Improved intratumoral penetration of radiolabeled streptavidin in intraperitoneal tumors pretargeted with biotinylated antibody.
Zhang M. Yao Z. Saga T. Sakahara H. Nakamoto Y. Sato N. Nakada H. Yamashina I. Konishi J.
Department of Nuclear Medicine, Faculty of Medicine, Kyoto University, Kyoto City, Japan.
Inefficient intratumoral penetration of pharmaceuticals is one of the major limiting factors against effective tumor-targeting therapy. This study investigated the effect of the distribution pattern of the binding site in tumors on the penetration of target material. METHODS: In the first experiment, radiolabeled biotinylated monoclonal antibody, MLS128, was injected intraperitoneally or intravenously into nude mice bearing intraperitoneal human colon cancer xenografts. In the second experiment, radiolabeled streptavidin was injected intraperitoneally in the tumor-bearing mice after the pretargeting with the unlabeled biotinylated antibody. Intratumoral distribution of radioactivity was examined with quantitative autoradiography. RESULTS: There was no difference in the biodistribution of biotinylated antibody between intraperitoneal and intravenous administrations, but autoradiography showed a higher uptake in the margin and a lower uptake in the center of radioactivity in tumor nodules with intraperitoneal injection and a more uniform intratumoral radioactivity distribution with intravenous injection. In the two-step method, radioactivity in a low dose of streptavidin with intraperitoneal pretargeting primarily localized at the tumor margin. By increasing the dose, streptavidin penetrated more deeply. In tumors with intravenous pretargeting, a more uniform intratumoral distribution of streptavidin was obtained. The biodistribution of radiolabeled streptavidin was the same between different pretargeting routes. CONCLUSION: The better intratumoral penetration of radiolabeled streptavidin after intravenous pretargeting than intraperitoneal pretargeting with biotinylated antibody may be the result of different intratumoral distribution of the binding site for the radiolabel.
Pharmacokinetics, dosimetry and toxicity of rhenium-188-labeled anti-carcinoembryonic antigen monoclonal antibody, MN-14, in gastrointestinal cancer.
Juweid M. Sharkey RM. Swayne LC. Griffiths GL. Dunn R. Goldenberg DM.
Garden State Cancer Center, Belleville, New Jersey 07109, USA.
The biodistribution, pharmacokinetics and dosimetry of 188Re-labeled MN-14, an IgG anti-carcinoembryonic antigen monoclonal antibody (MAb), were assessed in patients in advanced gastrointestinal cancer. In addition, the dose-limiting toxicity (DLT) and maximum tolerated dose of fractionated doses of this agent were determined. METHODS: Eleven patients were administered radioactive doses of directly labeled 188Re-MN-14 IgG, ranging from 20.5 mCi to 161.0 mCi (2.0 mg-4.9 mg). Ten of these patients received two or three MAb infusions, given 3-4 days apart, delivering total doses of 30 mCi/m2-80 mCi/m2. External scintigraphy was used to evaluate the MAb biodistribution, and quantitative external scintigraphic methods were used to determine the organ and tumor radiation doses. RESULTS: The biodistribution studies showed enhanced 188Re-MN-14 uptake in the liver, spleen and kidneys, compared to that of 131I-MN-14. The biological T(1/2) values for 188Re-MN-14 in the blood and whole body (in hours) were 8.2 +/- 4.1 (n = 7) and 107.8 +/- 104.2 (n = 9), respectively (mean +/- s.d.). The radiation absorbed doses (cGy/mCi) delivered to the total body, red marrow, lungs, liver, spleen and kidneys were 0.5 +/- 0.05, 3.6 +/- 1.6, 2.0 +/- 0.8, 5.9 +/- 2.5, 7.1 +/- 1.9 and 8.5 +/- 2.8, respectively. Red marrow suppression was the only DLT observed. The maximum tolerated dose of fractionated doses of 188Re-MN-14 was estimated to be 60 mCi/m2. CONCLUSION: Despite its relatively increased renal and hepatic uptake, red marrow suppression is the only DLT of 188Re-MN-14. The feasibility of administering relatively high doses of 188Re on a completely outpatient basis may make this agent a preferred candidate for radioimmunotherapy.
Preclinical characterization and in vivo imaging studies of an engineered recombinant technetium-99m-labeled metallothionein-containing anti-carcinoembryonic antigen single-chain antibody.
Pietersz GA. Patrick MR. Chester KA.
Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia.
We describe the engineering of a novel single-chain fragment (scFv) metallothionein (MET) containing anti-carcinoembryonic antigen (CEA) antibody (referred to as MET-scFv) for use as a diagnostic imaging agent in colorectal cancer. METHODS: Site-directed cloning of annealed oligonucleotides, containing both the MET and a c-myc tag sequence, into a pUC19-based expression vector enabled soluble secreted protein expression from Escherichia coli. Affinity purification was used to purify the protein using an anti-c-myc affinity column. The specificity of both the unlabeled and labeled MET-scFv for CEA was demonstrated by solid-phase enzyme-linked immunosorbent assay and radioimmunoassay and by fluorescence-activated cell sorting analysis on CEA-expressing human colorectal LS-174T cells. Technetium-99m labeling was achieved using a Zn2+ transchelation step, enabling direct 99mTc transfer without separate reduction of MET. In vitro stability was demonstrated by fast protein liquid chromatography analysis of labeled MET-scFv, incubated with bovine serum albumin (BSA), transferrin and mouse serum. Last, in vivo pharmacokinetics, biodistribution and imaging were performed. RESULTS: Yields of 6 mg/liter induced culture purified protein were achieved. Successful site-specific labeling was demonstrated using a Zn2+ transchelation modification of a pretinning method, which also enabled lower amounts of the reducing agent to be used. The specificity for CEA was retained after labeling. Despite a rapid serum clearance (t(1/2alpha) = 2.8 min), adequate localization to tumor of 5.37% injected dose/g at 4 hr was demonstrated. Moreover, the short-lived t(1/2alpha) of scFv, its early tumor targeting and rapid blood-pool clearance gave tumor-to-blood ratios of 2.07 by 4 hr, enabling early gamma camera imaging. Successful and specific imaging was achieved using LS-174T xenografts in nude mice by 3-6 hr. CONCLUSION: A recombinant MET containing scFv was successfully expressed, purified and labeled with 99Tc. The stable site-specific labeling of 99Tc, combined with the rapid plasma clearance of the scFv, led to successful early in vivo imaging of xenografted mice.
Tumor pretargeting for radioimmunodetection and radioimmunotherapy.
Zhu H. Jain RK. Baxter LT.
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
The limited success of the sole use of monoclonal antibodies for cancer detection and treatment has led to the development of multistep methods using antibodies in conjunction with low molecular weight agents. For tumor pretargeting, it is important to optimize dose and schedule of relevant agents and to understand barriers to targeted delivery. Here, we address these issues for the anti-carcinoembryonic antigen bifunctional antibody-hapten and the streptavidinylated antibody-biotin systems using a recently developed physiologically based pharmacokinetic model. METHODS: For baseline conditions of a standard 70-kg man with a 20-g tumor embedded in the liver, the model was used in conjunction with the Medical Internal Radiation Dosimetry schema to: estimate absorbed doses in tumor and normal tissues; determine the dose dependence of effector agent accumulation in tumor; simulate tumor-to-background effector agent uptake ratio; and calculate the therapeutic ratio for different antibody forms and radionuclides. Alternative drug administration schemes and variable tumor physiological conditions were considered. RESULTS: Model simulations showed that 131I-labeled biotin with the streptavidinylated F(ab')2 provided the highest therapeutic ratio under the optimized conditions. The simulations also showed that biotin with the bifunctional streptavidinylated immunoglobulin G provided the highest tumor-to-liver uptake ratio during the early period. Sensitivity analysis showed that antibody extravasation was the major factor limiting the accretion of the effector agent in tumor, whereas antigen expression in normal tissues and tumor antigen shedding had little effect on the absorbed doses. CONCLUSION: Tumor pretargeting should provide a definite advantage over direct antibody targeting with up to a 200% increase in tumor-to-background ratio in radioimmunodetection and up to a 76% increase in tumor-to-bone marrow therapeutic ratio in radioimmunotherapy. Rapid antibody clearance from the bloodstream before effector agent injection is expected to improve the therapeutic ratio marginally (3%-10%). However, continuous plasmapheresis dramatically increased the tumor-to-background ratio by a factor of 10 in RAID and the tumor-to-bone marrow therapeutic ratio by more than 110% for short-lived radionuclides in RAIT. Apart from drastic measures such as extended plasmapheresis, pretargeting selectivity was neither sensitive enough for radioimmunodetection nor effective enough for radioimmunotherapy in patients with typical solid tumors even using the optimized protocols.
Intravenous and intra-arterial oxygen-15-labeled water and fluorine-18-labeled fluorouracil in patients with liver metastases from colorectal carcinoma.
Dimitrakopoulou-Strauss A. Strauss LG. Schlag P. Hohenberger P. Irngartinger G. Oberdorfer F. Doll J. van Kaick G.
Department of Oncological Diagnostics, German Cancer Research Center, Heidelberg.
Intra-arterial chemotherapy can potentially increase drug delivery at the tumor sites and has therefore been used for the therapy of metastatic colorectal cancer. METHODS: Dynamic PET and [18F]fluorouracil (18F-FU) were used in patients with liver metastases from colorectal cancer to examine the pharmacokinetics of the drug up to 120 min after intravenous and intra-arterial injection of the same dose of fluorouracil (FU). All patients included in the study (n = 15) had surgically implanted catheters in the gastroduodenal artery. Dynamic PET studies (up to 5 min) with 15O-labeled water were performed for the evaluation of the access to the lesions immediately before the 18F-FU study using both administration routes. The final evaluation included 24 metastases, obtained from 15 patients. RESULTS: Of 24 lesions, 21 (87.5%) showed an improved access using the intra-arterial approach, and 20 (83.3%) demonstrated a better FU influx after intra-arterial 18F-FU infusion. Metastases reached the highest 18F-FU concentrations after intra-arterial administration, with a maximum standardized uptake values of 18.75 for the FU influx and of 5.03 for FU trapping. Of 24 metastases, eight (33.3%) demonstrated enhanced FU trapping after the intra-arterial administration. Cluster analysis revealed a group of metastases (n = 6) with a nonperfusion-dependent FU transport using the intravenous application. Of these six lesions, five (83.3%) did not show any enhancement of the 18F-FU trapping after intra-arterial application. The data gave evidence for at least one different, energy-dependent transport system, which can be saturated even after intravenous administration of the drug. CONCLUSION: The data show that the main limiting factor for a therapy response is the very high and rapid elimination of the cytostatic agent out of the tumor cells. Furthermore, it was not possible to predict the pharmacokinetics of FU after intra-arterial application using an intravenous PET study. It may be possible, using intravenous PET double-tracer studies, to identify metastases having a nonperfusion-dependent transport system and exclude them from an intra-arterial treatment protocol.
Indium-111- and yttrium-90-labeled human monoclonal immunoglobulin M targeting of human ovarian cancer in mice.
Borchardt PE. Quadri SM. Freedman RS. Vriesendorp HM.
Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
Most patients with ovarian cancer have disease in the peritoneal cavity. Treatment of this region is inadequate because recurrences are frequent. Increased radiation doses to tumor and, hence, greater tumor control may be possible with intraperitoneal (i.p.) administration of radiolabeled human monoclonal immunoglobulin M (IgM), which is reactive with tumor-associated antigens. METHODS: Biodistribution studies were performed in nude mice bearing i.p. nodules of human ovarian cancer after administration of human monoclonal IgMlambda (AC6C3-2B12), labeled with 111In or 90Y. Irrelevant 111In-labeled human IgMlambda (CH-1B9) and 90Y-aggregate served as specificity controls. RESULTS: Intravenous administration of 111In-labeled AC6C3-2B12 produced low tumor and high liver and spleen uptake. Intraperitoneal administration of AC6C3-2B12 labeled with 111In or 90Y resulted in rapid, high tumor uptake (>45% of injected dose per gram of tumor at 3 hr) that was at least three-fold higher than any normal organ. Biodistribution results were similar for 111In- and 90Y-labeled IgM. Tumor uptake of 111In-labeled AC6C3-2B12 was two-fold greater than that of 111In-labeled CH-1B9. Normal organ uptakes were similar for tumor-reactive and irrelevant IgM. Radioimmunoconjugates were retained in the peritoneal cavity for a prolonged period of time. Yttrium-90 aggregate demonstrated high tumor and bone uptake. CONCLUSION: Higher tumor uptake was observed after i.p. administration of tumor-reactive IgM than after irrelevant IgM. The in vivo behavior of tumor-reactive IgM was similar when it was radiolabeled with either 111In or 90Y. Therefore, 111In-based imaging studies can be used to predict the biodistribution of subsequently administered 90Y-labeled IgM. Further development of radiolabeled AC6C3-2B12 as a diagnostic and therapeutic agent for patients with advanced ovarian carcinoma is warranted.
Technetium-99m-DTPA-galactosyl human serum albumin liver scintigraphy evaluation of regional CT/MRI attenuation/signal intensity differences.
Akaki S. Mitsumori A. Kanazawa S. Togami I. Takeda Y. Joja I. Hiraki Y.
Department of Radiology, Okayama University Medical School, Japan.
Regional attenuation/signal intensity differences seen on CT/magnetic resonance imaging can be a clue in detecting regional hepatic blood flow abnormality. Sometimes, however, they can be misinterpreted as a hepatic neoplasm or, in the case of a true neoplasm, they can lead to an overestimation of its size because these regions often have similar attenuation or signal intensity to hepatic neoplasms. We evaluated 99mTc-diethylenetriaminepentaacetic acid-galactosyl human serum albumin (99mTc-DTPA-GSA) liver scintigrams in patients manifesting regional attenuation/signal intensity differences to further analyze the findings. METHODS: Technetium-99m-DTPA-GSA scintigrams of 23 patients with regional attenuation/signal intensity differences in the liver at dynamic contrast-enhanced CT/magnetic resonance imaging were evaluated. The causes of the differences were arterioportal (AP) shunts in seven patients, decreases in the portal venous flow in seven patients, occlusion of right hepatic vein in one patient, confluent hepatic fibrosis in one patient and unknown in seven patients. The accumulation of 99mTc-DTPA-GSA was compared with each known cause of attenuation/signal intensity difference. Count ratios of the regions to normal hepatic parenchyma also were calculated in all cases. RESULTS: In AP shunts, none of seven patients showed any decreased accumulation in the region. Accumulation of 99mTc-DTPA-GSA decreased in six of seven patients who had decreases in portal venous flow; this incidence was significantly higher than that in patients who had AP shunts (p < 0.005). In cases of unknown cause, two of seven patients showed a decrease in accumulation, but the other five showed no such decrease. The one patient with occlusion of the right hepatic vein showed no decrease, but the confluent hepatic fibrosis showed a significant decrease. The count ratio in AP shunts was significantly larger than that of the decrease in the portal venous flow (p < 0.005). CONCLUSION: Technetium-99m-DTPA-GSA accumulation in AP shunts has a different pattern from that found in patients with a decrease in portal venous flow. Therefore, differentiation between AP shunts, which showed no decrease in 99mTc-DTPA-GSA accumulation, and hepatic neoplasms can be made more easily.
Fluorine-18-fluorodeoxyglucose dual-head gamma camera coincidence imaging of recurrent colorectal carcinoma.
Abdel-Dayem HM. Radin AI. Luo JQ. Marans HY. Wong S. Naddaf SY. El-Zeftawy HM. Omar WS. Mithilesh K. Abujudeh H. Atay S.
Department of Radiology, St. Vincent's Hospital and Medical Center of New York, and New York Medical College, Valhalla 10011, USA.
We report our experience with coincidence detection imaging of 18F-fluorodeoxyglucose (FDG) using a dual-head gamma camera. Scanning of the pelvis and abdomen of a patient with recurrent colorectal carcinoma showed recurrent disease in the pelvic floor and the base of the urinary bladder and metastatic disease in the retroperitoneal space of the pelvis. Although the tumor involving the bladder and pelvic floor was detected by CT and magnetic resonance imaging (MRI), metastatic spread to the retroperitoneal nodes on the left side was detected only by 18F-FDG imaging. Based on the ultrasound, CT, MRI and cystoscopy, a local recurrence of cancer was presumed in our patient. An exploratory laparotomy was performed to resect the tumor in its entirety. At the time of surgery, the retroperitoneal metastasis in the pelvis was confirmed. Had the findings of the coincidence detection imaging study been considered, the patient would have been spared the surgical procedure.
Evaluation of esophageal cancers using fluorine-18-fluorodeoxyglucose PET.
Fukunaga T. Okazumi S. Koide Y. Isono K. Imazeki K.
Second Department of Surgery, Chiba University School of Medicine, Japan.
To evaluate glucose metabolism in esophageal cancer, 48 patients were studied using PET with 18F-2-fluoro-2-deoxy-D-glucose (FDG). METHODS: After transmission scans were obtained, 18F-FDG (148 MBq) was administered intravenously. In 11 patients, a dynamic study was performed to evaluate glucose metabolism. Using the changes of radioactivity in both plasma and tumor, rate constants (k1-k4) defined in the metabolic model for 18F-FDG were calculated. In 48 patients, static PET scans of the tumor (5-min scans) were obtained 60 min after administration. Fluorine-18-FDG activity within each tumor was corrected for physical decay and normalized by dose administration and patient weight to produce a standardized uptake value (SUV). RESULTS: Both the k3 value (n = 11) reflecting hexokinase activity and SUV (n = 13) were well correlated with hexokinase activity from the resected specimen (p < 0.05). Forty-seven of 48 patients before treatment revealed SUV greater than 2.0, but 10 normal control subjects and 1 esophageal benign tumor revealed less than 2.0 (accuracy rate 98.3%). Although clinicopathological findings did not correlate with SUV, except for two patients with carcinosarcoma, 23 patients with an SUV greater than 7.0 had a poor prognosis compared with 25 patients with SUVs less than 7.0. CONCLUSION: These findings suggest that 18F-FDG PET may be useful in distinguishing malignant tumors from benign lesions and in the preoperative evaluation of the prognostic factor.
FDG PET: elevated plasma glucose reduces both uptake and detection rate of pancreatic malignancies.
Diederichs CG. Staib L. Glatting G. Beger HG. Reske SN.
Department of Nuclear Medicine, University of Ulm, Germany.
The aim of the study was to evaluate the effects of elevated plasma glucose levels on tumor detection. METHODS: One-hundred and seventy-one fasted patients (100 malignant pancreatic tumors, 46 chronic pancreatitis and 25 patients with other benign pancreatic lesions) were studied with 18F-fluorodeoxyglucose (FDG) PET before planned resective pancreatic surgery. Nineteen of 171 patients had elevated plasma glucose levels above 130 mg/dl, and 24 of 171 had diabetes mellitus. Standard uptake values (SUVs) with and without glucose correction, tumor-to-muscle ratios and tumor-to-liver ratios were measured of the pancreatic lesion respective of the area with the highest uptake within the pancreas. The original qualitative PET reports concerning the dignity of the pancreatic lesion were translated into a five-point malignancy scale. Tumor detection rates and SUVs were compared according to plasma glucose levels above and below 130 mg/dl, the presence of diabetes and by using receiver operating characteristic (ROC) analysis. RESULTS: The detection rates (and mean SUVs) for pancreatic malignancies were 86% and 42% (4.2 and 2.3) if fasted plasma glucose levels were below and above 130 mg/dl, respectively. The sensitivities (and mean SUVs of malignant tumors) were 83% and 69% (3.3 and 2.5) for patients without and with known diabetes. Areas under ROC curves were nearly equal for glucose corrected SUV and visual qualitative results (0.86 and 0.85), followed by uncorrected SUV (0.83), tumor-to-liver ratios (0.80) and tumor-to-muscle ratios (0.79). SUVs for chronic pancreatitis, muscle and liver had a tendency to increase with elevated plasma glucose levels. CONCLUSION: Negative PET results of patients with elevated plasma glucose should be interpreted with caution.
Differentiation of prolonged colonic transit using scintigraphy with indium-111-labeled polystyrene pellets.
Eising EG. von der Ohe MR.
Clinic for Internal Medicine/Department of Gastroenterology, University of Essen, Germany.
Prolonged colonic transit can be caused either by slow transit constipation or by pelvic outlet obstruction needing different therapeutic regimes. The aim of this study was to prove the value of scintigraphic assessment. METHODS: Colon scintigraphy was performed in 32 patients (28 women, 4 men; age range 8-68 yr) with idiopathic constipation at 8, 24 and 48 hr in ventral and dorsal projection after oral administration of a pH-sensitive, methacrylate-coated capsule of nonresorbable 111In-labeled polystyrene (cathion exchanger) micropellets (3.5 MBq/capsule). The geometric center (GC) as the sum of products of colon segment activity and colon segment number (1 = colon ascendens; 2 = transverse colon; 3 = colon descendens; 4 = rectosigmoid colon; and 5 = stool) dividing by the total counts was used to determine the velocity of colonic transit at least at 24 hr as the proximal colonic emptying (PCE) rates. Stool activity was evaluated indirectly as decay-corrected colon activity loss between two examinations. Results were compared with data obtained from 22 healthy subjects. RESULTS: Twenty-six patients had a significant prolongation of colonic transit after 24 and 48 hr (the 95% confidence interval of the patient's GC showed no overlap to the 95% confidence interval of GC calculated from 22 healthy controls as normal range) revealing slow transit constipation. Six patients had normal or accelerated transit (GCs and PCE rates) up to the rectum but delayed rectal emptying indicating pelvic outlet obstruction. CONCLUSION: By the help of this method it was possible to differentiate the two subtypes of colon transit prolongation by use of the reported scintigraphic technique, which leads to different therapeutic management of the patients. Compared with x-ray methods (Hinton test), this method has the capability of a continuous observation of colonic transit without increasing radiation exposure.
Scintigraphic screening prior to visceral arteriography in acute lower gastrointestinal bleeding.
Gunderman R. Leef J. Ong K. Reba R. Metz C.
Department of Radiology, Indiana University, Indianapolis, USA.
We evaluated the effect on the diagnostic yield of visceral arteriography in patients with acute gastrointestinal bleeding of a protocol requiring a positive 99mTc-red blood cell scintiscan before the performance of arteriography (scintigraphic screening). METHODS: A retrospective review was conducted of 249 scintiscans and 271 arteriograms obtained over 99 mo, with scintigraphic screening implemented during the final 18 mo. RESULTS: Before the implementation of scintigraphic screening, arteriograms detected bleeding at a rate of 22%. After its implementation, 53% of the arteriograms detected bleeding. This represented a statistically significant increase (0.53 versus 0.22, p = 0.015). CONCLUSION: Scintigraphic screening appears to increase by a factor of 2.4 the diagnostic yield of arteriography by screening out patients who are not actively bleeding at the time of the examination, thus sparing them the risks and costs of a nondiagnostic invasive study.
In vitro demonstration of synergy between radionuclide and chemotherapy.
Chenoufi N. Raoul JL. Lescoat G. Brissot P. Bourguet P.
Centre E Marquis, and Institut National de la Sante et de la Recherche Medicale Unite 49, Hopital Pontchaillou, Rennes, France.
Radionuclide therapy is currently used in the treatment of some malignancies, including hepatocellular carcinoma. The effects of external beam radiotherapy are improved by combining it with chemotherapy. The aim of this study was to determine whether such a synergistic effect could be demonstrated in vitro with internal radiation therapy. METHODS: HepG2 cells were cultured from Day 0 to Day 8 under the following conditions: exposure for 4 hr on Day 2 to increasing concentrations of 5-fluorouracil (5FU), doxorubicin or cisplatin (CDDP); exposure from Day 2 to Day 8 to increasing concentrations of 131-iodide; exposure on Day 2 to low-toxicity doses of drugs for 4 hr, followed by exposure to 131I at increasing concentrations; and exposure to increasing concentrations of 131I from Day 2 to Day 8, with exposure for 4 hr on Day 6 to the drugs. Cell toxicity was assessed by enzyme release (lactate dehydrogenase and aspartate aminotransferase) in the culture medium and on cell survival (protein and tetrazolium dye test). All cultures were run in triplicate. RESULTS: A dose- and time-dependent toxicity was demonstrated with doxorubicin and CDDP but not with 5FU. When HepG2 cells were exposed to 131I, the toxicity was rather low, but significant, and was time- and dose-dependent. Treating these cells with combination radiotherapy and chemotherapy resulted in a toxicity that was significantly greater than that with 131I or chemotherapy drugs alone. CONCLUSION: The radiosensitivity of HepG2 cells is low; combining a chemotherapeutic drug with a radiotherapeutic agent improves the radiosensitivity in a synergistic fashion. This combination is thus able to strengthen the therapeutic effect of internal radiation therapy in different malignancies, particularly in hepatocellular carcinoma.