Immunoscintigraphy and Pharmacokinetics of Indium-111-labeled ZME-018 Monoclonal Antibody in Patients with Malignant Melanoma

Immunoscintigraphic and pharmacokinetic characteristics of ¹¹¹In-labeled ZME-018 monoclonal antibody were examined in 8 patients with malignant melanoma. Each patient received a single intravenous infusion of 20 mg of ZME-018, coupled to 3 mCi of ¹¹¹In without any acute toxicity. Scintigrams were taken 1, 3, and 6 days after the administration, and blood and urine samples were also taken frequently. Rapid clearance of some radioactivity was seen in early urine samples in the form of ¹¹¹In DTPA, but after 1 day, urinary excretion of radioactivity was slow and steady, with an average of 2.5% of the injected dose excreted per day. The scans demonstrated that there was blood retention of radioactivity in the heart and great vessels 1 day after infusion and considerable clearance from the blood pool occurred by 3 days. However, ¹¹¹In was deposited in the liver, spleen and bone for up to 6 days. The optimal time for imaging appeared to be at 3 days. Nineteen out of 26 known lesions or 6 out of 8 patients were positive. There were 21 lesions detected that were not suspected during the work-up the patient. Five patients developed human anti-mouse antibody in the serum by 3 weeks. These results suggest that immunoscintigraphy with ¹¹¹In-labeled ZME-018 antibody is safe and useful for the detection of metastatic lesions in a selected group of patients with malignant melanoma.     

Whole-body autoradiography of tumor-bearing hamsters with a new tumor imaging agent, indium-111-labeled porphyrin

We have synthesized a new tumor imaging agent, 111In-labeled porphyrin (111In-ATN-2). In order to image transplantable pancreatic carcinoma in Syrian golden hamsters, we investigated the biodistribution of 111In-ATN-2 72 hr after injecting the agent by means of whole-body autoradiography. The efficacy of the agent was compared with that of 67Ga citrate. The images with 111In-ATN-2 were found to be clearer than those with 67Ga citrate. Tumor-to-tissue radiodistribution ratios of the former were higher than those of the latter. Thus, 111In-ATN-2 seems to be more useful for tumor diagnosis.     

99mTc-MIBI亲肿瘤阳性显像的临床应用

目的 探讨99mTc-MIBI肿瘤阳性显像在多种恶性肿瘤临床诊断中的应用价值.方法 静脉注射99mTc-MIBI 15～30 min后,行病变局部平面和断层显像,计算肿瘤与本底比值(T/N),当T/N≥1.4时判定显像结果阳性.结果 23例受检者中诊断为恶性肿瘤21例,良性肿瘤2例.21例恶性肿瘤99mTc-MIBI阳性显像17例阳性,4例阴性;2例良性肿瘤患者显像结果均为阴性.99mTc-MIBI阳性显像的敏感性为89.5%,特异性为100.0%,阳性预测值为100.0%,阴性预测值为66.7%,准确率为91.3%.结论 99mTc-MIBI阳性显像在良恶性肿瘤临床诊断中有良好的应用前景.     

Imaging of carbonic anhydrase IX with an 111In-labeled dual-motif inhibitor

We developed a new scaffold for radionuclide-based imaging and therapy of clear cell renal cell carcinoma (ccRCC) targeting carbonic anhydrase IX (CAIX). Compound XYIMSR-01, a DOTA-conjugated, bivalent, low-molecular-weight ligand, has two moieties that target two separate sites on CAIX, imparting high affinity. We synthesized [¹¹¹In]XYIMSR-01 in 73.8–75.8% (n = 3) yield with specific radioactivities ranging from 118 – 1,021 GBq/μmol (3,200–27,600 Ci/mmol). Single photon emission computed tomography of [¹¹¹In]XYIMSR-01 in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors revealed radiotracer uptake in tumor as early as 1 h post-injection. Biodistribution studies demonstrated 26% injected dose per gram of radioactivity within tumor at 1 h. Tumor-to-blood, muscle and kidney ratios were 178.1 ± 145.4, 68.4 ± 29.0 and 1.7 ± 1.2, respectively, at 24 h post-injection. Retention of radioactivity was exclusively observed in tumors by 48 h, the latest time point evaluated. The dual targeting strategy to engage CAIX enabled specific detection of ccRCC in this xenograft model, with pharmacokinetics surpassing those of previously described radionuclide-based probes against CAIX.     

Imaging of colon carcinoma with 111-indium-labeled anti-CEA monoclonal antibodies (Indacea) prior to surgery

Patients with primary and/or metastatic colorectal cancer who had been scheduled for operative intervention were injected intravenously with 200 micrograms of a high-affinity anti-carcinoembryonic antigen (CEA) monoclonal antibody labeled with 2 mCi of 111-indium (Indacea). Patients were imaged by gamma camera at 24 and 48 hours. Primary tumors were identified in 3/10 cases and were not visualized in 3/10 cases. Four scans were considered equivocal. Hepatic metastases were identified as image defects in 5/13 cases and were not visualized in 8/13 cases. All tumors contained CEA by immunoperoxidase staining. In all cases, the primary tumor uptake (5.44 +/- 1.07% ID/kg) was much higher than the uptake of the adjacent fat (0.18 +/- 0.04% ID/kg). There was a direct correlation between tumor CEA content, tumor radioactivity, and the imaging of primary tumor by Indacea. High liver uptake (30.3 +/- 3.0% ID/kg), seen when scanning all patients, was the main limitation of imaging and led to photopenic visualization of hepatic metastases. These results suggest that selection of patients with colorectal carcinoma on the basis of tumor CEA content will lead to improved rates of tumor imaging by Indacea in post-surgical scanning.     

核素骨显像联合肿瘤标记物检测对乳腺癌骨转移的诊断价值

目的：观察核素骨显像联合肿瘤标记物对乳腺癌骨转移的诊断价值。方法选择乳腺癌患者82例,按照核素骨显像结果分为转移组43例及未转移组39例,另选取40例健康体检女性作为对照组。观察核素骨显像以及肿瘤标记物检测结果,并对其诊断价值进行考察。结果转移组血清CA125、CA15-3及CEA表达水平及阳性率显著高于未转移组及对照组,骨转移灶数目≤2患者血清CA125、CA15-3以及CEA表达水平及阳性率均显著低于骨转移灶数目＞2的患者,差异均具有统计学意义（P＜0．05）。且随着骨转移分级程度的升高,患者乳腺癌相关肿瘤标记物CA125、CA15-3及CEA表达水平及阳性率均呈升高趋势,各分级间差异有统计学意义（ P＜0．05）。结论核素骨显像联合肿瘤标记物检测可提高诊断敏感性,对于乳腺癌骨转移的诊断具有重要的参考价值。     

Imaging of a parapharyngeal hemangiopericytoma. Radioimmunoscintigraphy (SPECT) with indium-111-labeled anti-CEA antibody, and comparison to digital subtraction angiography, computed tomography, and immunohistochemistry

A 27-year-old male patient with a parapharyngeal hemangiopericytoma was investigated radiologically with orthopantomography, computed tomography, and digital subtraction angiography before the operation. Because a malignancy was suspected, the patient was imaged with gamma camera using radiolabeled monoclonal anticarcinoembryonal antigen antibody including single photon emission computed tomography. The radioantibody accumulated strongly into the neoplasm. Tumor to background ratio was 2.2. Samples of the excised tumor were stained immunohistochemically for desmin, vimentin, muscle actin, cytokeratin, CEA (carcinoembryonic antigen), and factor VIII. They showed that the antibody uptake was of unspecific nature and not due to CEA expression in the tumor.     

Pendolmycin, a New Tumor Promoter of the Teleocidin A Class on Skin of CD-1 Mice

Pendolmycin, isolated from Nocardiopsis , is a compound structurally similar to teleocidin A, one of the 12- O -tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters. Pendolmycin has a C₅ dimethyl allyl group attached to C-7 of (-)-indolactam-V, whereas teleocidin A has a C₁₀ linalyl group attached to the molecule. The structure-activity relationships of a hydrophobic moiety attached to (-)-indolactam-V were studied in four compounds, (-)-indolactam-V, pendolmycin, teleocidin A and newly synthesized 7-(nerolidyl)-(-)-indolactam-V in tests on inhibition of the specific [³H]TPA binding to a particulate fraction of mouse skin, activation of protein kinase C and induction of both adhesion of HL-60 cells and ornithine decarboxylase in mouse skin. The potencies of the compounds for these activities increased mainly depending on the length of the hydrophobic group. Pendolmycin had a tumor-promoting activity on mouse skin initiated with a single application of 7,12-dimethyl-benz[a]anthracene, and its potency was just between those of (-)-indolactam-V and teleocidin A. The role of the hydrophobic moiety is discussed with particular emphasis on the results obtained with 7-(nerolidyl)-(-)-indolactam-V.     

Neurofibromatosis 2: Report of an Affected Kindred,with a Discussion of Imaging Strategy

Three cases of neurofibromatosis 2 occurring in one family are presented. Features distinguishing this condition from the more common neurofibromatosis 1 are discussed and the important role of radiological screening in case detection and follow-up is emphasised.     

Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity

FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metabolite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death.