitle>Cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kelsen, David</au><au>Martin, Daniel S.</au><au>Colofiore, Joseph</au><au>Sawyer, Robert</au><au>Coif, Daniel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase II trial of biochemical modulation using N‐ phosphonacetyl‐L‐aspartate, high‐dose methotrexate, high‐dose 5‐fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site</atitle><jtitle>Cancer</jtitle><stitle>CANCER</stitle><addtitle>Cancer</addtitle><date>1992-10-01</date><risdate>1992</risdate><volume>70</volume><issue>7</issue><spage>1988</spage><epage>1992</epage><pages>1988-1992</pages><issn>0008-543X</issn><eissn>1097-0142</eissn><coden>CANCAR</coden><abstract>Background. 5‐Fluorouracil (5‐FU) has modest activity as a single agent in a number of human adenocarcinomas. The technique of biochemical modulation has been used preclinically to increase the activity of 5‐FU.
Methods. With doses based on a Phase I study, the authors performed a Phase II trial in patients with advanced metastatic adenocarcinoma of an unknown primary site using N‐phosphonacetyl‐I‐aspartate (PALA), methotrexate (MTX), 5‐FU, and leucovorin. In some patients, 5‐phosphoriosyl‐l‐pyrophosphate (PRPP) and uridine triphosphate (UTP) metabolite pools were assayed before and after PALA and MTX to assess metabolite pool shifts.
Results. Twenty‐one patients were treated in this Phase I1 trial. Toxicity was tolerable. Biopsy specimens of tumor tissue showed increases in PRPP and decreases in UTP levels in two of three and three of four patients, respectively. However, only one objective response was seen, which is not different from that expected with 5‐FU alone.
Conclusions. Expected PRPP and UTP metabolite pool shifts were seen when biochemical modulation was performed with these drugs according to this schedule. Because toxicity was mild, more intense dose schedules of 5‐FU are planned for future studies. Cancer 1992; 70:1988–1992.</abstract><cop>New York</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>1381991</pmid><doi>10.1002/1097-0142(19921001)70:7<1988::AID-CNCR2820700730>3.0.CO;2-K</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer, 1992-10, Vol.70 (7), p.1988-1992 |
| issn | 0008-543X 1097-0142 |
| language | eng |
| recordid | cdi_webofscience_primary_A1992JP69200029 |
| source | Web of Science - Science Citation Index Expanded - 1992<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; MEDLINE; Alma/SFX Local Collection |
| subjects | 5‐fluoroura‐cil Adenocarcinoma - drug therapy Adenocarcinoma - metabolism Adenocarcinoma - secondary adenocarcinoma of unknown primary site Adult Antimetabolites, Antineoplastic - administration & dosage Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - therapeutic use Aspartic Acid - administration & dosage Aspartic Acid - analogs & derivatives biochemical modulation Biological and medical sciences Chemotherapy Drug Evaluation Female Fluorouracil - administration & dosage Humans Leucovorin - administration & dosage Life Sciences & Biomedicine Male Medical sciences Methotrexate - administration & dosage Middle Aged Neoplasms, Unknown Primary - drug therapy Neoplasms, Unknown Primary - metabolism Oncology PALA Pharmacology. Drug treatments Phosphonoacetic Acid - administration & dosage Phosphonoacetic Acid - analogs & derivatives Phosphoribosyl Pyrophosphate - metabolism Science & Technology Uridine Triphosphate - metabolism |
| title | A phase II trial of biochemical modulation using N‐ phosphonacetyl‐L‐aspartate, high‐dose methotrexate, high‐dose 5‐fluorouracil, and leucovorin in patients with adenocarcinoma of unknown primary site |
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