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Inhibition of Lymphoma Growth in Vivo by Combined Treatment with Hydroxyethyl Starch Deferoxamine Conjugate and IgG Monoclonal Antibodies against the Transferrin Receptor¹

Departments of Pathology [J. D. K., T. C., E. K., P. W. N.], Microbiology [J. D. K., T. C.], Immunology [J. D. K.], and Internal Medicine [G. W.], University of Iowa College of Medicine, Iowa City, Iowa 52242; Pathology Laboratory, Veterans Affairs Medical Center, Iowa City, Iowa 52246 [J. D. K., B. C. S.]; and Biomedical Frontiers, Inc., Minneapolis, Minnesota 55414 [B. H.]

Synergistic inhibition of hematopoietic tumor growth can be observed in vitro when the iron chelator deferoxamine (DFO) is used in combination with an IgG mAb against the anti-transferrin receptor antibody (ATRA). Our goal was to ascertain whether similar findings could be seen in vivo. A high molecular weight conjugate of deferoxamine, known as hydroxyethyl starch (HES) DFO or HES-DFO, was tested in conjunction with C2, a well-defined rat antimouse transferrin receptor mAb, against the 38C13 tumor in C3H/HeN mice. It was shown that while neither HES-DFO alone nor C2 alone produced consistent, significant inhibition of tumor growth, the combination of HES-DFO and C2 produced virtually complete inhibition of initial tumor outgrowth. The latter combination failed, however, to inhibit the growth of established tumors. It was then found that when C2 was used in conjunction with RL34, another IgG ATRA, the two ATRAS were themselves capable of causing synergistic inhibition of the growth of 38C13 in vitro. When the two IgG ATRAS were used together in vivo, regressions of established tumors were observed. Moreover, the addition of HES-DFO to the IgG ATRA pair then caused more frequent regressions. Although there was never any obvious toxicity seen with a single IgG ATRA, the use of the IgG ATRA pair was associated with sporadic mortality. In addition, although HES-DFO by itself was also not associated with any obvious toxicity, combined treatment with HES-DFO and a single ATRA resulted in death due to bacterial infection in about half of the mice after 10–15 days. Combined treatment with HES-DFO and the ATRA pair resulted in death attributed to infection in nearly all of the mice after 6 days. Thus, an iron deprivation treatment protocol with HES-DFO and IgG ATRAS produced both a significant antitumor effect and an increased risk of infection in a murine model system.

¹ Supported in part by a Veterans Affairs Merit Review Grant, Grant DAMD17-95-1-5008 from the United States Army Medical Research and Development Command, NIH Grant 1 U43-CA64020-01, and a Children's Miracle Network Telethon Grant. This article is dedicated to Robert Kemp and John Naumann.

² To whom requests for reprints should be addressed, at 5238 Carver, University of Iowa Hospitals, Iowa City, IA 52242.

Received 4/ 3/95. Accepted 7/ 6/95.

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