Whereas
radioimmunotherapy of
hematologic malignancies has evolved into a viable treatment option, the responses of solid
tumors to
radioimmunotherapy are discouraging. The likely cause of this problem is the interstitial
hypertension inherent to all solid
tumors. Remarkable improvements in
tumor responses to
radioimmunotherapy were discovered after the inclusion of
STI571 in the
therapy regimen. A combination of the
tumor stroma-reactive
STI571, a potent
platelet-derived growth factor receptor-
beta (PDGFr-beta) antagonist, and the
tumor-seeking radiolabeled antibody
B72.3 yielded long-lasting growth arrest of the human colorectal
adenocarcinoma LS174T grown as s.c. xenografts in athymic mice. The interaction of
STI571 with the stromal
PDGFr-beta reduced
tumor interstitial fluid pressure (P(IF)) by >50% and in so doing improved the uptake of
B72.3. The attenuation of P(IF) also had a positive effect on the homogeneity of antibody distribution. These effects were dose-dependent and under optimized dosing conditions allowed for a 2.45 times increase in the
tumor uptake of
B72.3 as determined in the biodistribution studies. Single-photon emission computed tomography imaging studies substantiated these results and indicated that the homogeneity of the
radioisotope distribution was also much improved when compared with the control mice. The increased uptake of
radioimmunotherapy into the
tumor resulted in >400% increase in the
tumor absorbed radiation doses in
STI571 +
radioimmunotherapy-treated mice compared with PBS +
radioimmunotherapy-treated mice. The improved antibody uptake in response to the attenuation of
tumor P(IF) was identified as the primary reason for the growth arrest of the
STI571 +
radioimmunotherapy-treated
tumors. Two related causes were also identified: (a) the improved homogeneity of
monoclonal antibody distribution in
tumor and (b) the increased
tumor radiosensitivity resulting from the improved
tumor oxygenation.