Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model

Autor:	G. K. Lloyd, Ajita V. Singh, Barbara C. M. Potts, Michael A. Palladino, Kenneth C. Anderson, Dharminder Chauhan
Rok vydání:	2010
Předmět:	business.industry Bortezomib Kidney metabolism Spleen Hematology Pharmacology medicine.disease humanities medicine.anatomical_structure In vivo mental disorders Toxicity medicine Proteasome inhibitor Plasmacytoma business Multiple myeloma medicine.drug
Zdroj:	British Journal of Haematology. 149:550-559
ISSN:	1365-2141 0007-1048
DOI:	10.1111/j.1365-2141.2010.08144.x
Popis:	Our previous study showed that the novel proteasome inhibitor NPI-0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM-xenografts demonstrated that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase-1 clinical trial of NPI-0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI-0052 using human MM xenograft murine model. Our results showed that NPI-0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin-like (CT-L, beta5), trypsin-like (T-L, beta2), and caspase-like (C-L, beta1) activities in extra-vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (
Databáze:	OpenAIRE
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