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JD Kemp, KM Smith, LJ Kanner, F Gomez, JA Thorson and PW Naumann
Department of Pathology, University of Iowa College of Medicine, Iowa City.
Data are presented indicating that the growth of 5 out of 5 murine lymphoid
tumors can be inhibited in a synergistic fashion in vitro by combined
treatment with the iron chelator deferoxamine (DFO) and an immunoglobulin G
(IgG) monoclonal anti-transferrin receptor antibody (ATRA). A two-way
dose/response analysis shows that the ATRA becomes more efficient as an
inhibitor with increasing doses of DFO. Flow cytometric studies further
support the view that IgG ATRAS impair transferrin receptor (TR) function
by causing TR down-modulation and degradation, even when the presence of
DFO acts to promote increased cell surface TR expression. It is also shown
that an IgG ATRA is nearly as effective as an IgM ATRA in inhibiting tumor
cell growth when used in combination with DFO. Finally, studies with the
iron chelator picolinic acid show that it produces only additive, or very
slightly supra-additive, effects when used in combination with the ATRA.
Therefore, these studies not only continue to suggest that combination
chelator/ATRA therapy warrants further investigation as a tool in the
therapy of hematopoietic malignancies, but also make the following new
points: (1) the clinically familiar iron chelator deferoxamine, but not all
iron chelators, produces synergistic inhibition of tumor growth in vitro
with ATRAS; and (2) IgG ATRAS, which may be clinically more attractive
reagents than IgA or IgM ATRAS because of better access to extra vascular
tissue spaces, have unexpectedly been found to function as powerful growth
inhibitors when used in combination with DFO.
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