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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-03-0939.
Submitted March 27, 2002
Accepted July 12, 2002
Anti-myeloma efficacy of thalidomide in the SCID-hu model
Shmuel Yaccoby*, Cherie L Johnson, Susan C Mahaffey, Michele J Wezeman, Bart Barlogie, and Joshua Epstein
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
* Corresponding author; email: yaccobyshmuel{at}uams.edu.
To determine the mechanism of thalidomide's anti-myeloma efficacy, we studied the drug's activity in our SCID-hu host system for primary human myeloma. In this model tumor cells interact with the human microenvironment to produce typical myeloma manifestations in the hosts, including stimulation of neo-angiogenesis. Because mice are not able to metabolize thalidomide efficiently, SCID-hu mice were implanted with fetal human liver fragments under the renal capsule in addition to subcutaneous implantation of the fetal human bone. Myeloma cell growth in these mice was similar to their growth in hosts without liver implant, as assessed by change in levels of circulating human immunoglobulins and by histologic examinations. Thalidomide given daily by peritoneal injection significantly inhibited myeloma growth in 7 of 8 experiments, each with myeloma cells from a different patient, in hosts implanted with human liver. In contrast, thalidomide exerted an anti-myeloma effect only in 1 of 10 mice without liver implants. Microvessel density in the untreated controls was higher than in thalidomide-responsive hosts but not different from non-responsive ones. Vascular endothelial growth factor (VEGF) expression by myeloma cells and by other cells in the human bone, determined immunohistochemically, was not affected by thalidomide treatment in any experiment. Our study suggests that thalidomide metabolism is required for its anti-myeloma efficacy. Although response to thalidomide was strongly associated with decreased microvessel density, we were unable to conclude whether reduced microvessel density is a primary result of thalidomide's anti-angiogenic activity or is secondary to a lessened tumor burden.
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