INHIBITION OF LYMPHOMA GROWTH IN-VIVO BY COMBINED TREATMENT WITH HYDROXYETHYL STARCH DEFEROXAMINE CONJUGATE AND IGG MONOCLONAL-ANTIBODIES AGAINST THE TRANSFERRIN RECEPTOR

Synergistic inhibition of hematopoietic tumor growth can be observed i n vitro when the iron chelator deferoxamine (DFO) is used in combinati on with an IgG mAb against the anti-transferrin receptor antibody (ATR A). Our goal was to ascertain whether similar findings could be seen i re vivo. A high molecular weight conjugate of deferoxamine, known as h ydroxyethyl starch (HES) DFO or HES-DFO, was tested in conjunction wit h C2, a well-defined rat antimouse transferrin receptor mAb, against t he 38C13 tumor in C3H/HeN mice. It was shown that while neither HES-DF O alone nor C2 alone produced consistent, significant inhibition of tu mor growth, the combination of HES-DFO and C2 produced virtually compl ete inhibition of initial tumor outgrowth, The latter combination fail ed, 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 inhibit ion of the growth of 38C13 in vitro. When the two IgG ATRAS were used together in vivo, regressions of established tumors were observed, Mor eover, the addition of HES-DFO to the IgG ATRA pair then caused more f requent regressions. Although there was never any obvious toxicity see n 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 a lso 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 H ES-DFO and the ATRA pair resulted in death attributed to infection in nearly all of the mice after 6 days. Thus, an iron deprivation treatme nt protocol with RES-DFO and IgG ATRAS produced both a significant ant itumor effect and an increased risk of infection in a murine model sys tem.