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Effect of very high-dose thymidine infusions on leukemia and lymphoma patients
The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leuke...
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Published in: | Cancer research (Chicago, Ill.) Ill.), 1984-05, Vol.44 (5), p.2203-2207 |
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creator | BLUMENREICH, M. S WOODCOCK, T. M ANDREEFF, M HIDDEMANN, W TING-CHAO CHOU VALE, K ÓHEHIR, M CLARKSON, B. D YOUNG, C. W |
description | The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leukemia or lymphoma with marrow and blood involvement, by prolonged infusions of dThd, at dosages of 90 to 240 g/sq m/day for 14 to 29 days. Mean plasma dThd concentration ranged from 3.8 to 5.5 mM. Cerebrospinal fluid levels were measured on three occasions and ranged from 2 to 23.5% of simultaneous plasma levels. Diarrhea was dose limiting in one patient. The other side effects included nausea and vomiting in all patients, hepatotoxicity in two patients, electrolyte imbalance in one, progression of a pericardial effusion to tamponade in one, and mild central nervous system toxicity in five. In all cases, this therapy produced bone marrow aplasia. One patient with acute lymphoblastic leukemia, refractory to prior treatment, achieved a complete remission which lasted for 16 weeks. Another patient with lymphoblastic lymphoma had a greater than 50% reduction in his mediastinal mass which lasted for less than 1 month. At multiple points during therapy, the bone marrow S-phase fraction was measured by flow cytometry and autoradiography. In five patients, the proportion of cells in S phase increased during the first few days of the infusion but then returned to base line, concomitant with an overall reduction in the number of bone marrow blasts. Cytoreduction was evaluated by the technique of W. Hiddemann, B. D. Clarkson, T. Buchener, M. R. Melamed, and M. Andreeff (Blood, 59: 216-225, 1982). The magnitude of tumor cell kill ranged from 0.7 to 3.6 logs of blasts/cu mm of bone marrow. The data demonstrate that dThd is able to induce a complete remission in a patient with acute leukemia previously refractory to treatment. However, because of the very large drug quantities, fluid volumes, and the prolonged course required to produce the necessary tumor cell kill, this treatment approach is too impractical to be used extensively. |
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S ; WOODCOCK, T. M ; ANDREEFF, M ; HIDDEMANN, W ; TING-CHAO CHOU ; VALE, K ; ÓHEHIR, M ; CLARKSON, B. D ; YOUNG, C. W</creator><creatorcontrib>BLUMENREICH, M. S ; WOODCOCK, T. M ; ANDREEFF, M ; HIDDEMANN, W ; TING-CHAO CHOU ; VALE, K ; ÓHEHIR, M ; CLARKSON, B. D ; YOUNG, C. W</creatorcontrib><description>The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leukemia or lymphoma with marrow and blood involvement, by prolonged infusions of dThd, at dosages of 90 to 240 g/sq m/day for 14 to 29 days. Mean plasma dThd concentration ranged from 3.8 to 5.5 mM. Cerebrospinal fluid levels were measured on three occasions and ranged from 2 to 23.5% of simultaneous plasma levels. Diarrhea was dose limiting in one patient. The other side effects included nausea and vomiting in all patients, hepatotoxicity in two patients, electrolyte imbalance in one, progression of a pericardial effusion to tamponade in one, and mild central nervous system toxicity in five. In all cases, this therapy produced bone marrow aplasia. One patient with acute lymphoblastic leukemia, refractory to prior treatment, achieved a complete remission which lasted for 16 weeks. Another patient with lymphoblastic lymphoma had a greater than 50% reduction in his mediastinal mass which lasted for less than 1 month. At multiple points during therapy, the bone marrow S-phase fraction was measured by flow cytometry and autoradiography. In five patients, the proportion of cells in S phase increased during the first few days of the infusion but then returned to base line, concomitant with an overall reduction in the number of bone marrow blasts. Cytoreduction was evaluated by the technique of W. Hiddemann, B. D. Clarkson, T. Buchener, M. R. Melamed, and M. Andreeff (Blood, 59: 216-225, 1982). The magnitude of tumor cell kill ranged from 0.7 to 3.6 logs of blasts/cu mm of bone marrow. The data demonstrate that dThd is able to induce a complete remission in a patient with acute leukemia previously refractory to treatment. However, because of the very large drug quantities, fluid volumes, and the prolonged course required to produce the necessary tumor cell kill, this treatment approach is too impractical to be used extensively.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 6713407</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adult ; Antineoplastic agents ; Biological and medical sciences ; Bone Marrow - drug effects ; Chemotherapy ; Female ; Flow Cytometry ; Humans ; Infusions, Parenteral ; Kinetics ; Leukemia - drug therapy ; Lymphoma - drug therapy ; Male ; Medical sciences ; Pharmacology. Drug treatments ; Thymidine - administration & dosage ; Thymidine - blood ; Thymidine - therapeutic use</subject><ispartof>Cancer research (Chicago, Ill.), 1984-05, Vol.44 (5), p.2203-2207</ispartof><rights>1985 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=8863910$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/6713407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>BLUMENREICH, M. S</creatorcontrib><creatorcontrib>WOODCOCK, T. M</creatorcontrib><creatorcontrib>ANDREEFF, M</creatorcontrib><creatorcontrib>HIDDEMANN, W</creatorcontrib><creatorcontrib>TING-CHAO CHOU</creatorcontrib><creatorcontrib>VALE, K</creatorcontrib><creatorcontrib>ÓHEHIR, M</creatorcontrib><creatorcontrib>CLARKSON, B. D</creatorcontrib><creatorcontrib>YOUNG, C. W</creatorcontrib><title>Effect of very high-dose thymidine infusions on leukemia and lymphoma patients</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leukemia or lymphoma with marrow and blood involvement, by prolonged infusions of dThd, at dosages of 90 to 240 g/sq m/day for 14 to 29 days. Mean plasma dThd concentration ranged from 3.8 to 5.5 mM. Cerebrospinal fluid levels were measured on three occasions and ranged from 2 to 23.5% of simultaneous plasma levels. Diarrhea was dose limiting in one patient. The other side effects included nausea and vomiting in all patients, hepatotoxicity in two patients, electrolyte imbalance in one, progression of a pericardial effusion to tamponade in one, and mild central nervous system toxicity in five. In all cases, this therapy produced bone marrow aplasia. One patient with acute lymphoblastic leukemia, refractory to prior treatment, achieved a complete remission which lasted for 16 weeks. Another patient with lymphoblastic lymphoma had a greater than 50% reduction in his mediastinal mass which lasted for less than 1 month. At multiple points during therapy, the bone marrow S-phase fraction was measured by flow cytometry and autoradiography. In five patients, the proportion of cells in S phase increased during the first few days of the infusion but then returned to base line, concomitant with an overall reduction in the number of bone marrow blasts. Cytoreduction was evaluated by the technique of W. Hiddemann, B. D. Clarkson, T. Buchener, M. R. Melamed, and M. Andreeff (Blood, 59: 216-225, 1982). The magnitude of tumor cell kill ranged from 0.7 to 3.6 logs of blasts/cu mm of bone marrow. The data demonstrate that dThd is able to induce a complete remission in a patient with acute leukemia previously refractory to treatment. However, because of the very large drug quantities, fluid volumes, and the prolonged course required to produce the necessary tumor cell kill, this treatment approach is too impractical to be used extensively.</description><subject>Adult</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Bone Marrow - drug effects</subject><subject>Chemotherapy</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Infusions, Parenteral</subject><subject>Kinetics</subject><subject>Leukemia - drug therapy</subject><subject>Lymphoma - drug therapy</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacology. 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D</creator><creator>YOUNG, C. W</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></search><sort><creationdate>19840501</creationdate><title>Effect of very high-dose thymidine infusions on leukemia and lymphoma patients</title><author>BLUMENREICH, M. S ; WOODCOCK, T. M ; ANDREEFF, M ; HIDDEMANN, W ; TING-CHAO CHOU ; VALE, K ; ÓHEHIR, M ; CLARKSON, B. D ; YOUNG, C. 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S</creatorcontrib><creatorcontrib>WOODCOCK, T. M</creatorcontrib><creatorcontrib>ANDREEFF, M</creatorcontrib><creatorcontrib>HIDDEMANN, W</creatorcontrib><creatorcontrib>TING-CHAO CHOU</creatorcontrib><creatorcontrib>VALE, K</creatorcontrib><creatorcontrib>ÓHEHIR, M</creatorcontrib><creatorcontrib>CLARKSON, B. D</creatorcontrib><creatorcontrib>YOUNG, C. W</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BLUMENREICH, M. S</au><au>WOODCOCK, T. M</au><au>ANDREEFF, M</au><au>HIDDEMANN, W</au><au>TING-CHAO CHOU</au><au>VALE, K</au><au>ÓHEHIR, M</au><au>CLARKSON, B. D</au><au>YOUNG, C. W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of very high-dose thymidine infusions on leukemia and lymphoma patients</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1984-05-01</date><risdate>1984</risdate><volume>44</volume><issue>5</issue><spage>2203</spage><epage>2207</epage><pages>2203-2207</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leukemia or lymphoma with marrow and blood involvement, by prolonged infusions of dThd, at dosages of 90 to 240 g/sq m/day for 14 to 29 days. Mean plasma dThd concentration ranged from 3.8 to 5.5 mM. Cerebrospinal fluid levels were measured on three occasions and ranged from 2 to 23.5% of simultaneous plasma levels. Diarrhea was dose limiting in one patient. The other side effects included nausea and vomiting in all patients, hepatotoxicity in two patients, electrolyte imbalance in one, progression of a pericardial effusion to tamponade in one, and mild central nervous system toxicity in five. In all cases, this therapy produced bone marrow aplasia. One patient with acute lymphoblastic leukemia, refractory to prior treatment, achieved a complete remission which lasted for 16 weeks. Another patient with lymphoblastic lymphoma had a greater than 50% reduction in his mediastinal mass which lasted for less than 1 month. At multiple points during therapy, the bone marrow S-phase fraction was measured by flow cytometry and autoradiography. In five patients, the proportion of cells in S phase increased during the first few days of the infusion but then returned to base line, concomitant with an overall reduction in the number of bone marrow blasts. Cytoreduction was evaluated by the technique of W. Hiddemann, B. D. Clarkson, T. Buchener, M. R. Melamed, and M. Andreeff (Blood, 59: 216-225, 1982). The magnitude of tumor cell kill ranged from 0.7 to 3.6 logs of blasts/cu mm of bone marrow. The data demonstrate that dThd is able to induce a complete remission in a patient with acute leukemia previously refractory to treatment. However, because of the very large drug quantities, fluid volumes, and the prolonged course required to produce the necessary tumor cell kill, this treatment approach is too impractical to be used extensively.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>6713407</pmid><tpages>5</tpages></addata></record> |
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subjects | Adult Antineoplastic agents Biological and medical sciences Bone Marrow - drug effects Chemotherapy Female Flow Cytometry Humans Infusions, Parenteral Kinetics Leukemia - drug therapy Lymphoma - drug therapy Male Medical sciences Pharmacology. Drug treatments Thymidine - administration & dosage Thymidine - blood Thymidine - therapeutic use |
title | Effect of very high-dose thymidine infusions on leukemia and lymphoma patients |
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