Shota Konishi

Radionuclide cisternography in intracranial hypotension syndrome

A 44-year-old male patient complaining of severe headache right after twisting his body during aerobic exercises in a swimming pool underwent In-111 DTPA radionuclide cisternography. Leakage of cerebrospinal fluid (CSF) was proved on the right side of T2 and T3 vertebrae. Cisternography after bed and conservative treatments demonstrated the disappearance of abnormal tracer accumulations. Radionuclide cisternography is of great value in diagnosing cerebral-spinal fluid leak and in evaluating the therapeutic effect.

Efficacy, toxicity and mode of interaction of combination radioimmunotherapy with 5-fluorouracil in colon cancer xenografts

Purpose:The feasibility of radioimmunotherapy (RAIT) combined with 5-fluorouracil (5-FU) was examined in colon cancer xenografts. The mode of interaction of the two treatments was also investigated. Methods: Mice bearing human colon cancer were treated with a combination of 4.63 MBq (L-RAIT) or 9.25 MBq (H-RAIT) 131I-A7, an IgG1 against 45-kDa glycoprotein, and 5-FU at a dose of 30 mg kg−1 day−1 for 5 days. Myelotoxicity was monitored by blood cell counts and intestinal toxicity was assessed by the dosimetry. The results were compared with those of a single-modality therapy. Results: The combination of 5-FU with H-RAIT enhanced the antitumor effect, improving the tumor quadrupling time from 25.3 ± 9.59 days to 31.3 ± 8.32 days (P < 0.05) and inducing tumor regression in 7 out of 10 mice, compared to 3 out of 9 mice treated with H-RAIT alone. The efficacy of L-RAIT was also improved by the combination. Analysis of the dose/response relationship showed an additive interaction of the two modalities. The combination of 5-FU with RAIT induced slightly more severe myelotoxicity than a single-modality treatment, but blood cell counts recovered similarly. Dose estimation suggested that RAIT does not increase the intestinal toxicity of 5-FU. Conclusion: The combination of two modalities would be feasible for the treatment of colon cancer, increasing antitumor effect with minor effect on toxicity.

Combination radioimmunotherapy with local hyperthermia: increased delivery of radioimmunoconjugate by vascular effect and its retention by increased antigen expression in colon cancer xenografts

Hyperthermia (HT) may increase tumor targeting of a radiolabeled antibody by its effects on tumor vasculature and antigen expression. Expression of a 45-kDa glycoprotein antigen on LS180 colon cancer cells was 2.7-fold enhanced 2 days after heating at 43 degrees C for 1 h. Preferential tumor accumulation of 125I-A7 recognizing this antigen was doubled and the antitumor effect of 131I-A7 was significantly improved by HT. Hyperthermia also increased tumor uptake of an irrelevant antibody but its radioactivity was rapidly cleared. These results indicate that HT increased the initial delivery of an antibody to a tumor by its vascular effect, and radioactivity was retained in tumors by increased specific binding, resulting in a better radioimmunotherapy outcome.

Rhenium‐186‐mercaptoacetyltriglycine‐labeled Monoclonal Antibody for Radioimmunotherapy: In vitro Assessment, in vivo Kinetics and Dosimetry in Tumor‐bearing Nude Mice

Stability and immunoreactivity of 186Re‐labeled monoclonal antibody were examined, and its in vivo kinetics was investigated in tumor‐bearing Balb/c nu/nu female mice to assess the feasibility of using it in radioimmunotherapy (RIT). A murine IgG1, A7, against a 45 kD glycoprotein in human colon cancer was radiolabeled with 186Re by using a chelating method with a mercaptoacetyltriglycine (MAG3). 186Re‐MAG3 complex was conjugated to A7 after esterification of 186Re‐MAG3 with tetrafluorophenol (TFP). The efficiency of 186Re‐MAG3‐TFP production and the labeling efficiency of A7 were 51–59% and 57–60%, respectively. Immunoreactivity of purified 186Re‐MAG3‐A7 was 68.2% at infinite antigen excess. In 0.9% NaCl at 4°C, the radioactivity (12.7 MBq/mg, 3.55 MBq/ml) dissociated with time from 186Re‐MAG3‐A7 as a small molecular weight moiety because of autoradiolysis. The addition of ascorbic acid, 5 mg/ml, as a radioprotectant or storage at –80°C could effectively prevent the radiolysis of 186Re‐MAG3‐A7 for 7 days. Immunoreactivity of 186Re‐MAG3‐A7, 6.70 MBq/mg (6.66 MBq/ml), stored in the presence of ascorbic acid was well retained up to 8 days after the preparation. In colon cancer xenografted mice, 31.0% of the injected dose/g of 186Re‐MAG3‐A7 had accumulated in the tumors at 24 h postinjection. Estimated radiation dose to tumors was 14.9 cGy/37 kBq up to 8 days postinjection which was 12‐fold greater than the whole‐body radiation dose. These in vivo characteristics were superior to those of A7 labeled with radioiodine, affording greater therapeutic ratios than 131I‐A7. Because of the better image quality of 186Re‐MAG3‐A7 as well as more favorable dosimetry, 186Re‐MAG3‐A7 would be a better choice for RIT of colon cancer than 131I‐A7. These results indicated the feasibility of RIT with 186Re‐MAG3‐A7, though the prevention of radiolysis of the labeled antibody should be considered.

Enhanced Efficacy of Radioimmunotherapy Combined with Systemic Chemotherapy and Local Hyperthermia in Xenograft Model

We previously found that the efficacy of radioimmunotherapy (RIT) with 131I‐A7, an IgG1 against Mr 45000 glycoprotein on colon cancer, was enhanced by local hyperthermia (HT) or chemotherapy with 5‐fluorouracil (5‐FU). In this study, we aimed to further enhance its efficacy by combining these three modalities. Human colon cancer xenografts (146±12 mm3) in Balb/c nu/nu female mice were treated with 9.25 MBq 131I‐A7 i.v. combined with HT (43°C for 1 h) and 5‐FU (30 mg/kg/day i.p. for 5 days). Tumor growth delay, (Tqtreated‐Tqcontrol)/Tqcontrol where Tq is tumor quadrupling time, in mice treated with RIT+HT+5‐FU was improved to 12.7 from 5.90, 7.55 and 10.1 with RIT alone, RIT+5‐FU and RIT+HT, respectively. Complete response was observed in 4 out of 8 tumors with RIT+HT+5‐FU and 3 out of 10 with RIT+HT. No tumor showed complete response with RIT+5‐FU or RIT alone. 5‐FU slightly increased myelotoxicity of RIT, but HT did not affect it. Body weight loss was not enhanced by the combination. These results indicate that the combination of three modalities is a feasible approach to enhance the antitumor efficacy of RIT without serious increase of toxicity.

A case of double cancers with myocardial metastasis mimicking acute myocardial infarction both on an electrocardiogram and on Tc-99m-MIBI myocardial SPECT.

We report a rare case of double cancers with myocardial metastasis presenting acute myocardial infarction (AMI)-like findings both on an electrocardiogram (ECG) and on Tc-99m-MIBI myocardial SPECT. The ECG showed abnormal Q-waves and ST-segment elecvation in leads V1−V4, and Tc-99m-MIBI SPECT showed a photon deficient area in the anteroseptum. These findings were suggestive of AMI, but the patient had been simultaneously suffering from two adenocarcinomas, which were lung cancer and gastric cancer, and consecutive ultrasonic cardiography (UCG) demonstrated a growing mass lesion in the septal aspect of the left ventricle. After a month he died of severe heart failure. The histological diagnosis of a specimen of the cardiac mass lesion was invasive adenocarcinoma infiltrating to the heart, which revealed that the myocardial metastasis had mimicked AMI. This case shows that it is difficult to distinguish between myocardial infarction and myocardial metastasis with myocardial perfusion SPECT. It is necessary to consider the possibility of myocardial metastasis when a patient with malignancy presents AMI-like findings.

Technetium-99m-Tetrofosmin Would Be a Substrate for Multidrug Resistance-associated Protein (MRP): Comparison between a Leukemia Cell Line with High MRP Gene Expression and Its Parental Cell Line

UNLABELLED The kinetics of cellular accumulation and retention of technetium-99m-tetrofosmin (99mTc-TF) were investigated in wild type HL60/WT cell line and in its doxorubicin-resistant HL60/DOX cell line with multidrug resistance-associated protein (MRP), but without P-gp overexpression, to determine whether 99mTc-TF is a substrate for MRP. METHODS The accumulation and washout of 99mTc-TF were observed in both cell lines at 37 degrees C. The effect of verapamil on the kinetics was also assessed. RESULTS 99mTc-TF net accumulation was significantly lower in HL60/DOX (1.35 +/- 0.23%) than in HL60/WT (12.79 +/- 0.47%) at 60 min (P < 0.001). Three minutes after exchanging the incubation solution to the tracer-free medium, only 18.20 +/- 0.34% of 99mTc-TF remained in HL60/DOX, whereas 84.74 +/- 0.65% did in HL60/WT (P < 0.001). In the presence of 10 microM verapamil, 99mTc-TF net accumulation in HL60/DOX was 302% of the control and the washout was significantly delayed. CONCLUSION 99mTc-TF would be a substrate for MRP and 99mTc-TF may be used as a functional imaging agent of MRP in vivo.

Effect of induced hypertension with angiotensin II infusion on biodistribution of 111In-labeled monoclonal antibody☆

We investigated whether induced hypertension could enhance tumor uptake of monoclonal antibody. 111In-DTPA-A7 (IgG1 against 40kD tumor associated glycoprotein) was injected into colon carcinoma xenografted mice which were subcutaneously implanted with micro-osmotic pump containing angiotensin II (AT-II). Biodistribution was observed in groups of mice infused with AT-II at rate of 0.5 micrograms/kg/min (L) or 1 microgram/kg/min (H) and compared with a group of mice infused with saline (S). Tumor uptake of 111In-A7 in L and H was 1.32 and 1.57 times greater than S at 48 h after intravenous injection of A7. Normal organ uptakes also tended to be increased by AT-II infusion. Further study is needed to get optimum effect of hypertensive treatment on biodistribution of radiolabeled MoAb.

Asialoglycoprotein receptor concentration in tumor-bearing livers and its fate early after their sectorial resection

The aim of the present study was to investigate asialoglycoprotein receptor (ASGP-R) status in tumor-bearing livers and early after their sectorial resection employing99mTc-DTPA-galactosyl human serum albumin (99mTc-GSA) dynamic SPECT.Methods: Ten normal liver controls and 44 liver tumor patients who underwent sectorial hepatectomy were included in the study.99mTc-GSA dynamic SPECT study was performed 7±3 d before (pre-operative) and 34±13 d after surgery (post-operative) in liver tumour patients. Pre- and post-operative parameters including hepatic functional volume and99mTc-GSA clearance of unit hepatic functional volume, representing ASGP-R concentration, were measured. The sum of functional volume of the sectors uninvolved in hepatectomy was defined as residual functional volume. Subsequently, post-operative change in functional volume (the ratio of post-operative to residual functional volume), post-operative change in99mTc-GSA clerance of unit hepatic functional volume (the ratio of post- to pre-operative99mTc-GSA clearance of unit hepatic functional volume) and percent resection of functional volume were calculated.Results: Pre-operative99mTc-GSA clerance of unit hepatic functional volume in tumor-bearing livers was significantly lower than that in non-tumor bearing control liver. The ratio of post- to pre-operative99mTc-GSA clerance of unit hepatic functional volume showed marked variation from 0.57 to 2.14, which negatively correlated with the percent resection of functional volume (r=-0.58, p<0.0001). The ratio of post- to pre-operative99mTcGSA clearance of unit hepatic functional volume exhibited a negative correlation with the ratio of post-operative to estimated residual functional volume (r=-0.67, p<0.0001).Conclusion: ASGP-R concentration is reduced in the presence of liver tumor. ASGP-R concentration reveals variable changes early after sectorial resection; the change negatively correlates with percent resection of hepatic functional volume. Post-operative change in ASGP-R concentration negatively correlates with change in functional volume.

Short-period-induced hypertension could improve tumor-to-nontumor ratios of radiolabeled monoclonal antibody

This study was undertaken to find optimum period of hypertensive treatment for the improvement of tumor targeting of 111In-labeled monoclonal antibody. Angiotensin II was infused into tumor-bearing mice at an infusion rate of 2.0 micrograms/kg/min determined by the dose-finding study. The infusion was continued for up to 72 h, and biodistribution of 111In-DTPA-A7, a murine IgG1, was observed 72 h postinjection. Tumor-to-nontumor ratios were best improved with the infusion for 0.5-3 h. However, with the longer infusion, the effect deteriorated by the increase of nontumor uptakes, and body-weight loss became remarkable. It could be concluded that hypertensive treatment for a short period could be safely performed to benefit targeting of radiolabeled monoclonal antibody.