- Open Access
124I-HuCC49deltaCH2 for TAG-72 antigen-directed positron emission tomography (PET) imaging of LS174T colon adenocarcinoma tumor implants in xenograft mice: preliminary results
© Zou et al; licensee BioMed Central Ltd. 2010
- Received: 5 June 2010
- Accepted: 6 August 2010
- Published: 6 August 2010
18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is widely used in diagnostic cancer imaging. However, the use of 18F-FDG in PET-based imaging is limited by its specificity and sensitivity. In contrast, anti-TAG (tumor associated glycoprotein)-72 monoclonal antibodies are highly specific for binding to a variety of adenocarcinomas, including colorectal cancer. The aim of this preliminary study was to evaluate a complimentary determining region (CDR)-grafted humanized CH2-domain-deleted anti-TAG-72 monoclonal antibody (HuCC49deltaCH2), radiolabeled with iodine-124 (124I), as an antigen-directed and cancer-specific targeting agent for PET-based imaging.
HuCC49deltaCH2 was radiolabeled with 124I. Subcutaneous tumor implants of LS174T colon adenocarcinoma cells, which express TAG-72 antigen, were grown on athymic Nu/Nu nude mice as the xenograft model. Intravascular (i.v.) and intraperitoneal (i.p.) administration of 124I-HuCC49deltaCH2 was then evaluated in this xenograft mouse model at various time points from approximately 1 hour to 24 hours after injection using microPET imaging. This was compared to i.v. injection of 18F-FDG in the same xenograft mouse model using microPET imaging at 50 minutes after injection.
At approximately 1 hour after i.v. injection, 124I-HuCC49deltaCH2 was distributed within the systemic circulation, while at approximately 1 hour after i.p. injection, 124I-HuCC49deltaCH2 was distributed within the peritoneal cavity. At time points from 18 hours to 24 hours after i.v. and i.p. injection, 124I-HuCC49deltaCH2 demonstrated a significantly increased level of specific localization to LS174T tumor implants (p = 0.001) when compared to the 1 hour images. In contrast, approximately 50 minutes after i.v. injection, 18F-FDG failed to demonstrate any increased level of specific localization to a LS174T tumor implant, but showed the propensity toward more nonspecific uptake within the heart, Harderian glands of the bony orbits of the eyes, brown fat of the posterior neck, kidneys, and bladder.
On microPET imaging, 124I-HuCC49deltaCH2 demonstrates an increased level of specific localization to tumor implants of LS174T colon adenocarcinoma cells in the xenograft mouse model on delayed imaging, while 18F-FDG failed to demonstrate this. The antigen-directed and cancer-specific 124I-radiolabled anti-TAG-72 monoclonal antibody conjugate, 124I-HuCC49deltaCH2, holds future potential for use in human clinical trials for preoperative, intraoperative, and postoperative PET-based imaging strategies, including fused-modality PET-based imaging platforms.
- Xenograft Mouse
- Xenograft Mouse Model
- LS174T Cell
- Human Colon Adenocarcinoma Cell
- microPET Imaging
The origin of positron imaging dates back to the early 1950's , culminating in the development of positron emission tomography (PET) and its subsequent evolution over the last 40 years [1–4]. The clinical application of PET-based imaging strategies to the field of oncology has had a significant impact upon the care of cancer patients [5–11]. Therefore, the development and selection of the most appropriate and specific radiotracer for PET-based imaging is critical to its success in oncology [12–15].
18F-fluorodeoxyglucose (18F-FDG) is currently the most widely used radiotracer for PET-based imaging strategies . In this regard, 18F-FDG-PET-based imaging is considered state-of-the-art for the diagnostic imaging, staging, and follow-up of a wide variety of malignancies, including colorectal cancer [10, 11]. However, there are several intrinsic limitations related to the use of 18F-FDG-PET imaging that remain a challenge and a concern to those involved in the care of cancer patients [6–9, 16–24]. First, false positive results can occur with 18F-FDG-PET imaging in the presence of any pathologic conditions in which there is a high rate of glucose metabolism, such as inflammatory or infectious processes. Second, false negative results can occur with 18F-FDG-PET imaging secondary to poor avidity of 18F-FDG to certain tumor types and secondary to impaired uptake of 18F-FDG in patients with elevated blood glucose levels. Third, due to system resolution limitations, 18F-FDG-PET imaging is generally limited in its ability to detect small-volume, early-stage primary disease or to detect microscopic disease within the lymph nodes. Fourth, 18F-FDG-PET imaging can produce either false positive or false negative results secondary to the normal physiologic accumulation of 18F-FDG within certain tissues with an elevated level of glucose metabolism (most striking in the brain and heart, and to a lesser degree in the mucosa and smooth muscle of the stomach, small intestine and colon, as well as in liver, spleen, skeletal muscle, thyroid, and brown fat) and secondary to the excretion and accumulation of 18F-FDG within the urinary tract (kidneys, ureters, and bladder). Overall, these factors have a negative impact on optimizing the specificity and sensitivity of 18F-FDG-PET for accurate diagnostic cancer imaging [6–9, 16–24].
A PET-based imaging approach that specifically targets the cancer cell environment would clearly have a significant potential advantage for improving the accuracy of diagnostic cancer imaging over that of the more nonspecific nature of 18F-FDG. In that regard, tumor-associated glycoprotein-72 (TAG-72) is a mucin-like glycoprotein complex that is overexpressed by many adenocarcinomas, including colorectal, pancreatic, gastric, esophageal, ovarian, endometrial, breast, prostate, and lung [22, 24–27]. Such overexpression of TAG-72 is noted in up to approximately 90% of these various adenocarcinomas . In xenograft mice bearing subcutaneous tumor implants of the TAG-72-expressing human colon adenocarcinoma cell line, LS174T [27–29], anti-TAG-72 monoclonal antibodies have been shown to accumulate up to 18-fold higher in LS174T tumor implants than in normal tissues [25, 30, 31]. Over the last 25 years, our group at The Ohio State University, as well as others, have evaluated a variety of radioiodine labeled anti-TAG-72 monoclonal antibodies for tumor-specific antigen targeting at the time of surgery for known primary, recurrent, and metastatic disease, as well as for targeting occult disease and affected lymph nodes in colorectal cancer patients [22, 24, 32–59]. Most recently, we have evaluated the complimentary determining region (CDR)-grafted humanized CH2-domain-deleted anti-TAG-72 monoclonal antibody, HuCC49deltaCH2 [60–63], radiolabeled with iodine-125 (125I), for intraoperative tumor detection of colorectal cancer in both a preclinical xenograft mouse model and in a human clinical trial [22, 24, 57–59]. Collectively, our experience with radiolabeled anti-TAG-72 monoclonal antibodies in combination with a handheld gamma detection probe has clearly shown that this technology provides the surgeon with real-time intraoperative information for more precise tumor localization and resection and has demonstrated improved long-term patient survival after surgery [22, 24].
Because of the drawbacks of using 125I as the radioiodine label for anti-TAG-72 monoclonal antibodies, including the extremely long physical half-life of 125I of approximately 60 days (which generates handling, storage, and disposal issues within the operating room environment and in the surgical pathology department) and the inability of 125I to allow for diagnostic imaging capabilities, other radionuclides have been sought for use with anti-TAG-72 monoclonal antibodies. One such alternative is iodine-124 (124I) . In this regard, 124I is a positron emitting radionuclide that has a physical half-life of approximately 4.2 days, for which its positron emitting properties makes it well-suited for PET-based imaging and for which its shorter physical half-life simplifies the handling, storage, and disposal issues. Therefore, the aim of this preliminary study was to evaluate 124I-HuCC49deltaCH2 as an antigen-directed and cancer-specific targeting agent for PET-based imaging.
Tissue culture and reagents
Cell culture medium (DMEM), fetal bovine serum (FBS), trypsin, and other tissue culture materials were purchased from Invitrogen (Carlsbad, California).
The human colon adenocarcinoma cells (LS174T) [27–29] were purchased from American Type Culture Collection (ATCC) (Manassas, VA). LS174T cells were cultured in DMEM (10% FBS, 1% penicillin/streptomycin) at 37°C in a humidified atmosphere with 5% CO2 and with the medium changed daily. LS174T cells were divided weekly. LS174T cells were trypsinized, collected, and washed with PBS, and resuspended in DMEM (10% FBS) for the subculture process. LS174T cells were stored in DMEM (20% FBS, 10% DMSO) in liquid N2.
DOTA chelated HuCC49deltaCH2 antibody was supplied by Dr. Jeffrey Schlom (Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD).
Phosphate buffered 18F-FDG (200 MBq/ml) was supplied by IBA Molecular (Dulles, VA).
Iodination (124I) of HuCC49deltaCH2
Iodogen (1,3,4,6-tetrachloro-3α-6α-diphenylglycouril) (Pierce, Rockford, IL) was dissolved in methylene chloride (1.0 mg/ml), and 1 ml was pipetted into a sterile, pyrogen-free 10 ml vial. The vial was rotated and dried under nitrogen to evaporate methylene chloride.
Anion Exchange Resin Filters
100- to 200-mesh AG1X8 anion exchange resin (Bio-Rad Labs, Richmond, CA) was washed using sterile, pyrogen free water. The anion exchange resin was aseptically loaded onto a 0.22 μm filter disc (1.1 to 1.5 gram wet resin/filter unit) (Millipore Corporation, Milford, MA). The resin was washed using the following solutions in a sequence: 10 ml sterile, pyrogen-free water; 10 ml sterile 0.1 N NaOH; 10 ml pyrogen free water; 10 ml 0.1 N sodium phosphate buffer (pH 7.4); and finally by 3.3 ml 0.1 N sodium phosphate buffer with 1% HSA.
0.50 ml of HuCC49deltaCH2 antibody (1.5 mg/ml) was added to a 10 ml vial coated with 1 mg of iodogen. Then, 0.8 ml of phosphate buffered Na124I (150 MBq/ml) (IBA Molecular, Dulles, VA) was added to the vial. The reagents were allowed to react for 15 minutes. Free 124I was removed using an exchange resin filter disc. Then, 1 ml of 5% sucrose with 0.05% Tween 20 in saline was used to elute the labeled antibody. The purified 124I-HuCC49deltaCH2 was passed through a 0.22 mm Millipore filter (Millipore Corporation, Milford, MA) for in vivo applications. Radiolabeling efficiency was monitored using thin layer chromatography, which was performed on silica-gel-impregnated glass fiber sheets (Pall Corporation, East Hills, NY). 0.02 M citrate buffer (pH 5.0) was used as the mobile phase.
Xenograft mouse model with human colon adenocarcinoma cells (LS174T)
The human colon adenocarcinoma cells, LS174T, were trypsinized for 2 minutes, collected, and washed with PBS under 1000 rpm × 2 minutes. The washed cells (5×106 cells) were resuspended in a mixture of 50 μl of PBS and 50 μl of matrigel medium (Invitrogen, Carlsbad, California) and then injected subcutaneously into the dorsal surface (back) of female athymic Nu/Nu nude mice (National Cancer Institute at Frederick, Frederick, MD) that were 4 to 6 weeks of age. The resultant LS174T tumor implants on the xenograft mice were allowed to grow for approximately two weeks, reaching a tumor implant volume of up to 300 mm3. The xenograft mice used in this preliminary study were not pretreated with an oral saturated solution of potassium iodide (SSKI).
124I-HuCC49deltaCH2 and 18F-FDG injections of the xenograft mice
Two xenograft mice were successfully injected intravenously (i.v.), by way of tail vein injection, with 124I -HuCC49deltaCH2, at a dose of 0.6 MBq and 0.75 MBq, respectively. Two additional xenograft mice were successfully injected intraperitoneally (i.p.) with 124I-HuCC49deltaCH2, at a dose of 1.4 MBq and 2.5 MBq, respectively. As a control, one xenograft mouse was successfully injected i.v., by way of tail vein injection, with 7.4 MBq of 18F-FDG. Pre-injection and post-injection blood glucose levels were not monitored in the xenograft mice.
In vitro binding studies with Cy7-labeled HuCC49deltaCH2 on LS174T cells, in vivo pharmacokinetics and biodistribution studies with Cy7-labeled HuCC49deltaCH2 in xenograft mice, and ex-vivo post-mortem biodistribution studies with Cy7-labelled HuCC49deltaCH2 on excised tumor implants and organs (i.e., spleen, kidney, lung, heart, liver, stomach, and intestine) from xenograft mice were previously performed and reported elsewhere . These studies with Cy7-labeled HuCC49deltaCH2 were compared to results after nontreatment, Cy7 alone, Cy7-labeled nonspecific human IgG, Cy7-labeled murine CC49, and pretreatment with unlabeled murine CC49 prior to administration of Cy7-labeled HuCC49deltaCH2 .
MicroPET tumor imaging of the xenograft mice
Selection of microPET imaging time points was based on historical data as well as the physical half-lives of 18F (110 minutes) and 124I (4.2 days). For 18F-FDG, the standard accepted injection to scan time for humans and small animals is approximately 60 ± 10 minutes [68–70]. For 124I-HuCC49deltaCH2 injected xenograft mice, an initial 1 hour time point for baseline microPET imaging was used, as well as a time range of delayed microPET imaging from 18 hours to 24 hours after administration of 124I-HuCC49deltaCH2 to allow for distribution, uptake, and clearance. At selected time points (ranging from approximately 1 hour to 24 hours after injection of 124I-HuCC49deltaCH2), the xenograft mice were anesthetized with i.p. Ketamine (100 mg/kg)/Xylazine (10 mg/kg) and then scanned on an Inveon microPET scanner (Siemens Medical Solutions, Knoxville, TN). Image acquisition and analysis were performed by using Inveon Acquisition Workplace (Siemens Medical Solutions, Knoxville, TN). Xenograft mice initially underwent a transmission scan with a cobalt-57 source for 402 seconds for attenuation correction and quantification. Xenograft mice then underwent a PET emission scan at approximately 1 hour, 18 hours, and 20 hours after injection of 124I-HuCC49deltaCH2 with an acquisition time of 400 seconds and again at approximately 23 hours or 24 hours after injection of 124I-HuCC49deltaCH2 with an acquisition time of 800 seconds. For the 18F-FDG injected xenograft mouse, a PET emission scan was obtained at approximately 50 minutes after injection of 18F-FDG with an acquisition time of 400 seconds. The energy window of all PET emission scans was set to 350 keV to 650 keV, with a time resolution of 3.4 ns. Each emission acquisition data set was attenuation corrected with the attenuation transmission scan taken of each individual mouse at each designated time point and arranged into sinograms. The resultant sinograms were iteratively reconstructed into three dimensional volumes using an ordered-subset expectation maximization (OSEM) reconstruction algorithm. The transmission acquisition yielded an approximation of body volume and anatomic localization, such that regions of interest could be created to represent portions of the mouse anatomy, specifically, whole body, the LS174T tumor implant, and a designated background area (i.e., left lower quadrant of the abdomen).
The region of interest (ROI), for determination of tumor implant volume, was drawn manually by qualitative assessment to cover the entire tumor implant volume by summation of voxels using the Inveon software (Siemens Medical Solutions, Knoxville, TN) in a manner similar to that previously published by Jensen et al.. In the study by Jensen et al., they compared the accuracy of xenograft measurement by in vivo caliper measurement versus microCT-based and microPET-based measurement and found microCT to be the most accurate measurement method . We used a similar method in conjunction with the transmission image to generate the tumor implant volume. PET activity within the volumetric ROI then yielded the resultant average intensity counts for the tumor implant and for the designated background area. Finally, to generate a quantification measurement value for the activity of 124I-HuCC49deltaCH2 and of 18F-FDG that was imaged on microPET within a given LS174T tumor implant, we utilized the unitless value of the relative ratio of the average intensity counts. This relative ratio of the average intensity counts was determined by dividing the average intensity counts from the tumor implant volume by the average intensity counts of the designated background area. We elected to generate this relative ratio of the average intensity counts as a quantification measurement value due to the fact that mouse body weights and tumor implant weights were not recorded and microCT was not obtained on all of the xenograft mice during the course of the current preliminary study.
The software program IBM SPSS® 18 for Windows® (SPSS, Inc., Chicago, Illinois) was used for the data analysis. One-way analysis of variance (ANOVA) was utilized for the comparison of the relative ratio of average intensity counts of the LS174T tumor implants.
After chromatographic purification, 98% of 124I was bound to the chelated HuCC49deltaCH2 antibody, as determined by thin layer chromatography. The radioactivity of 124I-HuCC49deltaCH2 obtained was 15 MBq/ml.
To generate a quantification measurement value for the activity of 124I-HuCC49deltaCH2 and of 18F-FDG that was imaged on microPET within a given LS174T tumor implant, we utilized the unitless value of the relative ratio of the average intensity counts, as determined by dividing the average intensity counts of the LS174T tumor implant by the average intensity counts of the designated background area. For comparing the localization of 124I-HuCC49deltaCH2 within the LS174T tumor implants at approximately 1 hour after i.v. and i.p. injection versus at 18 hours to 24 hours after i.v. and i.p. injection, the mean relative ratio of the average intensity counts was determined to be 0.34 (SD ± 0.29, range 0.06 to 0.64, n = 4) at approximately 1 hour after injection as compared to 2.58 (SD ± 0.99, range 1.57 to 4.57, n = 8) at 18, 20, 23, and 24 hours after injection (p = 0.001). This finding verifies a significantly increased level of specific localization of 124I-HuCC49deltaCH2 to LS174T tumor implants as compared to background tissues at 18 hours to 24 hours after injection. For comparing the localization of 124I-HuCC49deltaCH2 within the LS174T tumor implants for the i.v. injection route versus the i.p. injection route, the mean relative ratio of the average intensity counts was determined to be 2.31 (SD ± 0.71, range 1.83 to 3.356, n = 4) for the i.v. injection route at 18 and 23 hours after injection as compared to 2.85 (SD ± 1.26, range 1.57 to 4.57, n = 4) for the i.p. injection route at 20 hours and 24 hours after injection (p = 0.481), suggesting that i.v. and i.p. administration of 124I-HuCC49deltaCH2 achieved similar delivery efficiency. For comparing the localization of 124I-HuCC49deltaCH2 within the LS174T tumor implants at differing doses of 124I-HuCC49deltaCH2, the mean relative ratio of the average intensity counts was determined to be 2.03 (SD ± 0.14, range 1.93 to 2.13, n = 2) at the lowest dose administered (i.e., 0.6 MBq i.v.) as compared to 3.70 (SD ± 1.23, range 2.84 to 4.57, n = 2) at the highest dose administered (i.e., 2.5 MBq i.p.) (p = 0.195). Finally, for comparing the localization of 124I-HuCC49deltaCH2 versus 18F-FDG within the LS174T tumor implants, the mean relative ratio of the average intensity counts was 2.58 (SD ± 0.99, range 1.57 to 4.57, n = 8) for 124I-HuCC49deltaCH2 at 18, 20, 23, and 24 hours after i.v. and i.p. injection as compared to 1.05 (n = 1) for 18F-FDG at approximately 50 minutes after i.v. injection (p = 0.188). Although this demonstrates that there was 2.46 times greater localization of 124I-HuCC49deltaCH2 within the LS174T tumor implants as compared to 18F-FDG, this particular p-value did not reach statistical significance, and this is likely attributable to the statistic restraints of comparing only one time point for a single 18F-FDG injected xenograft mouse to that of 8 time points for 4 xenograft mice injected with 124I-HuCC49deltaCH2.
In the current preliminary report, 124I-HuCC49deltaCH2 demonstrated a significantly increased level of specific localization to LS174T tumor implants as compared to background tissues (p = 0.001) in the xenograft mouse model at 18 hours to 24 hours after injection as compared to at approximately 1 hour after injection. In contrast, in the same xenograft mouse model, 18F-FDG failed to demonstrate any increased level of specific localization to a LS174T tumor implant as compared to background tissues at approximately 50 minutes after injection. These findings, although based on a limited number of xenograft mice, re-enforce the recognized limitations of an 18F-FDG-based PET imaging strategy as compared to an antigen-directed and cancer-specific 124I-HuCC49deltaCH2-based PET imaging strategy.
In the current preliminary report, both i.v. and i.p. administration of 124I-HuCC49deltaCH2 resulted in specific localization on microPET imaging to the LS174T tumor implants in the xenograft mouse model at 18 and 23 hours and at 20 and 24 hours after injection, respectively, validating the use of both injection routes for use in preclinical animal studies evaluating 124I-HuCC49deltaCH2. Therefore, the end result of the transport of 124I-HuCC49deltaCH2 from the peritoneal cavity to the LS174T tumor implants after i.p. administration was similar to the transport of 124I-HuCC49deltaCH2 from the systemic circulation to LS174T tumor implants after i.v. administration. These results with 124I-HuCC49deltaCH2 are consistent with previous studies which have demonstrated the efficacy of i.p. administered anti-TAG-72 monoclonal antibodies in patients with colorectal cancer [71, 72].
Overall, these preliminary results in the LS174T colon adenocarcinoma xenograft mouse model are very encouraging and lay the ground work for further investigations into the use of this antigen-directed and cancer-specific 124I-radiolabeled anti-TAG-72 monoclonal antibody conjugate in human clinical trials related to preoperative, intraoperative, and postoperative PET-based imaging strategies . Such an approach that utilizes PET-based imaging in conjunction with 124I-HuCC49deltaCH2 is clinically feasible and could potentially have a significant impact upon the current management of colorectal cancer, as well as upon other TAG-72 antigen-expressing adenocarcinomas.
Despite the promising results of our current preliminary report that clearly show that the 124I-radiolabled anti-TAG-72 monoclonal antibody conjugate, 124I-HuCC49deltaCH2, shows high degree of specific localization to TAG-72 antigen expressing tumor implants in the xenograft mouse model, there are several shortcomings of our current experimental study design which led to non-optimization of our reported results and that will need to be further addressed in future experiments. These shortcomings are the small sample size, the lack of thyroid block by oral administration of SSKI, the use of the chelated form of the HuCC49deltaCH2 antibody, and the anesthetic and time constraints at the time of these preliminary experiments that did not allow for obtaining fused microPET/CT imaging of all the xenograft mice studied.
First, as is shown in Figures 1, 2, 3, and 4, significant thyroid uptake was seen on microPET imaging at the time points of 18 hours and 23 hours after i.v. injection and at the time points of 20 hours and 24 hours after i.p. injection of 124I-HuCC49deltaCH2. It has long been well-known in the nuclear medicine literature that if the thyroid is not blocked by the oral administration of SSKI, then resultant thyroid uptake of circulating radioactive iodine will freely occur [74–76]. This has been previously experimentally evaluated with radioiodine labeled anti-TAG-72 monoclonal antibodies . As such, in the current animal experiments, the lack of thyroid blockade resulted in significant thyroid uptake of free 124I as the unbound 124I-HuCC49deltaCH2 was metabolized in the body and before the free circulating 124I was excreted into the urine. Therefore, pre-treatment of the xenograft mice with oral administration of SSKI to minimize thyroid uptake of free 124I would have resulted in more optimal microPET imaging, thus better illustrating our take-home message of specific localization of 124I-HuCC49deltaCH2 to LS174T tumor implants by minimizing the degree of thyroid localization of free 124I. This shortcoming was an oversight on our part and will be subsequently re-addressed in future xenograft mouse model experiments in which the xenograft mice are pretreated with oral SSKI.
Second, nonspecific liver uptake of 124I-HuCC49deltaCH2 was seen on microPET imaging. As best illustrated in Figure 4, significant nonspecific liver uptake was most pronounced at the time points of 20 hours and 24 hours after i.p. administration of the higher dose (2.5 MBq) of 124I-HuCC49deltaCH2. This nonspecific liver uptake was less intense on microPET imaging at the time points of 20 hours and 24 hours after i.p. administration of a lower dose (1.4 MBq) of 124I-HuCC49deltaCH2 (Figure 3) and was minimally present on microPET imaging at the time points of 18 hours and 23 hours after i.v. administration of either dose (0.6 MBq or 0.75 MBq) of 124I-HuCC49deltaCH2 (Figure 1 and Figure 2). A similar pattern of accumulation within the liver has been previously reported for various chelated radiolabeled CC49 monoclonal antibodies , as well as for a single-chain Fv version of the radiolabeled CC49 monoclonal antibody . It has been suggested that the high accumulation of these radiolabeled monoclonal antibody in the liver is likely due to the metabolism of the chelated form of the antibody within the liver . Clearance and metabolism of IgG antibodies occurs predominantly through the reticuloendothelial system (RES), primarily in the liver and spleen, which both contain Kupffer cells [78, 79]. Furthermore, IgG antibodies are bound and internalized by asialoglycoprotein receptors in the liver cells, increasing the retention of IgG antibodies within the liver. Therefore, it is our contention that the nonspecific liver uptake of 124I-HuCC49deltaCH2 seen on microPET imaging is explainable by our use of chelated form of the HuCC49deltaCH2 antibody. It should be noted that our inadvertent use of the chelated form of the HuCC49deltaCH2 antibody was not recognized until after analysis of the microPET imaging, as is best exemplified at the time points of 20 hours and 24 hours after i.p. administration of 2.5 MBq of 124I-HuCC49deltaCH2. Therefore, use of the non-chelated form of the HuCC49deltaCH2 antibody would have potentially eliminated the nonspecific liver uptake of 124I-HuCC49deltaCH2, thus better illustrating our take-home message of specific localization of 124I-HuCC49deltaCH2 to LS174T tumor implants. This shortcoming was an oversight on our part and will be subsequently re-addressed in future xenograft mouse model experiments in which the non-chelated form of the HuCC49deltaCH2 antibody is utilized.
Third, at the time of this preliminary animal experiment, due to limitations in the type of anesthetic available (i.e., only i.p. Ketamine/Xylazine was available and inhalation isoflurane anesthesia was not available), due to the time constraints necessary for repetitive scanning in both a microPET and a microCT format, and due to the limited number of xenograft mice available, fused microPET/CT imaging was only obtained on one of the five xenograft mice. Therefore, while all five xenograft mice were imaged by the dedicated microPET scanner, only one xenograft mouse (i.v. injection of 124I-HuCC49deltaCH2 at a dose of 0.6 MBq) was also imaged with the microCT scanner at the time point of 24 hours after i.v. injection, thus allowing for reconstruction of fused microPET/CT images. In this particular case of fused microPET/CT imaging, the microCT images demonstrated relatively good correlation of anatomy with the transmission images and assisted in the accurate determination of tumor implant volume from the transmission scan. It is evident within the molecular imaging literature that fused-modality PET-based imaging is superior to PET alone-based imaging, both for the PET/CT platform and for the PET/MRI platform [73, 80–83]. These fused imaging platforms can provide both molecular/functional information and structural information that can more accurately and more precisely localize various disease processes. It is our intention to subsequently re-address this shortcoming in future xenograft mouse model experiments by utilizing a fused microPET/CT imaging platform in all of the xenograft mice.
As a last notable point of discussion, some may contend that the lack of specific localization of 18F-FDG to the LS174T tumor implant as compared to the background tissues was the specific result of the type of anesthetic used for the Nu/Nu nude mice in the current preliminary study (i.e., i.p. Ketamine/Xylazine instead of inhalation isoflurane anesthesia). It has been previously reported that C57BL/6 mice injected with 18F-FDG and having received Ketamine/Xylazine anesthesia demonstrate increased blood glucose levels, as well as increased 18F-FDG activity within multiple normal tissues, such as in muscle, lung, liver, kidney, and blood, as compared to C57BL/6 mice injected with 18F-FDG that received no anesthesia [84, 85]. It has been suggested by some authors that these metabolic effects are mediated through the inhibition of insulin release, and that such effects are most prominent in mice kept fasting for only 4 hours, but are substantially attenuated by 20 hours of fasting . In our preliminary animal experiments, the xenograft mice were kept without food for approximately 14 hours prior to the injection of 18F-FDG and 124I-HuCC49deltaCH2. Therefore, the previously described metabolic effects resulting from only a short-duration fast should have been minimized. Furthermore, these same authors reported that Ketamine/Xylazine anesthesia did not significantly alter 18F-FDG activity within Lewis lung carcinoma (LLC) subcutaneous tumor implants on C57BL/6 mice as compared to the same scenerio with no anesthesia . In contrast to Ketamine/Xylazine, low dose (0.5%) inhalation isoflurane anesthesia has been reported to resulted in no significant increase in 18F-FDG activity within normal tissues (i.e., muscle, lung, liver, and kidney) of C57BL/6 mice as compared to the same scenerio with no anesthesia [84, 85]. These findings indirectly suggest that the use of low dose (0.5%) inhalation isoflurane anesthesia for the Nu/Nu nude mice in our current preliminary study could have potentially provided a means to eliminate any negative impact of the choice of anesthetic on the absolute level of 18F-FDG activity within the LS174T tumor implant and the various normal tissues. Based upon these findings, it is our plan to use inhalation isoflurane anesthesia in our future proposed animal studies in order to minimize the occurence of any such issues.
On microPET imaging, 124I-HuCC49deltaCH2 demonstrates an increased level of specific localization to tumor implants of LS174T colon adenocarcinoma cells as compared to background tissues in the xenograft mouse model, while 18F-FDG failed to demonstrate this same finding. Clearly, a PET-based imaging approach that utilizes 124I-HuCC49deltaCH2 is feasible and could potentially have a significant impact upon the current management of colorectal cancer and other TAG-72 antigen-expressing adenocarcinomas. This antigen-directed and cancer-specific 124I-radiolabled anti-TAG-72 monoclonal antibody conjugate holds future potential for use in human clinical trials for preoperative, intraoperative, and postoperative PET-based imaging strategies, including fused-modality PET-based imaging platforms.
The authors would like to thank Dr. Jeffrey Schlom (Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892) for his generous support with providing the anti-TAG-72 monoclonal antibody, HuCC49deltaCH2, and for his valuable input into this study.
This work was performed entirely at The Ohio State University and was partially supported by the grant RO1 CA120023 to DS from the National Cancer Institute (NCI).
- Brownell GL: A history of positron imaging. 1999,http://www.mit.edu/~glb/Google Scholar
- Chesler DA: Three-dimensional activity distribution from multiple positron scintigraphs. J Nucl Med. 1971, 12: 347-348.Google Scholar
- Ter-Pogossian MM, Phelps ME, Hoffman EJ, Mullani NA: A positron-emission transaxial tomograph for nuclear imaging (PETT). Radiology. 1975, 114: 89-98.View ArticlePubMedGoogle Scholar
- Hoffmann EJ, Phelps ME, Mullani NA, Higgins CS, Ter-Pogossian MM: Design and performance characteristics of a whole-body positron transaxial tomograph. J Nucl Med. 1976, 17: 493-502.PubMedGoogle Scholar
- Hoh CK, Schiepers C, Seltzer MA, Gambhir SS, Silverman DH, Czernin J, Maddahi J, Phelps ME: PET in oncology: will it replace the other modalities?. Semin Nucl Med. 1997, 27: 94-106. 10.1016/S0001-2998(97)80042-6.View ArticlePubMedGoogle Scholar
- Otsuka H, Graham M, Kubo A, Nishitani H: Clinical utility of FDG PET. J Med Invest. 2004, 51: 14-19. 10.2152/jmi.51.14.View ArticlePubMedGoogle Scholar
- Endo K, Oriuchi N, Higuchi T, Iida Y, Hanaoka H, Miyakubo M, Ishikita T, Koyama K: PET and PET/CT using 18F-FDG in the diagnosis and management of cancer patients. Int J Clin Oncol. 2006, 11: 286-296. 10.1007/s10147-006-0595-0.View ArticlePubMedGoogle Scholar
- Maldonado A, González-Alenda FJ, Alonso M, Sierra JM: PET-CT in clinical oncology. Clin Transl Oncol. 2007, 9: 494-505. 10.1007/s12094-007-0093-5.View ArticlePubMedGoogle Scholar
- Otsuka H, Morita N, Yamashita K, Nishitani H: FDG-PET/CT for cancer management. J Med Invest. 2007, 54: 195-199. 10.2152/jmi.54.195.View ArticlePubMedGoogle Scholar
- Poeppel TD, Krause BJ, Heusner TA, Boy C, Bockisch A, Antoch G: PET/CT for the staging and follow-up of patients with malignancies. Eur J Radiol. 2009, 70: 382-92. 10.1016/j.ejrad.2009.03.051.View ArticlePubMedGoogle Scholar
- Vriens D, de Geus-Oei LF, van der Graaf WT, Oyen WJ: Tailoring therapy in colorectal cancer by PET-CT. Q J Nucl Med Mol Imaging. 2009, 53: 224-244.PubMedGoogle Scholar
- Kumar R, Dhanpathi H, Basu S, Rubello D, Fanti S, Alavi A: Oncologic PET tracers beyond [(18)F]FDG and the novel quantitative approaches in PET imaging. Q J Nucl Med Mol Imaging. 2008, 52: 50-65.PubMedGoogle Scholar
- Dunphy MP, Lewis JS: Radiopharmaceuticals in preclinical and clinical development for monitoring of therapy with PET. J Nucl Med. 2009, 50 (Suppl 1): 106S-121S. 10.2967/jnumed.108.057281.PubMed CentralView ArticlePubMedGoogle Scholar
- Murphy PS, Bergström M: Radiopharmaceuticals for oncology drug development: a pharmaceutical industry perspective. Curr Pharm Des. 2009, 15: 957-965. 10.2174/138161209787581977.View ArticlePubMedGoogle Scholar
- Larson SM, Schoder H: New PET tracers for evaluation of solid tumor response to therapy. Q J Nucl Med Mol Imaging. 2009, 53: 158-166.PubMedGoogle Scholar
- Vallabhajosula S: (18)F-labeled positron emission tomographic radiopharmaceuticals in oncology: an overview of radiochemistry and mechanisms of tumor localization. Semin Nucl Med. 2007, 37: 400-419. 10.1053/j.semnuclmed.2007.08.004.View ArticlePubMedGoogle Scholar
- Pauwels EK, Ribeiro MJ, Stoot JH, McCready VR, Bourguignon M, Mazière B: FDG accumulation and tumor biology. Nucl Med Biol. 1998, 25: 317-322. 10.1016/S0969-8051(97)00226-6.View ArticlePubMedGoogle Scholar
- Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, Obradovich JE, Muzik O, Mangner TJ: Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998, 4: 1334-1336. 10.1038/3337.View ArticlePubMedGoogle Scholar
- Lind P, Igerc I, Beyer T, Reinprecht P, Hausegger K: Advantages and limitations of FDG PET in the follow-up of breast cancer. Eur J Nucl Med Mol Imaging. 2004, 31 (Suppl 1): S125-S134.PubMedGoogle Scholar
- Lim HS, Yoon W, Chung TW, Kim JK, Park JG, Kang HK, Bom HS, Yoon JH: FDG PET/CT for the detection and evaluation of breast diseases: usefulness and limitations. Radiographics. 2007, 27 (Suppl 1): S197-S213. 10.1148/rg.27si075507.View ArticlePubMedGoogle Scholar
- Metser U, Even-Sapir E: Increased (18)F-fluorodeoxyglucose uptake in benign, nonphysiologic lesions found on whole-body positron emission tomography/computed tomography (PET/CT): accumulated data from four years of experience with PET/CT. Semin Nucl Med. 2007, 37: 206-222. 10.1053/j.semnuclmed.2007.01.001.View ArticlePubMedGoogle Scholar
- Sun D, Bloomston M, Hinkle G, Al-Saif OH, Hall NC, Povoski SP, Arnold MW, Martin EW: Radioimmunoguided surgery (RIGS), PET/CT image-guided surgery, and fluorescence image-guided surgery: past, present, and future. J Surg Oncol. 2007, 96: 297-308. 10.1002/jso.20869.View ArticlePubMedGoogle Scholar
- Schöder H, Moskowitz C: PET imaging for response assessment in lymphoma: potential and limitations. Radiol Clin North Am. 2008, 46: 225-241. 10.1016/j.rcl.2008.04.002.View ArticlePubMedGoogle Scholar
- Povoski SP, Neff RL, Mojzisik CM, O'Malley DM, Hinkle GH, Hall NC, Murrey DA, Knopp MV, Martin EW: A comprehensive overview of radioguided surgery using gamma detection probe technology. World J Surg Oncol. 2009, 7: 11-10.1186/1477-7819-7-11.PubMed CentralView ArticlePubMedGoogle Scholar
- Horan Hand P, Colcher D, Salomon D, Ridge J, Noguchi P, Schlom J: Influence of spatial configuration of carcinoma cell populations on the expression of a tumor-associated glycoprotein. Cancer Res. 1985, 45: 833-840.PubMedGoogle Scholar
- Johnson VG, Schlom J, Paterson AJ, Bennett J, Magnani JL, Colcher D: Analysis of a human tumor-associated glycoprotein (TAG-72) identified by monoclonal antibody B72.3. Cancer Res. 1986, 46: 850-857.PubMedGoogle Scholar
- Sheer DG, Schlom J, Cooper HL: Purification and composition of the human tumor-associated glycoprotein (TAG-72) defined by monoclonal antibodies CC49 and B72.3. Cancer Res. 1988, 48: 6811-6818.PubMedGoogle Scholar
- Tom BH, Rutzky LP, Jakstys MM, Oyasu R, Kaye CI, Kahan BD: Human colonic adenocarcinoma cells. I. Establishment and description of a new line. In Vitro. 1976, 12: 180-191. 10.1007/BF02796440.View ArticlePubMedGoogle Scholar
- Tom BH, Rutzky LP, Oyasu R, Tomita JT, Goldenberg DM, Kahan BD: Human colon adenocarcinoma cells. II. Tumorigenic and organoid expression in vivo and in vitro. J Natl Cancer Inst. 1977, 58: 1507-1512.PubMedGoogle Scholar
- Colcher D, Keenan AM, Larson SM, Schlom J: Prolonged binding of a radiolabeled monoclonal antibody (B72.3) used for the in situ radioimmunodetection of human colon carcinoma xenografts. Cancer Res. 1984, 44: 5744-5749.PubMedGoogle Scholar
- Colcher D, Minelli MF, Roselli M, Muraro R, Simpson-Milenic D, Schlom J: Radioimmunolocalization of human carcinoma xenografts with B72.3 second generation monoclonal antibodies. Cancer Res. 1988, 48: 4597-4603.PubMedGoogle Scholar
- Sickle-Santanello BJ, O'Dwyer PJ, Mojzisik C, Tuttle SE, Hinkle GH, Rousseau M, Schlom J, Colcher D, Thurston MO, Nieroda C, Sardi A, Farrar WB, Minton JP, Martin EW: Radioimmunoguided surgery using the monoclonal antibody B72.3 in colorectal tumors. Dis Colon Rectum. 1987, 30: 761-764. 10.1007/BF02554623.View ArticlePubMedGoogle Scholar
- Tuttle SE, Jewell SD, Mojzisik CM, Hinkle GH, Colcher D, Schlom J, Martin EW: Intraoperative radioimmunolocalization of colorectal carcinoma with a hand-held gamma probe and MAb B72.3: comparison of in vivo gamma probe counts with in vitro MAb radiolocalization. Int J Cancer. 1988, 42: 352-358. 10.1002/ijc.2910420308.View ArticlePubMedGoogle Scholar
- Martin EW, Mojzisik CM, Hinkle GH, Sampsel J, Siddiqi M, Tuttle SE, Sickle-Santanello B, Colcher D, Thurston MO, Bell J, Farrar WB, Schlom J: Radioimmunoguided surgery using monoclonal antibody. Am J Surg. 1988, 156: 386-392. 10.1016/S0002-9610(88)80193-4.View ArticlePubMedGoogle Scholar
- Nieroda CA, Mojzisik C, Sardi A, Farrar WB, Hinkle G, Siddiqi MA, Ferrara PJ, James A, Schlom J, Thurston MO, Martin EW: Staging of carcinoma of the breast using a hand-held gamma detecting probe and monoclonal antibody B72.3. Surg Gynecol Obstet. 1989, 169: 35-40.PubMedGoogle Scholar
- Sardi A, Siddiqi MA, Hinkle GH, Rousseau M, Gersman M, Hill T, Olsen J, Tuttle SE, Young D, Houchens D, Thurston M, Martin EW: Localization by hand-held gamma probe of tumor labeled with antibody "cocktail". J Surg Res. 1989, 47: 227-234. 10.1016/0022-4804(89)90112-1.View ArticlePubMedGoogle Scholar
- Nieroda CA, Mojzisik C, Sardi A, Ferrara P, Hinkle G, Thurston MO, Martin EW: Radioimmunoguided surgery in primary colon cancer. Cancer Detect Prev. 1990, 14: 651-656.PubMedGoogle Scholar
- Nieroda CA, Mojzisik C, Hinkle G, Thurston MO, Martin EW: Radioimmunoguided surgery (RIGS) in recurrent colorectal cancer. Cancer Detect Prev. 1991, 15: 225-229.PubMedGoogle Scholar
- Cohen AM, Martin EW, Lavery I, Daly J, Sardi A, Aitken D, Bland K, Mojzisik C, Hinkle G: Radioimmunoguided surgery using iodine 125 B72.3 in patients with colorectal cancer. Arch Surg. 1991, 126: 349-352.View ArticlePubMedGoogle Scholar
- Martin EW, Carey LC: Second-look surgery for colorectal cancer. The second time around. Ann Surg. 1991, 214: 321-325. 10.1097/00000658-199109000-00014. discussion 326-327PubMed CentralView ArticlePubMedGoogle Scholar
- Arnold MW, Schneebaum S, Berens A, Petty L, Mojzisik C, Hinkle G, Martin EW: Intraoperative detection of colorectal cancer with radioimmunoguided surgery and CC49, a second-generation monoclonal antibody. Ann Surg. 1992, 216: 627-632. 10.1097/00000658-199212000-00003.PubMed CentralView ArticlePubMedGoogle Scholar
- Arnold MW, Schneebaum S, Berens A, Mojzisik C, Hinkle G, Martin EW: Radioimmunoguided surgery challenges traditional decision making in patients with primary colorectal cancer. Surgery. 1992, 112: 624-629. discussion 629-630PubMedGoogle Scholar
- Schneebaum S, Arnold MW, Houchens DP, Greenson JK, Cote RJ, Hitchcock CL, Young DC, Mojzisik CM, Martin EW: The significance of intraoperative periportal lymph node metastasis identification in patients with colorectal carcinoma. Cancer. 1995, 75: 2809-2817. 10.1002/1097-0142(19950615)75:12<2809::AID-CNCR2820751205>3.0.CO;2-0.View ArticlePubMedGoogle Scholar
- Bertsch DJ, Burak WE, Young DC, Arnold MW, Martin EW: Radioimmunoguided surgery improves survival for patients recurrent colorectal cancer. Surgery. 1995, 118: 634-638. 10.1016/S0039-6060(05)80029-7. discussion 638-639View ArticlePubMedGoogle Scholar
- Arnold MW, Young DC, Hitchcock CL, Schneebaum S, Martin EW: Radioimmunoguided surgery in primary colorectal carcinoma: an intraoperative prognostic tool and adjuvant to traditional staging. Am J Surg. 1995, 170: 315-318. 10.1016/S0002-9610(99)80295-5.View ArticlePubMedGoogle Scholar
- Cote RJ, Houchens DP, Hitchcock CL, Saad AD, Nines RG, Greenson JK, Schneebaum S, Arnold MW, Martin EW: Intraoperative detection of occult colon cancer micrometastases using 125 I-radiolabled monoclonal antibody CC49. Cancer. 1996, 77: 613-620. 10.1002/(SICI)1097-0142(19960215)77:4<613::AID-CNCR5>3.0.CO;2-H.View ArticlePubMedGoogle Scholar
- Arnold MW, Hitchcock CL, Young DC, Burak WE, Bertsch DJ, Martin EW: Intra-abdominal patterns of disease dissemination in colorectal cancer identified using radioimmunoguided surgery. Dis Colon Rectum. 1996, 39: 509-513. 10.1007/BF02058702.View ArticlePubMedGoogle Scholar
- Bertsch DJ, Burak WE, Young DC, Arnold MW, Martin EW: Radioimmunoguided surgery for colorectal cancer. Ann Surg Oncol. 1996, 3: 310-316. 10.1007/BF02306288.View ArticlePubMedGoogle Scholar
- Martinez DA, Barbera-Guillem E, LaValle GJ, Martin EW: Radioimmunoguided surgery for gastrointestinal malignancies: an analysis of 14 years of clinical experience. Cancer Control. 1997, 4: 505-516.PubMedGoogle Scholar
- Martin EW, Thurston MO: Intraoperative radioimmunodetection. Semin Surg Oncol. 1998, 15: 205-208. 10.1002/(SICI)1098-2388(199812)15:4<205::AID-SSU2>3.0.CO;2-S.View ArticlePubMedGoogle Scholar
- Bakalakos EA, Young DC, Martin EW: Radioimmunoguided surgery for patients with liver metastases secondary to colorectal cancer. Ann Surg Oncol. 1998, 5: 590-594. 10.1007/BF02303827.View ArticlePubMedGoogle Scholar
- Arnold MW, Young DM, Hitchcock CL, Barberá-Guillem E, Nieroda C, Martin EW: Staging of colorectal cancer: biology vs. morphology. Dis Colon Rectum. 1998, 41: 1482-1487. 10.1007/BF02237292.View ArticlePubMedGoogle Scholar
- Schneebaum S, Troitsa A, Avital S, Haddad R, Kashtan H, Gitstein G, Baratz M, Brazovsky E, Papo J, Skornick Y: Identification of lymph node metastases in recurrent colorectal cancer. Recent Results Cancer Res. 2000, 157: 281-292.View ArticlePubMedGoogle Scholar
- Avital S, Haddad R, Troitsa A, Kashtan H, Brazovsky E, Gitstein G, Skornick Y, Schneebaum S: Radioimmunoguided surgery for recurrent colorectal cancer manifested by isolated CEA elevation. Cancer. 2000, 89: 1692-1698. 10.1002/1097-0142(20001015)89:8<1692::AID-CNCR7>3.0.CO;2-2.View ArticlePubMedGoogle Scholar
- Schneebaum S, Troitsa A, Haddad R, Avital S, Kashtan H, Baratz M, Brazovsky E, Papo J, Skornick Y: Immunoguided lymph node dissection in colorectal cancer: a new challenge?. World J Surg. 2001, 25: 1495-1498. discussion 1499View ArticlePubMedGoogle Scholar
- Haddad R, Avital S, Troitsa A, Chen J, Baratz M, Brazovsky E, Gitstein G, Kashtan H, Skornick Y, Schneebaum S: Benefits of radioimmunoguided surgery for pelvic recurrence. Eur J Surg Oncol. 2001, 27: 298-301. 10.1053/ejso.2000.1108.View ArticlePubMedGoogle Scholar
- Agnese DM, Abdessalam SF, Burak WE, Arnold MW, Soble D, Hinkle GH, Young D, Kazaeli MB, Martin EW: Pilot study using a humanized CC49 monoclonal antibody (HuCC49ΔCH2) to localize recurrent colorectal carcinoma. Ann Surg Oncol. 2004, 11: 197-202. 10.1245/ASO.2004.05.010.View ArticlePubMedGoogle Scholar
- Xiao J, Horst S, Hinkle G, Cao X, Kocak E, Fang J, Young D, Khazaeli M, Agnese D, Sun D, Martin E: Pharmacokinetics and clinical evaluation of 125I-radiolabeled humanized CC49 monoclonal antibody (HuCC49deltaC(H)2) in recurrent and metastatic colorectal cancer patients. Cancer Biother Radiopharm. 2005, 20: 16-26. 10.1089/cbr.2005.20.16.View ArticlePubMedGoogle Scholar
- Fang L, Holford NH, Hinkle G, Cao X, Xiao JJ, Bloomston M, Gibbs S, Saif OH, Dalton JT, Chan KK, Schlom J, Martin EW, Sun D: Population pharmacokinetics of humanized monoclonal antibody HuCC49deltaCH2 and murine antibody CC49 in colorectal cancer patients. J Clin Pharmacol. 2007, 47: 227-237. 10.1177/0091270006293758.View ArticlePubMedGoogle Scholar
- Calvo B, Kashmiri SV, Hutzell P, Hand PH, Slavin-Chiorini DC, Schlom J, Zaremba S: Construction and purification of domain-deleted immunoglobulin variants of the recombinant/chimeric B72.3 (y1) monoclonal antibody. Cancer Biother. 1993, 8: 95-109.View ArticlePubMedGoogle Scholar
- Slavin-Chiorini DC, Horan Hand PH, Kashmiri SV, Calvo B, Zaremba S, Schlom J: Biologic properties of a CH2 domain-deleted recombinant immunoglobulin. Int J Cancer. 1993, 53: 97-103. 10.1002/ijc.2910530119.View ArticlePubMedGoogle Scholar
- Slavin-Chiorini DC, Kashmiri SV, Schlom J, Calvo B, Shu LM, Schott ME, Milenic DE, Snoy P, Carrasquillo J, Anderson K, Horan Hand P: Biological properties of chimeric domain-deleted anticarcinoma immunoglobulins. Cancer Res. 1995, 55 (23 Suppl): 5957s-5967s.PubMedGoogle Scholar
- Slavin-Chiorini DC, Kashmiri SV, Lee HS, Milenic DE, Poole DJ, Bernon E, Schlom J, Hand PH: A CDR-grafted (humanized) domain-deleted antitumor antibody. Cancer Biother Radiopharm. 1997, 12: 305-316. 10.1089/cbr.1997.12.305.View ArticlePubMedGoogle Scholar
- Pentlow KS, Graham MC, Lambrecht RM, Daghighian F, Bacharach SL, Bendriem B, Finn RD, Jordan K, Kalaigian H, Karp JS, Robeson WR, Larson SM: Quantitative imaging of iodine-124 with PET. J Nucl Med. 1996, 37: 1557-1562.PubMedGoogle Scholar
- Hinkle GH, Nabi HA, Miller EA, Schlanger LE, Houchens DP, Thurston MO, Aitken DR, Mojzisik CM, Olsen JO, Tuttle SE, Hansen HJ, Haagensen DE, Martin EW: Radioimmunodetection of implanted tumors with gamma probe. NCI Monogr. 1987, 3: 83-87.PubMedGoogle Scholar
- Unak T, Akgün Z, Yildirim Y, Duman Y, Erenel G: Self-radioiodination of iodogen. Appl Radiat Isot. 2001, 54: 749-752. 10.1016/S0969-8043(00)00337-7.View ArticlePubMedGoogle Scholar
- Zou P, Xu S, Povoski SP, Wang A, Johnson MA, Martin EW, Subramaniam V, Xu R, Sun D: Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice. Mol Pharm. 2009, 6: 428-440. 10.1021/mp9000052.PubMed CentralView ArticlePubMedGoogle Scholar
- Shankar LK, Hoffman JM, Bacharach S, Graham MM, Karp J, Lammertsma AA, Larson S, Mankoff DA, Siegel BA, Van den Abbeele A, Yap J, Sullivan D: Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med. 2006, 47: 1059-1066.PubMedGoogle Scholar
- Dandekar M, Tseng JR, Gambhir SS: Reproducibility of 18F-FDG microPET studies in mouse tumor xenografts. J Nucl Med. 2007, 48: 602-607. 10.2967/jnumed.106.036608.PubMed CentralView ArticlePubMedGoogle Scholar
- Jensen MM, Jørgensen JT, Binderup T, Kjaer A: Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper. BMC Med Imaging. 2008, 8: 16-10.1186/1471-2342-8-16.PubMed CentralView ArticlePubMedGoogle Scholar
- Colcher D, Esteban J, Carrasquillo JA, Sugarbaker P, Reynolds JC, Bryant G, Larson SM, Schlom J: Complementation of intracavitary and intravenous administration of a monoclonal antibody (B72.3) in patients with carcinoma. Cancer Res. 1987, 47: 4218-4224.PubMedGoogle Scholar
- Schlom J, Siler K, Colcher D, Carrasquillo JA, Reynolds JC, Sugarbaker P, Larson SM: Binding of radiolabeled MAb B72.3 administered intravenously and intraperitoneally in colorectal cancer patients. An overview. Acta Radiol Suppl. 1990, 374: 123-128.PubMedGoogle Scholar
- Hall NC, Zhang J, Povoski SP, Martin EW, Knopp MV: New developments in imaging and functional biomarker technology for the assessment and management of cancer patients. Expert Rev Med Devices. 2009, 6: 347-351. 10.1586/erd.09.21.View ArticlePubMedGoogle Scholar
- Pochin EE, Barnaby CF: The effect of pharmacological doses of non-radioactive iodide on the course of radio-iodine uptake by the thyroid. Health Phys. 1962, 7: 125-126. 10.1097/00004032-196201000-00001.View ArticlePubMedGoogle Scholar
- Blum M, Eisenbud M: Reduction of thyroid irradiation from 131-I by potassium iodide. JAMA. 1967, 200: 1036-1040. 10.1001/jama.200.12.1036.View ArticlePubMedGoogle Scholar
- Meck RA, Chen MS, Kenny PJ: Criteria for the administration of KI for thyroid blocking of radioiodine. Health Phys. 1985, 48: 141-157. 10.1097/00004032-198502000-00001.View ArticlePubMedGoogle Scholar
- Abdel-Nabi H, Waldman WJ, Hinkle GH, Miller EA, Trembath L, Olsen JO, Martin EW: Comparison of L-thyroxine and a saturated solution of potassium iodide in preventing damage to the thyroid following iodine-131-labeled antibody injection. NCI Monogr. 1987, 3: 63-66.PubMedGoogle Scholar
- Mohsin H, Jia F, Sivaguru G, Hudson MJ, Shelton TD, Hoffman TJ, Cutler CS, Ketring AR, Athey PS, Simón J, Frank RK, Jurisson SS, Lewis MR: Radiolanthanide-labeled monoclonal antibody CC49 for radioimmunotherapy of cancer: biological comparison of DOTA conjugates and 149Pm, 166Ho, and 177Lu. Bioconjug Chem. 2006, 17: 485-492. 10.1021/bc0502356.View ArticlePubMedGoogle Scholar
- Yokota T, Milenic DE, Whitlow M, Wood JF, Hubert SL, Schlom J: Microautoradiographic analysis of the normal organ distribution of radioiodinated single-chain Fv and other immunoglobulin forms. Cancer Res. 1993, 53: 3776-3783.PubMedGoogle Scholar
- Townsend DW: Dual-modality imaging: combining anatomy and function. J Nucl Med. 2008, 49: 938-955. 10.2967/jnumed.108.051276.View ArticlePubMedGoogle Scholar
- Townsend DW: Multimodality imaging of structure and function. Phys Med Biol. 2008, 53: R1-R39. 10.1088/0031-9155/53/4/R01.View ArticlePubMedGoogle Scholar
- Pichler BJ, Judenhofer MS, Pfannenberg C: Multimodal imaging approaches: PET/CT and PET/MRI. Handb Exp Pharmacol. 2008, 185 (Pt 1): 109-132. full_text.View ArticlePubMedGoogle Scholar
- Cherry SR: Multimodality imaging: beyond PET/CT and SPECT/CT. Semin Nucl Med. 2009, 39: 348-353. 10.1053/j.semnuclmed.2009.03.001.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee KH, Ko BH, Paik JY, Jung KH, Choe YS, Choi Y, Kim BT: Effects of anesthetic agents and fasting duration on 18F-FDG biodistribution and insulin levels in tumor-bearing mice. J Nucl Med. 2005, 46: 1531-1536.PubMedGoogle Scholar
- Woo SK, Lee TS, Kim KM, Kim JY, Jung JH, Kang JH, Cheon GJ, Choi CW, Lim SM: Anesthesia condition for (18)F-FDG imaging of lung metastasis tumors using small animal PET. Nucl Med Biol. 2008, 35: 143-150. 10.1016/j.nucmedbio.2007.10.003.View ArticlePubMedGoogle Scholar
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