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Titolo:
A PHASE-I STUDY OF TOPOTECAN FOLLOWED SEQUENTIALLY BY DOXORUBICIN IN PATIENTS WITH ADVANCED MALIGNANCIES
Autore:
TOLCHER AW; OSHAUGHNESSY JA; WEISS RB; ZUJEWSKI J; MYHAND RC; SCHNEIDER E; HAKIM F; GRESS R; GOLDSPIEL B; NOONE MH; BREWSTER LR; GOSSARD MR; COWAN KH;
Indirizzi:
BRITISH COLUMBIA CANC AGCY,600 W 10TH AVE VANCOUVER BC V7C 1Y4 CANADA NCI,MED BRANCH BETHESDA MD 20892 WALTER REED ARMY MED CTR WASHINGTON DC 20307 NIH,CTR CLIN BETHESDA MD 20892
Titolo Testata:
Clinical cancer research
fascicolo: 5, volume: 3, anno: 1997,
pagine: 755 - 760
SICI:
1078-0432(1997)3:5<755:APSOTF>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
DNA TOPOISOMERASE-I; LEUKEMIA GROUP-B; CYTO-TOXICITY; CELL-LINE; CANCER; CAMPTOTHECIN; INHIBITOR; TUMORS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
22
Recensione:
Indirizzi per estratti:
Citazione:
A.W. Tolcher et al., "A PHASE-I STUDY OF TOPOTECAN FOLLOWED SEQUENTIALLY BY DOXORUBICIN IN PATIENTS WITH ADVANCED MALIGNANCIES", Clinical cancer research, 3(5), 1997, pp. 755-760

Abstract

Inhibitors of topoisomerase I and topoisomerase II have demonstrated synergy when administered sequentially in several tumor models while having a diminished antitumor effect when given concurrently, To explore the potential for clinical sequence-dependent synergy, we instituteda Phase I study of topotecan (a topoisomerase I inhibitor) followed by doxorubicin (a topoisomerase II inhibitor) in patients with advancedmalignancies, Thirty-three patients with advanced malignancies or malignancies for whom no standard therapy exists were entered into the study, Topotecan was administered in escalating doses by 72-h continuousinfusion on days 1, 2, and 3, followed by a bolus of doxorubicin given on day 5, To explore the hematological toxicity associated with thissequence, bone marrow aspirates were obtained both prior to the topotecan infusion and immediately prior to the doxorubicin in 10 patients to determine by fluorescence-activated cell sorting analysis whether CD34+ cell synchronization was occurring using this sequential schedule, Dose-limiting hematological toxicity occurred at the first dose-level in three of six patients, Therefore, we defined the maximum-tolerated dose (MTD) below our starting dose-level, Further dose-escalation and a new MTD were defined with the addition of granulocyte-colony stimulating factor (G-CSF), The MTD was, therefore, topotecan 0.35 mg/m(2)/day continuous i,v, infusion on days 1, 2, and 3, followed by doxorubicin 45 mg/m(2) on day 5 without G-CSF, whereas the MTD with G-CSF was topotecan 0.75 mg/m(2)/day by 72-h continuous i,v, infusion, followed by doxorubicin 45 mg/m(2) i,v, bolus on day 5, Ten patients with paired bone marrow aspirates obtained before topotecan and before doxorubicin administrations were available for evaluation, In 7 of 10 patients,there was an increase (16.6 +/- 2.9% to 25.0 +/- 3.5%; P < 0.02) in the proportion of CD34+ cells in S-phase 24 h after the topotecan infusion and prior to doxorubicin compared to the pretreatment values, whereas 1 patient had a decrease in the proportion of CD34+ cells in S phase and 2 patients had no change, Topotecan and doxorubicin with this sequence and schedule can be given safely; the dose-limiting toxicity is hematological toxicity. Alterations in the fraction of hematopoieticprogenitor CD34+ cells in S-phase may account for the increased granulocytopenia and thrombocytopenia observed at relatively low dose levels of the combination with and without G-CSF.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/07/20 alle ore 15:33:17