Differences Between Cancer Survivors and Healthy Subjects in Factors that Facilitate and Obstruct the Use of the Foster Parent System and Special Adoption System: A Nationwide Cross-Sectional Study in Japan.

Purpose: To investigate factors that obstruct and facilitate the use of the foster parent and special adoption systems (i.e., foster systems) by cancer survivors, and examine how to effectively provide information. Methods: This was a cross-sectional study that compared the results of a questionnaire survey of foster parents and adoptive parents (i.e., foster parents) who were and were not cancer survivors belonging to foster parent associations in 33 locations in Japan. This study was supported by a 2022 Ministry of Health, Labor, and Welfare Grant-in-Aid for Scientific Research (Grant No. 20EA1004). Results: "Lack of information," an obstructive factor and "Sympathetic understanding and cooperation from my partner and family," a facilitative factor were the highest score in both groups. Significant differences between the two groups were found in "Support from government agencies and others for foster parents," a facilitative factor, which was lower in the cancer survivors' group. There were no other significant differences between both the groups. Conclusion: This study found that when considering the use of the foster systems, a lack of information was the biggest obstructive factor and family understanding was the most helpful for both cancer survivors and noncancer groups. It was thought that stronger government support for cancer survivors might encourage cancer survivors to consider becoming foster parents. It would be effective for cancer treatment facilities, reproductive medical facilities, the government, and foster parent associations to work together to provide information carefully to cancer survivors.

Evaluation of radioiodinated vesamicol analogs for sigma receptor imaging in tumor and radionuclide receptor therapy.

It has been reported that sigma receptors are highly expressed in a variety of human tumors. In this study, we selected (+)-2-[4-(4-iodophenyl)piperidino] cyclohexanol [(+)-pIV] as a sigma receptor ligand and evaluated the potential of radioiodinated (+)-pIV for tumor imaging and therapy. (+)-[(125/131)I]pIV was prepared by an iododestannylation reaction under no-carrier-added conditions with radiochemical purity over 99% after HPLC purification. Biodistribution experiments were performed by the intravenous injection of (+)-[(125)I]pIV into mice bearing human prostate tumors (DU-145). Blocking studies were performed by intravenous injection of (+)-[(125)I]pIV mixed with an excess amount of unlabeled sigma ligand into DU-145 tumor-bearing mice. For therapeutic study, (+)-[(131)I]pIV was injected at a dose of 7.4 MBq followed by measurement of the tumor size. In biodistribution experiments, (+)-[(125)I]pIV showed high uptake and long residence in the tumor. High tumor to blood and muscle ratios were achieved because the radioactivity levels of blood and muscle were low. However, the accumulations of radioactivity in non-target tissues, such as liver and kidney, were high. The radioactivity in the non-target tissues slowly decreased over time. Co-injection of (+)-[(125)I]pIV with an excess amount of unlabeled sigma ligand resulted in a significant decrease in the tumor/blood ratio, indicating sigma receptor-mediated tumor uptake. In therapeutic study, tumor growth in mice treated with (+)-[(131)I]pIV was significantly inhibited compared to that of an untreated group. These results indicate that radioiodinated (+)-pIV has a high potential for sigma receptor imaging in tumor and radionuclide receptor therapy.

Development of [(90)Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases.

INTRODUCTION: Based on the concept of bifunctional radiopharmaceuticals, we have previously developed (186)Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed (90)Y-labeled radiopharmaceutical could be developed. METHODS: In this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [(90)Y]DOTA-complex-conjugated bisphosphonate ([(90)Y]DOTA-HBP) was prepared by coordination with (90)Y, and its biodistribution was studied in comparison to [(90)Y]citrate. RESULTS: In biodistribution experiments, [(90)Y]DOTA-HBP and [(90)Y]citrate rapidly accumulated and resided in the bone. Although [(90)Y]citrate showed a higher level of accumulation in the bone than [(90)Y]DOTA-HBP, the clearances of [(90)Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [(90)Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [(90)Y]DOTA-HBP were lower than those of [(90)Y]citrate. CONCLUSIONS: [(90)Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [(90)Y]citrate. Since the DOTA ligand forms a stable complex not only with (90)Y but also with lutetium ((177)Lu), indium ((111)In), gallium ((67/68)Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging.

Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of 186Re-MAG3-conjugated bisphosphonate (186Re-MAG3-HBP), an agent for treatment of painful bone metastases.

PURPOSE: We have developed a (186)Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate ((186)Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of (186)Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of (99m)Tc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution. METHODS: The displacement effects of several protein-binding inhibitors on the protein binding of (186)Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering (186)Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline. RESULTS: The protein binding of (186)Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of (186)Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone. CONCLUSIONS: The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein.

The potential of (-)-o-[11C]methylvesamicol for diagnosing cholinergic deficit dementia.

(-)-o-Methylvesamicol ((-)-OMV) exhibited in vitro a high affinity for a vesicular acetylcholine transporter (VAChT) (Ki, 6.7 nM), and (-)-o-[(11)C]methylvesamicol [(-)-[(11)C]OMV] exhibited appropriate kinetics and bound mainly to VAChTs in the rat brain. In this study, the in vivo distribution and kinetics of (-)-[(11)C]OMV were evaluated in comparison with [(11)C]SA4503 in disability model monkeys produced by selectively destroying the p75NTR-positive cells in the right hemisphere of the brain using positron emission tomography. Time-activity curves of (-)-[(11)C]OMV showed peaks within 20 min in regions rich in acetylcholine transporters (AchT). (-)-[(11)C]OMV binding in the ipsilateral cortex to the lesion was significantly reduced by 22.0% +/- 6.7% when compared with that in the contralateral region. The decrease (19.3% +/- 2.2%) in (-)-[(11)C]OMV binding in the ipsilateral temporal cortex to the lesion was greater than that (7.4% +/- 4.6%) of [(11)C]SA4503. These results suggested that (-)-[(11)C]OMV may be useful in the study of dementia characterized by degeneration of the cholinergic neurotransmitter system.

Potential usefulness of D2R reporter gene imaging by IBF as gene therapy monitoring for cerebellar neurodegenerative diseases.

We investigated a gene expression imaging method to examine the level of therapeutic gene expression in the cerebellum. Using a human immunodeficiency virus derived lentivial vector, we expressed the dopamine D(2) receptor (D(2)R) as a reporter protein to mouse cerebellar Purkinje cells. Biodistribution and ex vivo autoradiography studies were performed by giving [(125)I]5-iodo-7-N-[(1-ethyl-2-pyrrolidinyl)methyl]carboxamide-2,3-dihydrobenzofuran ([(125)I]IBF) (1.85 MBq), as a radioactive D(2)R ligand, to model mice expressing the D(2)R with an HA tag (HA-D(2)R) in the cerebellum. In this study, [(125)I]IBF was bound to the D(2)R expressed in the cerebellum of the model mice selectively. Immunostaining was performed to confirm the HA-D(2)R expression in the cerebellum of the model mice. A significant correlation (r=0.900, P<0.001) between areas that expressed HA-D(2)R by immunostaining and areas in which [(125)I]IBF accumulated by the ex vivo autoradiograms was found. These results indicated that radioiodinated IBF is useful as a reporter probe to detect D(2)R reporter gene expression, which can be used for monitoring therapeutic gene expression in the cerebellum.

alpha(v)beta(3) Integrin-targeting radionuclide therapy and imaging with monomeric RGD peptide.

The alpha(v)beta(3) integrin plays a pivotal role in angiogenesis and tumor metastasis. Angiogenic blood vessels overexpress alpha(v)beta(3) integrin, as in tumor neovascularization, and alpha(v)beta(3) integrin expression in other microvascular beds and organs is limited. Therefore, alpha(v)beta(3) integrin is a suitable receptor for tumor-targeting imaging and therapy. Recently, tetrameric and dimeric RGD peptides have been developed to enhance specificity to alpha(v)beta(3) integrin. In comparison to the corresponding monomeric peptide, however, these peptides show high levels of accumulation in kidney and liver. The purpose of this study is to evaluate tumor-targeting properties and the therapeutic potential of 111In- and 90Y-labeled monomeric RGD peptides in BALB/c nude mice with SKOV-3 human ovarian carcinoma tumors. DOTA-c(RGDfK) was labeled with 111In or 90Y and purified by HPLC. A biodistribution study and scintigraphic images revealed the specific uptake to alpha(v)beta(3) integrin and the rapid clearance from normal tissues. These peptides were renally excreted. At 10 min after injection of tracers, 111In-DOTA-c(RGDfK) and 90Y-DOTA-c(RGDfK) showed high uptake in tumors (7.3 +/- 0.6% ID/g and 4.6 +/- 0.8% ID/g, respectively) and gradually decreased over time (2.3 +/- 0.4% ID/g and 1.5 +/- 0.5% ID/g at 24 hr, respectively). High tumor-to-blood and -muscle ratios were obtained from these peptides. In radionuclide therapeutic study, multiple-dose administration of 90Y-DOTA-c(RGDfK) (3 x 11.1 MBq) suppressed tumor growth in comparison to the control group and a single-dose administration (11.1 MBq). Monomeric RGD peptides, 111In-DOTA-c(RGDfK) and (90)Y-DOTA-c(RGDfK), could be promising tracers for alpha(v)beta(3) integrin-targeting imaging and radiotherapy.

A change of in vivo characteristics depending on specific activity of radioiodinated (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-pIV] as a ligand for sigma receptor imaging.

The radioiodinated (+)-p-iodovesamicol [(+)-pIV], which shows a high binding affinity for sigma-1 (sigma-1) receptors, is prepared by an exchange reaction. The specific activity (SA) is fairly low and therefore is insufficient for clinical use. In this study, we prepared (+)-[(125)I]pIV with a high SA from tributylstannyl precursor and compared the in vivo characteristics between high and low SA by imaging sigma-1 receptors in the central nervous system. In the biodistribution study, a difference in brain accumulation was observed between the two methods. At 30 min postinjection, the brain accumulation (1.58%ID/g) of low SA [0.6-1.1 TBq/mmol (16-30 Ci/mmol)] (+)-[(125)I]pIV was higher than that (1.34%ID/g) of high SA [>88.8 TBq/mmol (>2400 Ci/mmol)] (+)-[(125)I]pIV. In the blocking study, the brain uptake of high SA (+)-[(125)I]pIV was reduced more significantly by the coadministration of sigma ligands such as pentazocine, haloperidol or SA4503 than that of low SA (+)-[(125)I]pIV. These results showed that nonspecific binding of high SA (+)-[(125)I]pIV in the brain was lower than that of low SA (+)-[(125)I]pIV, and high SA (+)-[(125)I]pIV bound more specifically to sigma-1 receptors in the brain than low SA (+)-[(125)I]pIV. In contrast, in the blood-binding study, high SA (+)-[(125)I]pIV (58.4%) bound to blood cells with higher affinity than low SA (+)-[(125)I]pIV (46.0%). In metabolite studies, blood metabolites of high SA (+)-[(125)I]pIV (57.3+/-3.5%) were higher than those of low SA (+)-[(125)I]pIV (45.5+/-4.1%) at 30 min postinjection. Higher SA may be apt to bind to blood cells with higher affinity and to be metabolized faster.

In vivo characterization of radioiodinated (+)-2-[4-(4-iodophenyl) piperidino] cyclohexanol as a potential sigma-1 receptor imaging agent.

In this study, the (+)-enantiomer of radioiodinated 2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[(125)I]-p-iodovesamicol] [(+)-[(125)I]pIV], which is reported to bind with high affinity to sigma-1 receptors in vitro, was tested for its usefulness in imaging sigma-1 receptors in the central nervous system (CNS) in vivo. In biodistribution studies, significant amounts (approximately 3% of the injected dose) of (+)-[(125)I]pIV accumulated in rat brain, and its retention was prolonged. In blocking studies, the accumulation of (+)-[(125)I]pIV in the rat brain was significantly reduced by the coadministration of sigma-ligands such as pentazocine (5.0 micromol), haloperidol (0.5 micromol) or SA4503 (0.5 micromol). The blocking effect of pentazocine (selective sigma-1 ligand) was similar to the blocking effects of SA4503 and haloperidol [nonselective sigma (sigma-1 and sigma-2) ligands]. Ex vivo autoradiography of the rat brain at 45 min following intravenous injection of (+)-[(125)I]pIV showed high localization in brain areas rich in sigma-1 receptors. Thus, the distribution of (+)-[(125)I]pIV was thought to bind to sigma-1 receptors in the CNS in vivo. These results indicate that radioiodinated (+)-pIV may have the potential to image sigma-1 receptors in vivo.

Therapeutic effects of a 186Re-complex-conjugated bisphosphonate for the palliation of metastatic bone pain in an animal model.

UNLABELLED: Previously, based on the concept of bifunctional radiopharmaceuticals, we developed a highly stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re-MAG3-HBP), for the treatment of painful bone metastases. This agent showed a superior biodistribution as a bone-seeking agent in normal mice when compared with (186)Re-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP). In this study, we evaluated the therapeutic effects of (186)Re-MAG3-HBP using an animal model of bone metastasis. METHODS: The model was prepared by injecting syngeneic MRMT-1 mammary tumor cells into the left tibia of female Sprague-Dawley rats. (186)Re-MAG3-HBP (55.5, 111, or 222 MBq/kg) or (186)Re-HEDP (55.5 MBq/kg) was then administered intravenously 21 d later. To evaluate the therapeutic effects and side effects, tumor size and peripheral blood cell counts were determined. Palliation of bone pain was evaluated by a von Frey filament test. RESULTS: In the rats treated with (186)Re-HEDP, tumor growth was comparable with that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Allodynia induced by bone metastasis was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective. CONCLUSION: These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent for the palliation of metastatic bone pain.

Intraperitoneal radioimmunotherapy to treat the early phase of peritoneal dissemination of human colon cancer cells in a murine model.

BACKGROUND AND AIM: In patients with a high risk of peritoneal dissemination of colon cancer, a treatment adjuvant to surgical resection would improve their prognosis. We aimed to determine whether radioimmunotherapy employing radiolabelled monoclonal antibody would work in this situation. METHODS: A murine model of peritoneal dissemination was established in female Balb/c nu/nu mice by intraperitoneal injection of LS180 human colon cancer cells. Radioimmunotherapy with 7.4 MBq of a murine IgG1, anti-colorectal A7 monoclonal antibody, radiolabelled with (131)I by the chloramine-T method was conducted intraperitoneally on days 0, 3, 7 and 14 after cell inoculation, respectively. RESULTS: Radioimmunotherapy at any timing improved survival of mice as compared with those of non-treated mice and mice treated with a daily dose of 30 mg x kg(-1) of 5-fluorouracil for 4 consecutive days. The best improvement was obtained when radioimmunotherapy was conducted on day 0. CONCLUSION: These results indicate that intraperitoneal radioimmunotherapy may effectively kill colon cancer cells disseminated in the peritoneal cavity before formation of tumours and, therefore, may work as an adjuvant treatment to prevent peritoneal metastasis of colon cancer.

Synthesis and evaluation of vesamicol analog (-)-O-[11C]methylvesamicol as a PET ligand for vesicular acetylcholine transporter.

(-)-O-Methylvesamicol ((-)-OMV) exhibited in vitro a high affinity for vesicular acetylcholine transporter (VAChT) (Ki, 6.7 nM) and a relatively low affinity for sigmal receptor (Ki, 33.7 nM). We prepared (-)-[11C]OMV by a palladium-promoted cross-coupling reaction using [11C]methyl iodide, in a radiochemical yield of 38 +/- 6.9% (n=3), a radiochemical purity of 98 +/- 2.3% (n = 5), and a specific activity of 11 +/- 7.0 TBq/mmol at 30 minutes after EOB (n=5). Then, we evaluated in vivo whether (-)-[11C]OMV has properties as a PET radioligand for mapping VAChT. In rats, the brain uptake of (-)-[11C]OMV was 1.1%ID/g at 5 minutes postinjection, and was retained of a high level for 60 minutes. The brain uptake was significantly inhibited by the co-injection (500 nmol/kg) of cold (-)-OMV (58-66%), (-)-vesamicol (57-65%), and two sigma receptor ligands with modulate affinities for VAChTs: SA4503 (56-71%) and haloperidol (39-64%) in all of the brain regions, including the cerebellum with a low density of VAChTs, but not of sigmal-selective ligand (+)-pentazocine. However, the pretreatment with a large excess amount of (+/-)-pentazocine (50 micromol/kg) reduced the uptake in a different manner in the brain regions: 25% reduction in the striatum with a high density of VAChTs, and a 50-55% reduction in the other regions with a lower density of VAChTs. Ex vivo autoradiography using (-)-[11C]OMV showed a similar regional brain distribution of [3H](-)-vesamicol. In the PET study of the monkey brain, the regional brain distribution pattern of (-)-[11C]OMV was different from that of [11C]SA4503. The uptake of (-)-[11C]OMV was relatively higher in the striatum, was reversible, and an apparent equilibrium state was found at 20-40 minutes. In conclusion, (-)-[11C]OMV exhibited appropriate brain kinetics during the time frame of 11C-labeled tracers and bound mainly to VAChTs; however, the binding to sigmal receptors was not disregarded. Therefore, (-)-[11C]OMV-PET together with help of [11C]SA4503-PET may evaluate VAChTs.

A simple and rapid radiochemical choline acetyltransferase (ChAT) assay screening test.

A simple radiochemical choline acetyltransferase (ChAT) assay screening test was developed by measuring for [(3)H]acetylcholine ([(3)H]ACh) formed from 0.2 mM [(3)H]acetyl-coenzyme A ([(3)H]acetyl-CoA) and 1 mM choline by 0.2 mg of rat brain homogenates containing ChAT into 96-well microplates. A simple and rapid procedure for isolating [(3)H]ACh from the incubation mixture into 96-well microplates was achieved by using a sodium tetraphenylboron (Kalibor) solution (in ethyl acetate, 0.75%, w/v) and a hydrophobic liquid scintillator mixture (1:5, v/v, 0.2 mL) as an extraction solvent. The benefits of this radiochemical method using 96-well microplates are as follows: (1) this method is reliable and reproducible; (2) many samples can be examined at the same time by this method; (3) this method is economical and effective in reducing radioactive waste. The development of a new simple radiochemical ChAT assay screening test is the first stage of development of radiolabeled ChAT mapping agent.

Evaluation of (+)-p-[11C]methylvesamicol for mapping sigma1 receptors: a comparison with [11C]SA4503.

Vesamicol is a leading compound for positron emission tomography (PET) and single photon emission computed tomography (SPECT) tracers for mapping the vesicular acetylcholine transporter (VAChT). Recently, we found that (+)-p-methylvesamicol ((+)-PMV) has low affinity for VAChT (K(i)=199 nM), but has moderate to high affinity for sigma receptors: K(i)=3.0 nM for sigma1 and K(i)=40.7 nM for sigma2, and that sigma1-selective SA4503 (K(i)=4.4 nM for sigma1 and K(i)=242 nM for sigma2) has moderate affinity for VAChT (K(i)=50.2 nM). In the present study, we examined the potential of (+)-[11C]PMV as a PET radioligand for mapping sigma1 receptors as compared with [11C]SA4503. In rat brain, similar regional distribution patterns of (+)-[11C]PMV and [11C]SA4503 were shown by tissue dissection and by ex vivo autoradiography. Blocking experiments using (+/-)-PMV, (-)-vesamicol, SA4503, haloperidol and (+/-)-pentazocine showed that the two tracers specifically bound to sigma1 receptors, and that [11C]SA4503 exhibited greater specific binding than (+)-[11C]PMV. No sign of VAChT-specific binding by [11C]SA4503 was observed in the striatum, which is rich in VAChT sites. In conclusion, (+)-[11C]PMV specifically bound to sigma1 receptors in the brain, but to a lesser extent than [11C]SA4503, suggesting that (+)-[11C]PMV is a less preferable PET ligand than [11C]SA4503. On the other hand, the moderate affinity of [11C]SA4503 for VAChT is negligible in vivo.

99mTc-sestamibi to monitor treatment with antisense oligodeoxynucleotide complementary to MRP mRNA in human breast cancer cells.

OBJECTIVE: Technetium-99m sestamibi (MIBI) has been utilized to evaluate multi-drug resistance (MDR) phenomenon of malignant tumors and to predict chemotherapeutic effects on them. The current investigation examined the possibility of monitoring changes with respect to mRNA expression of multi-drug resistance associated protein (MRP) following antisense oligodeoxynucleotide (AS-ODN) treatment involving 99mTc-MIBI. METHODS: The human breast cancer MCF-7 cell line and its MDR-induced MCF-7/VP cell line were employed. Cell suspensions of the two cell lines at 1 x 10(4) cells/ml were inoculated in 24-well plates (0.2 ml/well) and incubated for one day. Antisense (AS) 20-mer phosphorothioate ODN complementary to the coding region of MRP mRNA and its sense (S) ODN were administered at final concentrations up to 25 microM, followed by a 5-day incubation. 99mTc-MIBI solution was added to each well and incubated for 30 min. Cellular 99mTc-MIBI uptake was corrected for protein concentration. MRP mRNA expression levels were analyzed via the reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Cellular uptake of 99mTc-MIBI in MCF-7/VP cells was only 15% of that of MCF-7 cells. Following AS-ODN treatment at 25 microM for five days, 99mTc-MIBI uptake in MCF-7/VP cells increased 2.4-fold in comparison with non-treated control cells. 99mTc-MIBI uptake in MCF-7 cells was unaffected by AS-ODN administration. Sense ODN did not alter uptake in either cell line. RT-PCR confirmed reduction of MRP mRNA in MCF-7/VP cells following AS-ODN treatment. CONCLUSION: Effects of AS-ODN administration on MRP function can be monitored via assessment of cellular uptake of 99mTc-MIBI.

Synthesis and binding affinities of methylvesamicol analogs for the acetylcholine transporter and sigma receptor.

We synthesized methylvesamicol analogs 13-16 and investigated the binding characteristics of 2-[4-phenylpiperidino]cyclohexanol (vesamicol) and methylvesamicol analogs 13-16, with a methyl group introduced into the 4-phenylpiperidine moiety, to sigma receptors (sigma-1, sigma-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (-)-o-methylvesamicol [(-)-OMV] (13) (Ki=6.7 nM), as well as (-)-vesamicol (Ki=4.4 nM), had a high affinity for VAChT. (+)-p-Methylvesamicol [(+)-PMV] (16) (Ki=3.0 nM), as well as SA4503 (Ki=4.4 nM), reported as a sigma-1 mapping agent for positron emission tomography (PET), had a high affinity for the sigma-1 receptor. The binding affinity of (+)-PMV (16) for the sigma-1 receptor (Ki=3.0 nM) was about 13 times higher than that for the sigma-2 (sigma-2) receptor (Ki=40.7 nM). (+)-PMV (16) (Ki=199 nM) had a much lower affinity for VAChT than SA4503 (Ki=50.2 nM) and haloperidol (Ki=41.4 nM). These results showed that the binding characteristics of (-)-OMV (13) to VAChT were similar to those of (-)-vesamicol and that (+)-PMV (16) bound to the sigma-1 receptor with high affinity. In conclusion, (-)-OMV (13) and (+)-PMV (16), which had a suitable structure, with a methyl group for labeling with 11C, may become not only a new VAChT ligand and a new type of sigma receptor ligand, respectively, but may also become a new target compound of VAChT and the sigma-1 receptor radioligand for PET, respectively.

Anti-angiogenic therapy and chemotherapy affect 99mTc sestamibi and 99mTc-HL91 accumulation differently in tumour xenografts.

BACKGROUND: Favourable effects of cytotoxic chemotherapy for tumours are characterized by the reduced accumulation of radiotracers such as 99mTc sestamibi (MIBI). Anti-angiogenic therapy is primarily cytostatic; consequently, its influence on tracer accumulation may differ from that of cytotoxic treatments. METHODS: Anti-angiogenic therapy employing 2-methoxyestradiol was administered in mice bearing subcutaneous xenografts of LS180 colon cancer cells. The effects of chemotherapy with 5-fluorouracil were examined as a cytotoxic counterpart. Treatments were conducted for 4 days from day 8. Distribution of 99mTc-MIBI and Tc-HL91, a hypoxic marker, was observed on days 8 and 12. Oxygen tension (PO2) in tumours was measured by a microelectrode. Cellular uptake of tracers was examined in vitro in normoxic and hypoxic conditions. RESULTS: 99mTc-MIBI accumulation decreased with increasing tumour weight when no treatment was conducted. Tumour growth was suppressed by anti-angiogenic therapy and chemotherapy. 99mTc-MIBI accumulation in tumours decreased after chemotherapy as compared to pre-therapeutic values, whereas accumulation of 99mTc-HL91 increased. In contrast, accumulation of tracers did not significantly change after anti-angiogenic therapy as compared to that observed pre-therapeutically. Tumour PO2 decreased with increasing tumour volume when no treatment was conducted. Chemotherapy reduced PO2 in tumours. PO2 in tumours treated with anti-angiogenic therapy was as high as that observed before treatment. 2-Methoxyestradiol or 5-fluorouracil did not significantly affect tracer accumulation in cells under both normoxic and hypoxic conditions in vitro. CONCLUSION: These findings indicate that scintigraphic assessment of therapeutic efficacy of anti-angiogenic therapy should be performed from a perspective distinct from that of cytotoxic treatment.

Locoreginal radioimmunotherapy with 186Re-labeled monoclonal antibody in treating small peritoneal carcinomatosis of colon cancer in mice in comparison with 131I-counterpart.

The efficacy of locoregional radioimmunotherapy (RIT) in treating peritoneal tumors of colon cancer of <2 mm in diameter was examined at maximum tolerated doses, focusing the comparison between 186Re and 131I labeled to an anti-colorectal cancer IgG1. Estimated radiation doses to tumors were considerably higher with 186Re-RIT than with 131I-RIT. The advantage of 186Re-RIT decreased with decreasing tumor size, but 186Re-RIT delivered 1.6-times higher radiation to tumors of 1 mm. Consequently, 186Re-RIT attained better survival of mice than 131I-RIT or chemotherapy with 5-fluorouracil did. Therefore, locoregional 186Re-RIT may be an option in an adjuvant setting of colon cancer with high risk of peritoneal dissemination.

In vitro characterization of radioiodinated (+)-2-[4-(4-iodophenyl) piperidino]cyclohexanol [(+)-pIV] as a sigma-1 receptor ligand.

We investigated the binding characteristics of a (+)-enantiomer of radioiodinated 2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[125I]pIV], radioiodinated at the para-position of the 4-phenylpiperidine moiety, to sigma receptors (sigma-1, sigma-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (+)-pIV (Ki=1.30 nM) had more than 10 times higher affinity to the sigma-1 (sigma-1) receptor than (+)-pentazocine (Ki=19.9 nM) or haloperidol (Ki=13.5 nM) known as sigma ligands. Also, the binding affinity of (+)-pIV for the sigma-1 receptor (Ki=1.30 nM), was about 16 times higher than the sigma-2 (sigma-2) receptor (Ki=20.4 nM). (+)-pIV (Ki=1260 nM) had a much lower affinity for VAChT than (-)-vesamicol (Ki=13.0 nM) or (-)-pIV (Ki=412 nM). (+)-[125I]pIV had low affinity for the dopamine, serotonin, adrenaline, and acetylcholine receptors. Furthermore, in a saturation binding study, (+)-[125I]pIV exhibited a K) of 6.96 nM with a Bmax of 799 fmol/mg of protein. These results showed that (+)-pIV binds to the sigma-1 receptor with greater affinity than sigma receptor ligands such as (+)-pentazocine or haloperidol, and that radioiodinated (+)-pIV is suitable as radiotracer for sigma-1 receptor studies in vitro.

Limitations of (99m)Tc tetrofosmin in assessing reversal effects of verapamil on the function of multi-drug resistance associated protein 1.

BACKGROUND: Previous reports have demonstrated the feasibility of scintigraphic assessment of the multi-drug resistance (MDR) of tumours caused by ATP binding cassette (ABC) transporters by using Tc cationic tracers such as Tc tetrofosmin (TF). Furthermore, the potential of these tracers for evaluating the effects of reversal agents for MDR has been documented. However, most reversal agents simultaneously affect cationic ion transporters related to tracer accumulation in tumours. METHODS: The uptake of Tc-TF was examined in the MCF7/WT cell line, a wild-type breast cancer cell line that does not exhibit MDR, and its subclonal etoposide resistant cell line MCF7/VP, which expresses high levels of MRP1, one of the multi-drug resistance associated proteins (MRPs), in the presence of increasing concentrations of verapamil, a classical MDR modulator. In the absence of verapamil, MCF7/VP cells showed significantly lower Tc-TF uptake than did MCF7/WT cells, indicating that Tc-TF is a substrate for MRP1. The presence of verapamil enhanced the uptake of Tc-TF in MCF7/VP cells. On the other hand, verapamil also increased tracer uptake in MCF7/WT cells, which was readily appreciated when the uptake values were corrected by viable cell numbers: an approximately 100% increase of Tc-TF uptake was observed in comparison with that in the absence of verapamil in viable MCF7/WT cells whereas a 100-200% increase occurred in viable MCF7/VP cells. In addition, verapamil prolonged the retention of radioactivity in both MCF7/WT cells and MCF7/VP cells. CONCLUSION: These results suggest that cellular functions other than MRP1 function, probably cationic ion transporters, are simultaneously and significantly involved in the verapamil induced changes of cellular uptake of Tc-TF. Tc-TF scintigraphy may overestimate the reversal effects of modulators on chemoresistance caused by MRP1 when the modulators simultaneously affect ion transporters.