Physiologic modeling of PET data: quantitative conflict and challenge.
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Blood-Brain Barrier↗
Biomedical subjects
J R Ballinger
Publications and source records attributed to J R Ballinger.
Technetium-99m-furifosmin as an agent for functional imaging of multidrug resistance in tumors.
UNLABELLED: There has been a preliminary report that furifosmin, like the other lipophilic 99mTc cations sestamibi and tetrofosmin, is a substrate for P-glycoprotein, the membrane transporter that is a mechanism of multidrug resistance (MDR) in tumors. This has been further investigated in the rat mammary carcinoma cell line MatB/WT and its doxorubicin-selected resistant variant MatB/AdrR. METHODS: In vitro studies were performed by adding furifosmin to stirred single-cell suspensions of MatB/WT and MatB/AdrR in the presence or absence of the Pgp-modulating drug PSC833. Dynamic imaging studies over 30 min were performed in rats bearing MatB/WT or MatB/AdrR tumors growing in the leg. RESULTS: Accumulation of furifosmin in MatB/AdrR cells in vitro was much lower than that in MatB/WT cells. The addition of 1 microM PSC833 increased the plateau accumulation in MatB/AdrR cells 2.4-fold, but did not affect accumulation in MatB/WT cells. In rats, furifosmin accumulated rapidly in MatB/WT tumors and washed out with a mean t3 of 78 min. Washout from MAtB/AdrR tumors was more rapid, with a t3 of 46 min (p < 0.025). Following dissection of animals at 30 min, mean tumor-to-muscle ratios were 1.57 and 1.05 in MatB/WT and MatB/ AdrR tumors, respectively (p < 0.025). CONCLUSION: Furifosmin is suitable for functional imaging of multidrug resistance in tumors.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Power efficient on-resonance saturation pulses for magnetization transfer in magnetic resonance imaging.
A family of new on-resonance saturation pulses for magnetization transfer in MRI is proposed. These pulses can be represented as a product of a shaped function and a cosine function. The shaped function can have many different forms, one of which is a Gaussian function. The experimental results on a 1.0 T whole body scanner show that the new on-resonance pulses are more efficient for magnetization transfer than either on-resonance binomial sequence pulses or off-resonance Gaussian pulses at the same power level.
Humans↗
Radiologic imaging in cancer.
Radiologic procedures are extremely valuable in the diagnostic work-up of many cancers but are limited for screening purposes to a few diseases. Radiologists have developed an extensive armamentarium of tools, from plain radiographs and nuclear-medicine scans to ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography. This article includes suggested protocols for working up the most common cancers.
Algorithms↗
From graphical analysis to multilinear regression analysis of reversible radioligand binding.
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Humans↗
Imaging inflammation with 99Tcm-labeled chemotactic peptides: analogues with reduced neutropenia.
Two 99Tcm-labelled analogues of the chemotactic peptide ForMLF were evaluated as potential agents for imaging inflammation and infection, in the hope that they would be simple to use and would give diagnostically useful images shortly after injection. The peptides differed in the chelation site for 99Tcm and the presence of a hydrophilic spacer. The sequences of RP050 and RP056 were ForNleLFNleYK(G)G-C(Acm)-GPic and ForNleLFNleYKK(DG)GC(Acm)SPic respectively, where Pic is picolinic acid. In in vitro tests of binding to the ForMLF receptor on polymorphonuclear neutrophils and potency for release of myeloperoxidase, RP056 was similar in potency to ForMLF, whereas RP050 was 10 times more potent. When administered in 5-nmol doses to rats, RP050 produced less extensive neutropenia than ForMLF, whereas RP056 produced very little neutropenia. Following labelling by ligand exchange from tartrate or glucoheptonate at 100 degrees C and purification using a C-18 solid-phase extraction cartridge, 4-MBq doses were administered to rats bearing infectious (Escherichia coli) or sterile (zymosan) inflammation sites in the thigh. The inflammation-to-normal muscle ratios at 30 min after injection were 3.9 +/- 0.4 for RP050 and 4.7 +/- 0.3 for RP056 (mean +/- S.E.M., n = 4), and the ratios were maintained for up to 3 h. These peptides are promising agents for imaging inflammation and infection.
Amino Acid Sequence↗
In vitro and in vivo evaluation of a technetium-99m-labeled 2-nitroimidazole (BMS181321) as a marker of tumor hypoxia.
UNLABELLED: The 99mTc-labeled 2-nitroimidazole derivative BMS181321, previously studied in experimental models of myocardial and cerebral ischemia, has been evaluated in single-cell and tumor models. METHODS: Accumulation of BMS181321 was studied in aerobic and hypoxic (<10 PPM O2) suspension cultures of Chinese hamster ovary (CHO) cells at 37 degrees C and the oxygen dependency and stability of the accumulated radioactivity determined. Biodistribution studies of the tracer after intravenous injection in C3H mice bearing three different murine solid tumors were performed noninvasively using a gamma camera, as well as invasively by determining blood and tissue levels of radioactivity from 10 min to 24 hr after injection. RESULTS: Accumulation of BMS181321 in aerobic cells in vitro equilibrated within 5 min at a approximately 10-fold level over the external medium. Hypoxic cells showed a linear increase in radioactivity up to 4 hr for cell densities < or = 1 x 10(6)/ml. At higher cell densities (2-4 x 10(6)/ml) there was substantial depletion of radioactivity from the growth medium and increased alteration in the chemical state of the tracer that remained. Low O2 levels (approximately 40 ppm) inhibited the maximal accumulation rate by 50%. Approximately 30% of radioactivity accumulated under hypoxic conditions remained cell-associated after 24 hr. Following intravenous injection, the tracer rapidly distributed throughout the mouse and was predominately cleared through the hepatobiliary system. Blood levels of radioactivity cleared quickly and plateaued at approximately 4% of the total dose from 2-24 hr. Absolute uptake in the tumors was highest 10 min after injection, and the tumor-to-muscle activity ratios increased and plateaued from 4-8 hr at values of 3.5-4.0. Two drugs which affect blood flow and increase hypoxic cell fraction in these tumors, hydralizine and nitro-L-arginine, significantly increased levels of BMS181321 radioactivity over control levels with minimal effects on normal tissue retention. CONCLUSION: These results suggest BMS181321 or an analog of it will be a useful agent to investigate the status of hypoxia in solid tumors experimentally and potentially in the clinic.
Animals↗
BMS181321 accumulation in rodent and human cells: the role of P-glycoprotein.
A 2-nitroimidazole with a side chain that contains technetium-99m as a chelate, BMS181321, is undergoing evaluation as an imaging agent for myocardial and cerebral ischaemia, as well as a diagnostic probe for hypoxic cells in solid tumours. Its accumulation in hypoxic and aerobic populations of three lines of Chinese hamster ovary cells of differing P-glycoprotein status, as well as one rat and two human cell lines has been determined. There was selective accumulation of BMS181321 in hypoxic vs aerobic cells. P-glycoprotein level was not a factor in this accumulation and hypoxic human cells accumulated BMS181321 more rapidly than the rodent cells. These results indicate P-glycoprotein levels in tumour cells will not confound the use of BMS181321 as a hypoxic cell marker.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Noninvasive quantification of dopamine D2 receptors with iodine-123-IBF SPECT.
UNLABELLED: Iodine-123-iodobenzofuran (IBF) is a potent dopamine D2 receptor ligand suited for quantitative receptor studies. The purpose of this study was to evaluate three noninvasive methods of estimating the receptor parameter k3/k4 in humans with IBF-SPECT. METHODS: Scans were acquired every 5 min for 180 min using a triple-headed SPECT system following a bolus injection of IBF (296 +/- 37 MBq) in 14 normal volunteers. k3/k4 was estimated by the peak equilibrium ratio (RPE) method and two proposed methods: a variation of the graphic method that derives the ratio of ligand distribution volumes (RV) and area ratio (RA) method, in which the ratio is calculated from the areas under the specific binding and nondisplaceable activity curves. RESULTS: The mean RPE, RV and RA were 2.74 +/- 0.40, 3.06 +/- 0.42 and 2.26 +/- 0.28, respectively. Both RPE and RA underestimated RV. The relationship between RPE or RA and RV was linear (p < or = 10(-5), RA showed higher correlation (r = 0.94) with RV than did RPE (r = 0.90). Simulations based on a tracer kinetic model showed that RV, unlike RPE or RA, is affected by neither regional cerebral blood flow (rCBF) nor peripheral clearance rate (CR) of IBF. All three measures showed a significant decline with increasing age (r = 0.54-0.58, p < 0.05). CONCLUSION: RV is preferred because it provides a theoretically valid estimate of k3/k4, independently of rCBF or CR. Alternatively, RA might be preferred to RPE because the former is simpler than the latter to implement yet the former provides a measure that equally well correlates with k3/k4.
Adult↗
Technetium-99m-tetrofosmin as a substrate for P-glycoprotein: in vitro studies in multidrug-resistant breast tumor cells.
UNLABELLED: The accumulation of 99mTc-tetrofosmin (TFos) was studied in wildtype (WT) and doxorubicin-resistant (AdrR) variants of the rat MatB and human MCF-7 breast tumor cell lines to determine whether TFos, like 99mTc-sestamibi (MIBI), is a substrate for P-glycoprotein (P-gp), a multidrug-resistance transporter. METHODS: The time course of accumulation of TFos and MIBI in WT and AdrR cells over 1 hr was studied using single-cell suspensions at 1 x 10(6) cells/ml incubated at 37 degrees C in the presence or absence of PSC833, a potent modulator of P-gp. Modulator dose-response curves were generated for PSC833, cyclosporin A, and verapamil. RESULTS: In both MatB and MCF-7 cells, TFos and MIBI accumulated extensively in WT cells and accumulation was not affected by PSC833. In contrast, ADrR cell lines accumulated very little of either tracer, but addition of PSC833 or other modulator increased this accumulation in a dose-dependent fashion. TFos and MIBI did not differ significantly in their behavior. CONCLUSION: TFos shares with MIBI the property of being a substrate for P-gp and thus TFos may be useful for functional imaging of tumor P-gp status.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
SPECT imaging of dopamine receptors.
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Brain↗
Susceptibility artifact reduction in fat suppression.
Strong fat signal in regions where a large susceptibility difference exists, for instance at the interface between air and tissue near the maxillary sinus, may not be eliminated by currently available fat suppression techniques without sacrificing the overall quality of the images. In this article, we show that this fat signal, which appears as a susceptibility artifact, can be significantly reduced by using an optimized presaturation pulse with sharp edges and a broad bandwidth, while causing minimal disturbance of the water signal. Several optimized presaturation pulses can be reproduced by the Fourier coefficients provided in the Appendix.
Adipose Tissue↗
P-31 changes as a measure of therapy response in resistant and sensitive osteosarcomas implanted into nude mice.
OBJECTIVE: To determine if changes in PCr/Pi and PME can be used to predict lack of tumor response to chemotherapy in a murine model of a chemotherapy-resistant human osteosarcoma. MATERIAL AND METHODS: Cisplatin-resistant sublines were grown from high-grade cisplatin-sensitive human osteosarcoma. Surface coil localized 31P NMR spectroscopy of implanted cisplatin-resistant and sensitive osteosarcoma tumors in nude mice was performed. RESULTS: A cisplatin-resistant subline of a sensitive human osteosarcoma was developed that was five times more resistant to cisplatin than the parent cell line. Our NMR data shows a statistically significant difference in the change in the PCr/Pi ratio after treatment between sensitive and resistant osteosarcomas at the alpha = 0.05 level. Changes in PME were seen in the sensitive tumors but were not statistically significant. CONCLUSIONS: Changes in PCr/Pi predict lack of tumor treatment response in human osteosarcoma implanted into nude mice with a specificity of 70% and a sensitivity of 54%. Monitoring of PCr/Pi in human osteosarcoma patients may allow detection of response to chemotherapy before conventional imaging techniques.
Animals↗
Labelling small quantities of monoclonal antibodies and their F(ab')2 fragments with technetium-99m.
Addition of sulfhydryl groups with 2-iminothiolane (2-IT) is an important new method for labelling monoclonal antibodies (mAb) and fragments with 99mTc. F(ab')2 fragments were prepared by digestion of 1B7.11 and BCD-F9 with pepsin. Optimal conditions for labelling 20-100 micrograms mAb or F(ab')2 involved a 2000:1 molar ratio of 2-IT:protein in phosphate buffer pH 7.4 for 30 min followed by addition of 99mTc-pertechnetate and stannous glucoheptonate. Recovered yields were > 70% and radiochemical purities were > 90% with a total preparation time of < 90 min.
Antibodies, Monoclonal↗
99Tcm-sestamibi as an agent for imaging P-glycoprotein-mediated multi-drug resistance: in vitro and in vivo studies in a rat breast tumour cell line and its doxorubicin-resistant variant.
Multi-drug resistance mediated by the transmembrane pump P-glycoprotein (Pgp) is an important mechanism of resistance of certain tumours against chemotherapeutic drugs. The myocardial perfusion imaging agent 99Tcm-sestamibi is a substrate for Pgp. Further characterization of 99Tcm-sestamibi has now been carried out in the transplantable rat breast adenocarcinoma cell line, MatB, and its doxorubicin-resistant variant, AdrR. In vitro accumulation of the tracer in wild-type (WT) MatB was high and was not affected by the Pgp modulator, PSC833. Conversely, AdrR cells did not accumulate significant amounts of tracer unless PSC833 was present. Imaging studies in rats bearing MatB-WT and AdrR tumours showed that 99Tcm-sestamibi washed out of the resistant tumours at three times the rate of WT tumours. These results support the potential use of 99Tcm-sestamibi for functional imaging of Pgp activity in patients undergoing chemotherapy.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A novel anti-seminoma monoclonal antibody (M2A) labelled with technetium-99m: potential application for radioimmunoscintigraphy.
OBJECTIVE: To study the potential usefulness of monoclonal antibody (mAb) M2A specific for seminoma to image tumour nodules in a preclinical nude mouse model. MATERIALS AND METHODS: MAb M2A was labelled with technetium-99m (99mTc) following reduction and was administered intraperitoneally to nude mice bearing subcutaneous HEY cell xenografts against which the antibody was originally raised. Biodistribution and gamma scintigraphy studies were performed 24 h after administration of 99mTc-M2A. RESULTS: Biodistribution studies showed specific targeting of 99mTc-M2A to HEY tumours in comparison with control mAb 99mTc-6E8 and 99mTc-2G3 which do not bind to HEY cells. Subcutaneous HEY cell tumours (0.5-1.0 g) were successfully imaged using gamma-scintigraphy following administration of 99mTc-M2A. CONCLUSION: The results of this study indicate the potential usefulness of 99mTc-M2A as a clinical reagent for imaging seminoma metastases.
Animals↗
Differences between accumulation of 99mTc-MIBI and 201Tl-thallous chloride in tumour cells: role of P-glycoprotein.
Both 99mTc-MIBI and 201Tl have been used for tumour imaging. It has recently been reported that 99mTc-MIBI is a substrate for P-glycoprotein (Pgp), a membrane pump which mediates multidrug resistance. We have evaluated the role of Pgp in the cellular accumulation of 201Tl by using sensitive and resistant strains of Chinese hamster ovary (CHO) fibroblasts (AuxB1 and CHRC5, respectively) grown in suspension culture. 201Tl accumulation was the same in sensitive and resistant cells, whereas 99mTc-MIBI accumulation was much lower in resistant cells than in sensitive ones. Down-modulation of Pgp with 100 microM verapamil did not alter cellular accumulation of 201Tl while it significantly increased 99mTc-MIBI accumulation in both types of cell. Similarly, 10 microM verapamil did not affect the rate of washout of 201Tl from preloaded cells, while 99mTc-MIBI washout was greatly reduced in the presence of verapamil. These results suggest that 201Tl will accumulate in both sensitive and resistant tumour cells, whereas 99mTc-MIBI will be extruded from resistant cells and therefore may be less useful for tumour detection when the tumour cells express high Pgp levels.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
31P changes as a measure of therapy response in human osteosarcomas implanted into nude mice.
Our objective was to determine whether changes in PME and PCr/Pi can be used to predict lack of tumor response to chemotherapy in a murine model of human osteosarcoma. A chemotherapy-sensitive human osteosarcoma cell line was implanted into the flank of 22 nude mice. Cisplatin was administered to 11 of the mice 9 days postimplantation. 31P MR spectroscopy was performed pre- and post-chemotherapy in both sets of mice. Statistically significant changes in PCr/Pi occur from post-chemotherapy in the treated mice, but not in the untreated mice during the same time. Change in PME parallels changes in tumor volume. Changes in PCr/Pi predict lack of chemotherapy treatment in human osteosarcoma implanted into nude mice with a specificity of 80% and a sensitivity of 63%. The change in PCr/Pi occurs prior to any changes in volume of the tumor [corrected].
Animals↗