Effect of Platelet-Derived Growth Factor Receptor-β Inhibition with STI571 on Radioimmunotherapy

Abstract

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-B (PDGFr-B) 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-B 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. (Cancer Res 2005; 65(17): 7824-31)

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Tumours were shown to regress and vessel normalisation was demonstrated, indicated by normalised pericyte coverage, tumour perfusion and increased chemotherapy sensitivity. The treatment both removed pericytes which were loosely connected to the diseased vasculature, causing vessel collapse, while simultaneously did not affect normal vessels, thereby enabling the delivery of cytotoxic drugs to the tumour (Baranowska- Kortylewicz et al, 2005;Jain and Booth, 2003). Therefore, targeting pericyte-EC interactions by inhibiting PDGF signalling with treatments such as Gleevec (imatinib) (Wilkinson-Berka et al, 2004) have strong potential in cancer therapy by disrupting pericyte support of the tumour vasculature.…”

Small-Animal SPECT and SPECT/CT: Important Tools for Preclinical Investigation

“…Small-animal SPECT/CT will become increasingly important for the evaluation and advancement of molecular radiotherapeutics, as has been exemplified in the development of somatostatin receptor ligand analogs (33), development of folate-based radiopharmaceuticals (89,90), and enhancement of radiation dose delivery by adjuvant agents (91). As more molecular radiotherapeutics are realized and the quantitative accuracy of SPECT improves, some level of imaging-based dosimetry will likely become a requisite for Food and Drug Administration approval.…”

Emerging Trends for Radioimmunotherapy in Solid Tumors

“…72 The utility of PDGFR inhibitor imatinib mesylate to improve the efficacy of anti-TAG72 was previously demonstrated using LS174T colorectal cancer xenografts. 73 This effect was accompanied by decreased tumor IFP that was attributed to the effect of imatinib on stromal fibroblasts. In contrast, in prostate cancer xenografts, the inhibition of PDGFR-b signaling did not result in significant lowering of tumor IFP but still appeared to improve the efficacy of RIT possibly by modulating HIF1-a and reducing hypoxia.…”