Structure-activity relationship studies on an antitumor marine macrolide using aplyronine a-swinholide A hybrid.

An aplyronine A-swinholide A hybrid, consisting of the macrolactone part of aplyronine A and the side chain part of swinholide A, was designed, synthesized, and biologically evaluated. This hybrid induced protein-protein interactions between two major cytoskeletal proteins actin and tubulin in the same manner as aplyronine A, and exhibited potent cytotoxicity and actin-depolymerizing activity. The importance of the methoxy group in the N,N,O-trimethylserine ester was clarified by the structure-activity relationship studies of the amino acid moiety by using the hybrid analogs. Furthermore, the comparison of the actin-depolymerizing activities between the side chain analogs of aplyronine A and swinholide A showed that the side chain analog of swinholide A had much weaker actin-depolymerizing activity than that of aplyronine A.

Pharmacokinetics and biodistribution of 111In- and 177Lu-labeled J591 antibody specific for prostate-specific membrane antigen: prediction of 90Y-J591 radiation dosimetry based on 111In or 177Lu?

UNLABELLED: 111In-Labeled antibodies and peptides have been routinely used as chemical and biologic surrogates for 90Y-labeled therapeutic agents. However, recent studies have shown that there are significant differences in biodistribution between 111In- and 90Y-labeled agents. Yttrium and lutetium metals favor the +3 oxidation state, similar to indium, but there are minor differences in the solution and coordination chemistries among these metals. These 3 metals, however, form strong complexes with the macrocyclic chelator, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). We, therefore, compared the pharmacokinetics and biodistribution of 111In- and 177Lu-labeled J591 antibody. The radiation dosimetry of 90Y-J591 was estimated based on both 111In and 177Lu data to validate the usage of 111In as a chemical and biologic surrogate for 90Y. METHODS: J591 is a deimmunized monoclonal antibody with specificity for the extracellular domain of prostate-specific membrane antigen. In patients with prostate cancer, phase I dose-escalation studies were conducted with 90Y-J591 (n = 29) and 177Lu-J591 (n = 25). Each patient had pharmacokinetics and imaging studies with 111In-J591 (185 MBq/20 mg) over a period of 1 wk and before treatment with 90Y-J591 antibody. In the 177Lu trial, the pharmacokinetics and imaging studies were performed after treatment with the 177Lu-J591 dose (370-2,590 MBq/m2/10 mg/m2) over a 2-wk period after treatment. RESULTS: Blood and urinary pharmacokinetics were similar for both tracers. Based on biexponential decay, the terminal half-life was 44 +/- 15 h for both tracers. In addition, the total-body retention of radioactivity over a 7-d period was also similar between the 2 isotopes. The percentage uptake in liver was about 20% greater with 111In than with 177Lu. Radiation dosimetry estimates for 90Y-J591 calculated on the basis of 111In or 177Lu data were mostly similar and showed that liver is the critical organ, followed by spleen and kidney. Based on blood radioactivity, the radiation dose (mGy/MBq) to the bone marrow was 3 times higher with 90Y (0.91 +/- 0.43) compared with that with 177Lu (0.32 +/- 0.10). CONCLUSION: 111In- and 177Lu-labeled J591 antibodies have similar plasma and whole-body clearance kinetics. The net retention of 111In activity by lung, liver, and spleen is slightly higher compared with that with 177Lu. These results justify using 111In as a chemical and biologic surrogate for 90Y. However, the radiation dose to the liver may be overestimated by about 25% based on 111In data. In addition, the data also suggest that 177Lu may be a potential alternative for estimating the pharmacokinetics and biodistribution of 90Y-labeled radiopharmaceuticals.

Prediction of myelotoxicity based on bone marrow radiation-absorbed dose: radioimmunotherapy studies using 90Y- and 177Lu-labeled J591 antibodies specific for prostate-specific membrane antigen.

UNLABELLED: In radioimmunotherapy, myelotoxicity due to bone marrow radiation-absorbed dose is the predominant factor and frequently is the dose-limiting factor that determines the maximum tolerated dose (MTD). With (90)Y- and (131)I-labeled monoclonal antibodies, it has been reported that myelotoxicity cannot be predicted on the basis of the amount of radioactive dose administered or the bone marrow radiation-absorbed dose (BMrad), estimated using blood radioactivity concentration. As part of a phase I dose-escalation study in patients with prostate cancer with (90)Y-DOTA-J591 (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) ((90)Y-J591) and (177)Lu-DOTA-J591 ((177)Lu-J591), we evaluated the potential value of several factors in predicting myelotoxicity. METHODS: Seven groups of patients (n = 28) received 370-2,775 MBq/m(2) (10-75 mCi/m(2)) of (177)Lu-J591 and 5 groups of patients (n = 27) received 185-740 MBq (5-20 mCi/m(2)) of (90)Y-J591. Pharmacokinetics and imaging studies were performed for 1-2 wk after (177)Lu treatment, whereas patients receiving (90)Y had these studies performed with (111)In-DOTA-J591 ((111)In-J591) as a surrogate. The BMrad was estimated based on blood radioactivity concentration. Myelotoxicity consisting of thrombocytopenia or neutropenia was graded 1-4 based on criteria of the National Cancer Institute. RESULTS: Blood pharmacokinetics are similar for both tracers. The radiation dose (mGy/MBq) to the bone marrow was 3 times higher with (90)Y (0.91 +/- 0.43) compared with that with (177)Lu (0.32 +/- 0.10). The MTD was 647.5 MBq/m(2) with (90)Y-J591 and 2,590 MBq/m(2) with (177)Lu-J591. The percentage of patients with myelotoxicity (grade 3-4) increased with increasing doses of (90)Y (r = 0.91) or (177)Lu (r = 0.92). There was a better correlation between the radioactive dose administered and the BMrad with (177)Lu (r = 0.91) compared with that with (90)Y (r = 0.75). In addition, with (177)Lu, the fractional decrease in platelets (FDP) correlates well with both the radioactive dose administered (r = 0.88) and the BMrad (r = 0.86). In contrast, with (90)Y, there was poor correlation between the FDP and the radioactive dose administered (r = 0.20) or the BMrad (r = 0.26). Similar results were also observed with white blood cell toxicity. CONCLUSION: In patients with prostate cancer, myelotoxicity after treatment with (177)Lu-J591 can be predicted on the basis of the amount of radioactive dose administered or the BMrad. The lack of correlation between myelotoxicity and (90)Y-J591 BMrad may be due to several factors. (90)Y-J591 may be less stable in vivo and, as a result, higher amounts of free (90)Y may be localized in the bone. In addition, the cross-fire effect of high-energy beta(-)-particles within the bone and the marrow may deliver radiation dose nonuniformly within the marrow.

Cooperative effect of radioimmunotherapy and antiangiogenic therapy with thalidomide in human cancer xenografts.

UNLABELLED: Antiangiogenic therapy may prolong the dormancy of cancer lesions. Moreover, radioimmunotherapy (RIT) may eradicate this population of cells. This study dealt with determining the benefits associated with the combined usefulness of these 2 therapies with respect to inhibition of tumor growth. METHODS: Antiangiogenic therapy using oral thalidomide (daily dose, 200 mg/kg) and RIT involving a single intravenous injection (4.63 MBq (131)I-A7, an IgG1 murine monoclonal antibody) were conducted in mice bearing LS180 human colon cancer xenografts. RIT with an irrelevant IgG1, HPMS-1, was also performed as a control. Antiangiogenesis of thalidomide was investigated by immunohistochemical analysis of tumor sections. RESULTS: Antiangiogenic therapy and RIT with (131)I-A7 significantly suppressed the growth of xenografts. This combination produced more efficient tumor growth inhibition than did the monotherapy (P < 0.005). RIT using (131)I-HPMS-1 was far less effective than (131)I-A7, even when combined with thalidomide administration. Immunohistochemistry revealed a decrease in the microvessel number within tumors treated with thalidomide (P < 0.0001). Combined therapy further reduced the microvessel number (P < 0.01 vs. thalidomide monotherapy). CONCLUSION: The combination of RIT and thalidomide antiangiogenic therapy produces a better response of tumors than does monotherapy. Acting in concert, antiangiogenic therapy may prolong the dormancy of cancer lesions and RIT may eradicate this population of cells.

Determination of immunoreactive fraction of radiolabeled monoclonal antibodies: what is an appropriate method?

Determination of the immunoreactive fraction (IF) of radiolabeled monoclonal antibodies (MAb) is essential to the understanding of the effects of radiolabeling and subsequent target-specific tumor localization. There has been generally no accepted method of determining the IF of MAbs. The conventional method is based on a radioimmunoassay technique in which the fraction of radiolabeled MAb bound to antigen under conditions of "antigen excess" is determined. Lindmo et al. introduced a modified method in which the IF is determined by extrapolation to conditions representing "infinite antigen excess." Although the Lindmo method, in principle, is insensitive to experimental parameters, it does not always provide a reliable estimate of IF. We, therefore, evaluated an alternate method in which percent cell bound fraction is measured under conditions of fixed antigen concentration and various dilutions of radiolabeled MAb. We developed a mathematical equation to estimate immunoreactivity. J591 MAb specific for prostate-specific membrane antigen was radiolabeled with (111)In, (90)Y and (177)Lu to specific activities of 1-20 mCi/mg. We compared the effect of several experimental conditions on the determination of IF using all three different methods. The Lindmo method requires careful optimization of experimental conditions for each radiolabeled MAb. The alternate method, based on a fixed antigen concentration, appears to be practical and may provide a more reliable measure of immunoreactivity.

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.

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

UNLABELLED: The aim of the present study was to investigate asialoglycoprotein receptor (ASGP-R) status in tumor-bearing livers and early after their sectorial resection employing 99mTc-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 and 99mTc-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 in 99mTc-GSA clearance of unit hepatic functional volume (the ratio of post- to pre-operative 99mTc-GSA clearance of unit hepatic functional volume) and percent resection of functional volume were calculated. RESULTS: Pre-operative 99mTc-GSA clearance 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-operative 99mTc-GSA clearance 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-operative 99mTc-GSA 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.

Site-selective C-H borylation of quinolines at the C8 position catalyzed by a silica-supported phosphane-iridium system.

Site-selective C-H borylation of quinoline derivatives at the C8 position has been achieved by using a heterogeneous Ir catalyst system based on a silica-supported cage-type monophosphane ligand SMAP. The efficient synthesis of a corticotropin-releasing factor1 (CRF1) receptor antagonist based on a late-stage C-H borylation strategy demonstrates the utility of the C8 borylation reaction.

Fluorodeoxyglucose accumulation in the left atrial appendage of a patient with paroxysmal atrial fibrillation.

A 69-year-old man with a history of paroxysmal atrial fibrillation (PAF) and subsequent cerebral infarction was referred to our hospital because of an abnormal accumulation of 18F-fluorodeoxyglucose (FDG) in the left atrial appendage (LAA) that was detected on positron emission tomography-computed tomography (PET-CT) imaging during a health screening. Transesophageal echocardiography (TEE) demonstrated thrombus formation in the LAA. Even after the thrombus disappeared by strictly guided oral anticoagulant therapy, intense abnormal FDG uptake in the LAA on PET-CT imaging persisted. In low-risk patients such as this, inflammation may have played some role in LAA thrombus formation.