LAGλ1: A clinically relevant drug resistant human multiple myeloma tumor murine model that enables rapid evaluation of treatments for multiple myeloma

Richard A. Campbell, Steven J. Manyak, Honghao H. Yang, Nelida N. Sjak-Shie, Haiming Chen, Dorina Gui, Laura Popoviciu, Cathy Wang, Melinda Gordon, Shen Pang, Benjamin Bonavida, Jonathan Said, James R. Berenson

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

We set out to generate new human myeloma tumors that grow in immunodeficient mice and can be used for pathophysiological studies and rapid evaluation of new therapies. Fresh whole core bone marrow (BM) biopsies taken from 33 myeloma patients were engrafted into the hind limb muscle of severe combined immunodeficient (SCID) mice. Human Ig was detected in 28/33 mice and three grew palpable tumors displaying many features of human myeloma including morphology, immunophenotype and BM plasmacytosis. Following intramuscular passage, we generated large numbers of mice with predictable increases in tumor growth and human paraprotein levels. We further characterized the model generated from an IgGλ-producing tumor known as LAGλ-1 and determined the effects of the proteasome inhibitor bortezomib, the alkylating agent melphalan, and the DNA damaging agent liposomal doxorubicin, on the growth of this tumor. LAGλ-1-bearing mice receiving higher doses of bortezomib showed reduced tumor growth whereas a lower dose had no effect. In contrast, melphalan did not significantly alter tumor growth, except minimally at high doses, reflecting the resistance of this patient's tumor to this drug. We also used our intramuscular (i.m.) LAGλ-1 model to optimize the dosing schedule of liposomal doxorubicin. Low doses administered once daily three days per week decreased tumor growth and human paraprotein levels whereas much higher doses given once weekly had no anti-myeloma effects. Furthermore, LAGλ-1 cells produce local tumors when injected subcutaneously and lytic lesions when injected intravenously allowing for multiple methods of evaluating the anti-myeloma effects of a variety of agents. Our new clinically relevant SCID models of human myeloma should greatly facilitate drug development and enable novel therapies to quickly move from the laboratory to the clinic.

Original languageEnglish (US)
Pages (from-to)1409-1417
Number of pages9
JournalInternational Journal of Oncology
Volume28
Issue number6
StatePublished - Jun 1 2006
Externally publishedYes

Fingerprint

Multiple Myeloma
Pharmaceutical Preparations
Neoplasms
Paraproteins
Therapeutics
Growth
Melphalan
Bone Marrow
Proteasome Inhibitors
SCID Mice
Alkylating Agents
Appointments and Schedules
Extremities
Immunoglobulin G
Biopsy
Muscles
DNA

Keywords

  • Animal model
  • Multiple myeloma
  • Murine model
  • SCID mouse

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

LAGλ1 : A clinically relevant drug resistant human multiple myeloma tumor murine model that enables rapid evaluation of treatments for multiple myeloma. / Campbell, Richard A.; Manyak, Steven J.; Yang, Honghao H.; Sjak-Shie, Nelida N.; Chen, Haiming; Gui, Dorina; Popoviciu, Laura; Wang, Cathy; Gordon, Melinda; Pang, Shen; Bonavida, Benjamin; Said, Jonathan; Berenson, James R.

In: International Journal of Oncology, Vol. 28, No. 6, 01.06.2006, p. 1409-1417.

Research output: Contribution to journalArticle

Campbell, RA, Manyak, SJ, Yang, HH, Sjak-Shie, NN, Chen, H, Gui, D, Popoviciu, L, Wang, C, Gordon, M, Pang, S, Bonavida, B, Said, J & Berenson, JR 2006, 'LAGλ1: A clinically relevant drug resistant human multiple myeloma tumor murine model that enables rapid evaluation of treatments for multiple myeloma', International Journal of Oncology, vol. 28, no. 6, pp. 1409-1417.
Campbell, Richard A. ; Manyak, Steven J. ; Yang, Honghao H. ; Sjak-Shie, Nelida N. ; Chen, Haiming ; Gui, Dorina ; Popoviciu, Laura ; Wang, Cathy ; Gordon, Melinda ; Pang, Shen ; Bonavida, Benjamin ; Said, Jonathan ; Berenson, James R. / LAGλ1 : A clinically relevant drug resistant human multiple myeloma tumor murine model that enables rapid evaluation of treatments for multiple myeloma. In: International Journal of Oncology. 2006 ; Vol. 28, No. 6. pp. 1409-1417.
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AU - Popoviciu, Laura

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