دورية أكاديمية
A phase I pharmacokinetic and pharmacodynamic correlative study of the antisense Bcl-2 oligonucleotide g3139, in combination with carboplatin and paclitaxel, in patients with advanced solid tumors.
| العنوان: | A phase I pharmacokinetic and pharmacodynamic correlative study of the antisense Bcl-2 oligonucleotide g3139, in combination with carboplatin and paclitaxel, in patients with advanced solid tumors. |
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| المؤلفون: | Liu G; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792, USA. gxl@medicine.wisc.edu, Kolesar J, McNeel DG, Leith C, Schell K, Eickhoff J, Lee F, Traynor A, Marnocha R, Alberti D, Zwiebel J, Wilding G |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2008 May 01; Vol. 14 (9), pp. 2732-9. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Print ISSN: 1078-0432 (Print) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Antineoplastic Combined Chemotherapy Protocols/*therapeutic use , Carboplatin/*therapeutic use , Neoplasms/*drug therapy , Oligonucleotides, Antisense/*therapeutic use , Paclitaxel/*therapeutic use , Thionucleotides/*therapeutic use, Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Carboplatin/administration & dosage ; Carboplatin/pharmacokinetics ; Combined Modality Therapy ; Down-Regulation ; Female ; Gene Expression ; Genes, bcl-2 ; Humans ; Male ; Neoplasms/genetics ; Neoplasms/metabolism ; Oligonucleotides, Antisense/pharmacokinetics ; Paclitaxel/administration & dosage ; Paclitaxel/pharmacokinetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Thionucleotides/administration & dosage ; Thionucleotides/adverse effects ; Thionucleotides/pharmacokinetics ; bcl-2-Associated X Protein/metabolism |
| مستخلص: | Purpose: This phase I trial assessed the safety and tolerability of G3139 when given in combination with carboplatin and paclitaxel chemotherapy. The effect of G3139 treatment on Bcl-2 expression in peripheral blood mononuclear cells (PBMC) and paired tumor biopsies was also determined. Experimental Design: Patients with advanced solid malignancies received various doses of G3139 (continuous i.v. infusion days 1-7), carboplatin (day 4), and paclitaxel (day 4), repeated in 3-week cycles, in a standard cohort-of-three dose-escalation schema. Changes in Bcl-2/Bax transcription/expression were assessed at baseline and day 4 (prechemotherapy) in both PBMCs and paired tumor biopsies. The pharmacokinetic interactions between G3139 and carboplatin/paclitaxel were measured. Results: Forty-two patients were evaluable for safety analysis. Primary toxicities were hematologic (myelosuppression and thrombocytopenia). Dose escalation was stopped with G3139 at 7 mg/kg/d, carboplatin at area under the curve of 6, and paclitaxel at 175 mg/m(2) due to significant neutropenia seen in cycle 1 and safety concerns in further escalating chemotherapy in this phase I population. With G3139 at 7 mg/kg/d, 13 patients underwent planned tumor biopsies, of which 12 matched pairs were obtained. Quantitative increases in intratumoral G3139 with decreases in intratumoral Bcl-2 gene expression were seen. This paralleled a decrease in Bcl-2 protein expression observed in PBMCs. Conclusions: Although the maximal tolerated dose was not reached, the observed toxicities were consistent with what one would expect from carboplatin and paclitaxel alone. In addition, we show that achievable intratumoral G3139 concentrations can result in Bcl-2 down-regulation in solid tumors and PBMCs. |
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| معلومات مُعتمدة: | U01 CA062491 United States CA NCI NIH HHS; 22XS096 United States PHS HHS; M01 RR03186 United States RR NCRR NIH HHS; U01 CA062491-12 United States CA NCI NIH HHS; M01 RR003186-200429 United States RR NCRR NIH HHS; M01 RR003186 United States RR NCRR NIH HHS |
| المشرفين على المادة: | 0 (BAX protein, human) 0 (Oligonucleotides, Antisense) 0 (Proto-Oncogene Proteins c-bcl-2) 0 (Thionucleotides) 0 (bcl-2-Associated X Protein) 85J5ZP6YSL (oblimersen) BG3F62OND5 (Carboplatin) P88XT4IS4D (Paclitaxel) |
| تواريخ الأحداث: | Date Created: 20080503 Date Completed: 20080918 Latest Revision: 20211020 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC2950700 |
| DOI: | 10.1158/1078-0432.CCR-07-1490 |
| PMID: | 18451239 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1078-0432 |
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| DOI: | 10.1158/1078-0432.CCR-07-1490 |