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

Abstract

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 (<24 h). Tissue distribution analysis of radiolabeled compound (3H-NPI-0052) in mice demonstrated that NPI-0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S-bearing mice with NPI-0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.

• Authors: Ajita V Singh, Michael A Palladino, George Kenneth Lloyd, Barbara C Potts, Dharminder Chauhan, Kenneth C Anderson
• Journal: British journal of haematology (Br J Haematol) Vol. 149 Issue 4 Pg. 550-9 (May 2010) ISSN: 1365-2141 [Electronic] England
• PMID: 20331453 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Lactones
• Proteasome Inhibitors
• Pyrroles
• marizomib

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Humans
• Kidney (metabolism)
• Lactones (pharmacokinetics, pharmacology, therapeutic use)
• Male
• Mice
• Plasmacytoma (drug therapy, metabolism, pathology)
• Proteasome Inhibitors
• Pyrroles (pharmacokinetics, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays