¹⁵O-Water PET Study of the Effect of Imatinib, a Selective Platelet-Derived Growth Factor Receptor Inhibitor, Versus Anakinra, an IL-1R Antagonist, on Water-Perfusable Tissue Fraction in Colorectal Cancer Metastases

Abstract

High interstitial fluid pressure (IFP) in colorectal cancer metastases may decrease the uptake and, thus, the effects of antitumor drugs. Imatinib, a selective inhibitor of platelet-derived growth factor receptors, and anakinra, an interleukin-1 receptor antagonist, respectively, increase drug uptake or decrease IFP in preclinical models of carcinoma. Drug-induced decrease in IFP in human metastases has not been objectively shown but should be reflected by an increase in water-perfusable tissue fraction (PTF) or tumor blood flow (TBF) using 15 O-water PET/CT and kinetic modeling. Hence, the aim of this study was to assess the effects of imatinib and anakinra on PTF and TBF in colorectal cancer metastases in patients. Methods: Nine patients with documented progressive disease despite all established therapy underwent 15 O-water PET/CT at baseline and at 2 d and 6-7 d after the start of oral administration of imatinib (400 mg/d). After a washout period of 1 wk, the protocol was repeated with anakinra (100 mg/d) subcutaneously. Six patients underwent a second baseline scan on the same day to assess reproducibility of PTF and TBF measurements. Volumes of interest were drawn over liver metastases and aorta. PTF and TBF were calculated using the standard single-tissue-compartment model. Results: Imatinib administration during 6-7 d increased PTF from 0.62 ± 0.12 to 0.69 ± 0.13, compared with baseline and day 2 (P 5 0.02, Wilcoxon test). No significant changes were found in TBF. PTF values were no longer significantly different from baseline 1 wk after the last imatinib dosage. Anakinra induced no significant change in PTF or TBF. The repeatability coefficients of PTF and TBF in liver lesions were 22% and 28%, respectively. Conclusion: Imatinib increases PTF of colorectal cancer metastases in patients and hence may increase the delivery of antitumor drugs. 15 O-water PET/CT and kinetic modeling provide insights into the microenvironment of human cancers.

The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

“…Because the ECV is largely contained within the interstitial (stromal) ECM-compartment (12), the data suggest that treatment with STI571 increases the volume of the ECM in the carcinoma and that this compartment amounts to about 25% of the carcinoma volume. These preclinical data agree with the findings that treatment of patients with STI571 increases the water-perfusable tumor fraction in metastases from colorectal adenocarcinoma (20). In the current study, we used MRI to investigate how STI571 affects the uptake of low-molecular weight contrast agents.…”

The Role of Interleukins in Colorectal Cancer

“…High levels of IFP in CRC metastasis may reduce the efficacy of antitumour drugs. The experiment showed that anakinra couldn't change the PTF or TBF, because of the experimental design and dearth of data samples, this result needs to be further studied 14 . In contrast, TRAP IL-1, which is a soluble receptor, reduced the proliferation of CRC cells by inhibiting IL-1R1 15 .…”

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

“…On the other hand, the effect of these drugs has to be studied carefully and hence hybrid imaging like PET/CT takes a unique role. A research on water-perfusable tissue fraction (PTF) with help of 15 O-water PET/CT helped to analyze the outcome of Imatinib on the IFP in colorectal cancer [54]. …”