MRI methods for evaluating the effects of tyrosine kinase inhibitor administration used to enhance chemotherapy efficiency in a breast tumor xenograft model.

A PROMISING APPROACH to improving antitumor efficacy in cancer treatment involves the combination of targeted agents aimed at inhibiting signal transduction in tumors with cytotoxic drugs. An advantage to this approach is that signaling pathways and associated receptors implicated in different cancer types can be specifically targeted. The human growth factor receptor (HER) family of tyrosine kinases (TKs) plays an important role in cell differentiation, proliferation, migration, and survival (1). HER TKs have been implicated in breast cancer (2) and mediate some of the angiogenic properties of cancer cells (3,4). Dysregulation of HER TKs has been shown to promote the development and growth of cancer (1). This makes HER TKs an attractive target for the design of antitumor targeting agents. Gefitinib (Iressa), an HER family tyrosine kinase inhibitor (TKI), has demonstrated antitumor activity in HER family overexpressing breast tumor cells in vitro and in vivo (5,6). Preclinical studies have shown enhanced efficacy from the combined administration of gefitinib with chemotherapy (7,8). However, this effect was moderate and recent evidence suggests that the ability of gefitinib to suppress survival signaling might be transient, requiring much higher doses to effectively suppress HER family survival signaling (9). High daily doses of HER TKIs are impractical due to their dose-limiting toxicities. However, when used as chemosensitizers, HER TKIs can be administered for short periods in much higher doses immediately prior to chemotherapy and can potentially serve to prime tumor microenvironments for better delivery of chemotherapeutic agents. Optimal priming of the tumor microenvironment will likely depend on precise timing of HER TKI administration relative to chemotherapy. Measurement methods that are sensitive to the effects of HER TKIs and can be used for in vivo monitoring are needed. MRI methods have been used to detect changes induced by other targeting agents, notably those directed toward the vascular endothelial growth factor (VEGF) (10), but few studies have applied MRI to study the effects of HER family targeting agents. The present study assessed the ability of multiple MRI parameters, including tumor volume, apparent diffusion coefficient (ADC), transendothelial permeability (Kps), and fractional plasma volume (fPV) to detect gefitinib induced changes in a breast tumor xenograft model. The ADC, obtained from diffusion-weighted MRI, is a noninvasive imaging technique that measures the mobility of water in tissues. Diffusion in MRI is generally observed through the introduction of a pair of bipolar motion sensitizing gradient pulses (11). Studies have shown that the ADC is inversely correlated with tissue cellularity (12,13), reflecting greater restriction to motion in denser tissue. In recent years the ADC has emerged as a potential surrogate indicator of tumor response to therapy (14–16) and has been used to differentiate malignant tumors from benign lesions and normal tissue (17–20). Dynamic contrast-enhanced (DCE)-MRI is a technique for evaluating the physiology of microcirculation. It entails serial acquisition of MR images before, during, and after intravenous injection of contrast media into tissues of interest. By fitting DCE-MRI data acquired using macromolecular contrast media such as albumin-(GdDTPA)30 to an appropriate pharmacokinetic model, it is possible to extract quantitative physiologic parameters that describe microvascular wall permeability (Kps) and the fPV. Numerous studies have used DCE-MRI to assess vascular changes associated with response to antiangiogenic therapy (21–24). Several studies have demonstrated decreased Kps in response to effective antiangiogenic therapy, which is generally attributed to less leaky vessels. The fPV has also been used as a surrogate marker of tumor angiogenesis. The aims of the present study were to evaluate the ability of MRI parameters to detect the effects of gefitinib administered as a potential means of improving chemotherapy administration and to evaluate whether MRI parameters can differentiate between two different gefitinib treatment regimens.