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المصدر: Leukemia Research. 39:371-379
مصطلحات موضوعية: Cancer Research, Indoles, Blotting, Western, Antineoplastic Agents, Apoptosis, Hydroxamic Acids, Article, Bortezomib, Lactones, chemistry.chemical_compound, Refractory, hemic and lymphatic diseases, Panobinostat, Tumor Cells, Cultured, medicine, Humans, Pyrroles, Multiple myeloma, Cell Proliferation, business.industry, Myeloid leukemia, Hematology, Flow Cytometry, medicine.disease, Boronic Acids, Drug Combinations, Leukemia, Myeloid, Acute, Oncology, chemistry, Drug Resistance, Neoplasm, Caspases, Pyrazines, Immunology, Cancer research, Proteasome inhibitor, DNA fragmentation, business, Proteasome Inhibitors, medicine.drug
الوصف: Current relapse rates in acute myeloid leukemia (AML) highlight the need for new therapeutic strategies. Panobinostat, a novel pan-histone deacetylase inhibitor, and marizomib, a second-generation proteasome inhibitor, are emerging as valuable therapeutic options for hematological malignancies. Here we evaluated apoptotic effects of this combinatorial therapy in AML models and report earlier and higher reactive oxygen species induction and caspase-3 activation and greater caspase-8 dependence than with other combinations. In a bortezomib refractory setting, panobinostat induced high levels of DNA fragmentation, and its action was significantly augmented when combined with marizomib. These data support further study of this combination in hematological malignancies.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6a8f26d4275c9b8beea2f448efb55571Test
https://doi.org/10.1016/j.leukres.2014.12.014Test -
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المؤلفون: Xin Yan Pei, Yun Dai, Shuang Chen, Robert Z. Orlowski, Liang Zhou, Yun Leng, Richard J. Jones, Steven Grant, Maciej Kmieciak, Yu Zhang, Hui Lin
المصدر: Blood. 124:2687-2697
مصطلحات موضوعية: cells, Fluorescent Antibody Technique, Apoptosis, Mice, SCID, Hydroxamic Acids, Biochemistry, Bortezomib, Small hairpin RNA, immune system diseases, Mice, Inbred NOD, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Cells, Cultured, Mice, Knockout, Gene knockdown, Lymphoid Neoplasia, Bcl-2-Like Protein 11, hemic and immune systems, Hematology, Boronic Acids, Tumor Burden, Pyrazines, RNA Interference, biological phenomena, cell phenomena, and immunity, Multiple Myeloma, medicine.drug, Immunoblotting, Immunology, Biology, Downregulation and upregulation, Cell Line, Tumor, Proto-Oncogene Proteins, Autophagy, medicine, Animals, Humans, neoplasms, Membrane Proteins, Cell Biology, Xenograft Model Antitumor Assays, Molecular biology, Histone Deacetylase Inhibitors, Drug Resistance, Neoplasm, Cell culture, Cancer research, Histone deacetylase, Apoptosis Regulatory Proteins
الوصف: Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bim(hi)) in most MM cell lines and primary CD138(+) MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bim(hi) cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim(hi) cells. In Bim(low) cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim(-/-) mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bfb906a6b85294c357a4a699ef6fac4eTest
https://doi.org/10.1182/blood-2014-03-564534Test -
3
المؤلفون: Donna M. Weber, Caimiao Wei, R. Eric Davis, Deborah J. Kuhn, Zuzana Berkova, Timothy Madden, Sheeba K. Thomas, Veerabhadran Baladandayuthapani, Robert Z. Orlowski, Richard Woessner, Michael Wang, Hua Wang, Chad C. Bjorklund, Richard J. Jones, Jatin J. Shah, Wencai Ma, Pei Lin
المصدر: Blood. 120:3260-3270
مصطلحات موضوعية: medicine.medical_treatment, Blotting, Western, Immunology, Antineoplastic Agents, Apoptosis, Enzyme-Linked Immunosorbent Assay, Mice, SCID, Pharmacology, Biochemistry, Receptor, IGF Type 1, Bortezomib, Mice, Paracrine signalling, Insulin-like growth factor, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Tumor Cells, Cultured, medicine, Animals, Humans, Insulin-Like Growth Factor I, Autocrine signalling, Receptor, Multiple myeloma, Cell Proliferation, Oligonucleotide Array Sequence Analysis, Lymphoid Neoplasia, biology, Cell growth, Gene Expression Profiling, Imidazoles, Drug Synergism, Cell Biology, Hematology, Flow Cytometry, medicine.disease, Boronic Acids, Xenograft Model Antitumor Assays, Survival Rate, Insulin receptor, Drug Resistance, Neoplasm, Pyrazines, biology.protein, Multiple Myeloma, medicine.drug
الوصف: Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)–1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA–mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bor-tezomib. Importantly, OSI-906 in combination with bortezomib also overcame bor-tezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0fb1ec3310b35c2bd7d5caecbbfd8b34Test
https://doi.org/10.1182/blood-2011-10-386789Test -
4
المؤلفون: Jatin J. Shah, Robert Z. Orlowski
المصدر: Leukemia. 23:1964-1979
مصطلحات موضوعية: Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Article, Bortezomib, Lactones, chemistry.chemical_compound, Chemosensitization, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Protease Inhibitors, Pyrroles, Multiple myeloma, Hematology, business.industry, medicine.disease, Boronic Acids, Carfilzomib, Proteasome, chemistry, Pyrazines, Immunology, Proteasome inhibitor, Multiple Myeloma, business, Oligopeptides, Salinosporamide A, medicine.drug
الوصف: Targeting intracellular protein turnover by inhibiting the ubiquitin-proteasome pathway as a strategy for cancer therapy is a new addition to our chemotherapeutic armamentarium, and has seen its greatest successes against multiple myeloma. The first-in-class proteasome inhibitor bortezomib was initially approved for treatment of patients in the relapsed/refractory setting as a single agent, and was recently shown to induce even greater benefits as part of rationally-designed combinations that overcome chemoresistance. Modulation of proteasome function is also a rational approach to achieve chemosensitization to other anti-myeloma agents, and bortezomib has now been incorporated into the front-line setting. Bortezomib-based induction regimens are able to achieve higher overall response rates and response qualities than was the case with prior standards of care, and unlike these older approaches, maintain efficacy in patients with clinically- and molecularly-defined high-risk disease. Second-generation proteasome inhibitors with novel properties, such as NPI-0052 and carfilzomib, are entering the clinical arena, and showing evidence of anti-myeloma activity. In this spotlight review, we provide an overview of the current state of the art use of bortezomib and other proteasome inhibitors against multiple myeloma, and highlight areas for future study that will further optimize our ability to benefit patients with this disease.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::70dbb635bcff79a2b7bb4d033728c302Test
https://doi.org/10.1038/leu.2009.173Test -
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المؤلفون: William Riordan, Robert Z. Orlowski, Jason M. Collins, Anastasia Ivanova, Celeste Lindley, E. Claire Dees, Dixie Lee Esseltine, Frances A. Collichio, Lisa A. Carey, Bert H. O'Neil
المصدر: Cancer Chemotherapy and Pharmacology. 63:99-107
مصطلحات موضوعية: Adult, Male, Drug, Cancer Research, Maximum Tolerated Dose, Gastrointestinal Diseases, media_common.quotation_subject, Salvage therapy, Pharmacology, Toxicology, Article, Polyethylene Glycols, Bortezomib, Refractory, immune system diseases, Neoplasms, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Combined Modality Therapy, Pharmacology (medical), Doxorubicin, cardiovascular diseases, neoplasms, Fatigue, Aged, media_common, Salvage Therapy, Liposome, Dose-Response Relationship, Drug, business.industry, Middle Aged, Boronic Acids, Hematologic Diseases, Neoplasm Proteins, Treatment Outcome, Oncology, Pyrazines, Liposomes, Proteasome inhibitor, Female, business, Proteasome Inhibitors, medicine.drug
الوصف: Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.Patients received bortezomib, 0.9-1.5 mg/m(2), on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m(2), on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination.A total of 37 patients with four median prior therapies were treated. Frequent grade 1-2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib at 1.2 mg/m(2), and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m(2). Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m(2) levels, bortezomib at 1.3 mg/m(2) and PLD at 30 mg/m(2) are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs.A regimen of bortezomib, 1.3 mg/m(2) on days 1, 4, 8, and 11 with PLD, 30 mg/m(2), on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be8c7f1a8847115f803de5c9f5b2ff84Test
https://doi.org/10.1007/s00280-008-0716-8Test -
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المؤلفون: Deborah J. Kuhn, Jeffrey A. Nemeth, Peter M. Voorhees, Mohamed H. Zaki, Robert Corringham, Sally A. Hunsucker, George W. Small, John S. Strader, Qing Chen, Robert Z. Orlowski
المصدر: Clinical Cancer Research. 13:6469-6478
مصطلحات موضوعية: STAT3 Transcription Factor, Cancer Research, Stromal cell, Myeloid, Cell, Antineoplastic Agents, Apoptosis, Bone Marrow Cells, DNA Fragmentation, Biology, Bortezomib, immune system diseases, hemic and lymphatic diseases, medicine, Humans, HSP70 Heat-Shock Proteins, Multiple myeloma, Interleukin-6, Antibodies, Monoclonal, medicine.disease, Boronic Acids, Gene Expression Regulation, Neoplastic, STAT1 Transcription Factor, medicine.anatomical_structure, Oncology, Proteasome, Drug Resistance, Neoplasm, Pyrazines, Proteasome inhibitor, Cancer research, Immunotherapy, Syndecan-1, Bone marrow, Multiple Myeloma, Signal Transduction, medicine.drug
الوصف: Purpose: Inhibition of the proteasome leads to the activation of survival pathways in addition to those that promote cell death. We hypothesized that down-regulation of interleukin-6 (IL-6) signaling using the monoclonal antibody CNTO 328 would enhance the antitumor activity of the proteasome inhibitor bortezomib in multiple myeloma by attenuating inducible chemoresistance.Experimental Design: The cytotoxicity of bortezomib, CNTO 328, and the combination, along with the associated molecular changes, was assessed in IL-6–dependent and IL-6–independent multiple myeloma cell lines, both in suspension and in the presence of bone marrow stromal cells and in patient-derived myeloma samples.Results: Treatment of IL-6–dependent and IL-6–independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion. This effect was additive to synergistic and was preserved in the presence of bone marrow stromal cells and in CD138+ myeloma samples derived from patients with relative clinical resistance to bortezomib. CNTO 328 potentiated bortezomib-mediated activation of caspase-8 and caspase-9 and the common downstream effector caspase-3; attenuated bortezomib-mediated induction of antiapoptotic heat shock protein-70, which correlated with down-regulation of phosphorylated signal transducer and activator of transcription-1; and inhibited bortezomib-mediated accumulation of myeloid cell leukemia-1, an effect that was associated with down-regulation of phosphorylated signal transducer and activator of transcription-3.Conclusions: Taken together, our results provide a strong preclinical rationale for the clinical development of the bortezomib/CNTO 328 combination for patients with myeloma.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::97d80fcc7d270795afdc7ae89e3e0f8fTest
https://doi.org/10.1158/1078-0432.ccr-07-1293Test -
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المؤلفون: Sen H. Zhuang, Liang Xiu, Ivan Spicka, Jean Luc Harousseau, Tadeusz Robak, Pieter Sonneveld, Joan Bladé, Wayne Rackoff, Trilok V. Parekh, Andrew Spencer, Arnon Nagler, Alexander Suvorov, Jesús F. San Miguel, Zhilong Yuan, Robert Z. Orlowski, Heather J. Sutherland, Anna Dmoszynska, Roman Hájek, Noemi Horvath
المساهمون: Hematology
المصدر: Journal of Clinical Oncology, 25, 3892-3901. American Society of Clinical Oncology
مصطلحات موضوعية: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Randomization, Combination therapy, Disease-Free Survival, Polyethylene Glycols, Bortezomib, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Doxorubicin, Survival rate, Multiple myeloma, Aged, Aged, 80 and over, business.industry, Incidence, Hazard ratio, Middle Aged, medicine.disease, Boronic Acids, Hematologic Diseases, Surgery, Regimen, Cardiovascular Diseases, Drug Resistance, Neoplasm, Pyrazines, Disease Progression, Female, Neoplasm Recurrence, Local, Multiple Myeloma, business, medicine.drug
الوصف: Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m2 on day 4. Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome. Conclusion PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4064f6874c5cbadfcd04e516972fe3d8Test
https://doi.org/10.1200/jco.2006.10.5460Test -
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المؤلفون: Robert Z. Orlowski, Peter M. Voorhees
المصدر: Annual Review of Pharmacology and Toxicology. 46:189-213
مصطلحات موضوعية: Proteasome Endopeptidase Complex, medicine.medical_treatment, Antineoplastic Agents, Toxicology, Bortezomib, Ubiquitin, Neoplasms, hemic and lymphatic diseases, Heat shock protein, medicine, Animals, Humans, Multiple myeloma, Pharmacology, Chemotherapy, biology, Cancer, medicine.disease, Boronic Acids, Cell Transformation, Neoplastic, Proteasome, Drug Resistance, Neoplasm, Pyrazines, Cancer research, Proteasome inhibitor, biology.protein, Proteasome Inhibitors, medicine.drug
الوصف: ▪ Abstract The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f887002dcb90f3b28292980505a10e0Test
https://doi.org/10.1146/annurev.pharmtox.46.120604.141300Test -
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المؤلفون: Joan Bladé, Pieter Sonneveld, Jamie Cavenagh, Sagar Lonial, Heinz Ludwig, Jesús F. San Miguel, Robert Z. Orlowski, Axel Glasmacher, Mario Boccadoro, Sundar Jagannath
المساهمون: Hematology
المصدر: Oncologist, 11(1), 51-61. AlphaMed Press
مصطلحات موضوعية: Oncology, Cancer Research, medicine.medical_specialty, Combination therapy, Antineoplastic Agents, Bortezomib, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Adverse effect, Survival analysis, Multiple myeloma, Dexamethasone, Hematology, business.industry, Peripheral Nervous System Diseases, medicine.disease, Prognosis, Boronic Acids, Survival Analysis, Thrombocytopenia, Surgery, Pyrazines, Proteasome inhibitor, business, Multiple Myeloma, medicine.drug
الوصف: Despite intensive therapy, multiple myeloma (MM) remains an incurable disease, and novel treatment approaches are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory or relapsed MM following the failure of at least two prior lines of therapy. Recently, it also received approval from the FDA for use as a second-line agent. An expert panel of hematologists met at the Ninth Congress of the European Hematology Association to review clinical data and experience in the treatment of MM with bortezomib, including bortezomib-based combination therapy. The conclusions of this expert panel, together with updated clinical data from the American Society of Hematology 46th Annual Meeting, provide a practical update on the use of bortezomib in MM. Bortezomib has demonstrated significant antitumor activity as a single agent in refractory and/or relapsed MM, with a significantly longer survival than with dexamethasone (1-year overall survival rate of 80% vs. 66%) and a 78% longer median time to progression. In combination therapy, patient responses suggest the possibility of chemosensitization and synergy. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem cell therapy. Bortezomib is well tolerated; most side effects are only mild to moderate and are manageable. Information is given on the practical management of the most common adverse events, including peripheral neuropathy and thrombocytopenia, and the use of bortezomib in renal and hepatic impairment.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9aef65f164d7baa7d1663365fbc1b38aTest
https://hdl.handle.net/1765/75024Test -
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المؤلفون: Anastasia Ivanova, Beverly S. Mitchell, Marie Green, Anandhi R. Johri, Peter M. Voorhees, Hendrik W. van Deventer, Elizabeth G. Trehu, Dixie Lee Esseltine, Reynaldo Garcia, Fred J. Kudrik, Thomas C. Shea, Julian Adams, Don A. Gabriel, Celeste Lindley, Paul Jones, Melissa D. Hall, E. Claire Dees, Mary Jo Lehman, Robert Z. Orlowski, Tammy Allred, Susan Natoli, Jason M. Collins
المصدر: Blood. 105:3058-3065
مصطلحات موضوعية: Adult, Male, Oncology, medicine.medical_specialty, Immunology, Neutropenia, Pharmacology, Biochemistry, Polyethylene Glycols, Bortezomib, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Protease Inhibitors, Doxorubicin, Multiple myeloma, Aged, Aged, 80 and over, Antibiotics, Antineoplastic, business.industry, Myeloid leukemia, Cell Biology, Hematology, Middle Aged, medicine.disease, Boronic Acids, Regimen, Treatment Outcome, Hematologic Neoplasms, Pyrazines, Liposomes, Proteasome inhibitor, Female, business, Proteasome Inhibitors, Febrile neutropenia, medicine.drug
الوصف: Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9be63e30634119a9aa1ae7c9cb6a37b5Test
https://doi.org/10.1182/blood-2004-07-2911Test
