Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

Abstract

Purpose To evaluate the feasibility of delivering experimental radiotherapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by X-ray CT. With this technique we delineated the pancreas, and both orthotopic xenografts and genetically engineered disease. CT imaging was validated by comparison with magnetic resonance (MR) imaging. Therapeutic radiation was delivered via a 1 cm diameter field. Selective X-ray radiation therapy (XRT) of the non-invasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360-degree arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic XRT to orthotopic tumors. Results Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times post-treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions This advance permits evaluation of radiation planning and dosing parameters. Accurate non-invasive longitudinal imaging and monitoring of tumor progression and therapeutic response in pre-clinical models is now possible, and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.

A Combination of Radiation and the Hypoxia-Activated Prodrug Evofosfamide (TH-302) is Efficacious against a Human Orthotopic Pancreatic Tumor Model

“…The procedure for CT imaging and arc radiotherapy has been described previously [21] . Both imaging and treatment are carried out on a Precision X-ray 225CX small animal micro-irradiator (Precision X-Ray, North Branford, CT).…”

iNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy

“…Pancreatic tumors were visualized using an image-guided small animal micro-irradiator (XRad225Cx, Precision X-Ray, North Brantford, CT) following a protocol previously described by Thorek and colleagues [37]. Mice were injected with a 3 mL solution of 75 mg Iodine mL -1 (iohexol; Omnipaque, GE Heathcare) at 5 min prior to imaging.…”

“…Mice were injected with a 3 mL solution of 75 mg Iodine mL -1 (iohexol; Omnipaque, GE Heathcare) at 5 min prior to imaging. Data visualization was performed as previously described [37] and tumor volumes were determined using Amira regiongrow tool.…”

“…Immediately after visualization of the pancreatic tumor by X-ray CT using a solution of 15 mg Iodine mL -1 , radiation Arc therapy was performed in mice bearing orthotopic pancreatic tumors [37]. See Supporting Information for details.…”

“…FC1245 pancreatic cancer cells isolated from KPC (Kras LSL-G12D/+ ;Trp53 LSL-R172H/+ ;Pdx1-Cre) mice in the C57BL/6 (B6) genetic background represent a valuable biological PDAC model [38] as they mimic the pathophysiological features of human PDAC, and when transplanted into mice they develop invasive metastatic PDAC characterized by extensive stroma [39]. Murine RT treatment planning utilized CT imaging with intraperitoneal (IP)-administrated contrast agent to define the orthotopic PDAC tumor area and the entire tumor mass was selectively irradiated with a single RT therapeutic absorbed dose of 12 Gy using an arc treatment [37]. The use of a 12 Gy dose to study RT-mediated iNOS production was based on previous studies demonstrating that RT at this dose accelerates the progression of PDAC invasion [11], which we hypothesize will correspondingly effectuate RT-mediated iNOS production.…”