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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-03-0939.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4162-4168
NEOPLASIA
Antimyeloma efficacy of thalidomide in the SCID-hu
model
Shmuel Yaccoby,
Cherie L. Johnson,
Susan C. Mahaffey,
Michele J. Wezeman,
Bart Barlogie, and
Joshua Epstein
From the Myeloma Institute for Research and Therapy,
University of Arkansas for Medical Sciences, Little Rock.
To determine the mechanism of thalidomide's antimyeloma efficacy,
we studied the drug's activity in our severe combined
immunodeficiency-human (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 neoangiogenesis. Because mice are not
able to metabolize thalidomide efficiently, SCID-hu mice
received implants of fetal human liver fragments under the renal
capsule in addition to subcutaneous implants 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 antimyeloma 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 nonresponsive ones.
Expression of vascular endothelial growth factor 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 antimyeloma 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 antiangiogenic activity or is secondary to a lessened tumor burden.
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