Radiolabeled nucleoside analogs in cancer diagnosis and therapy

Radiolabeled nucleosides, specifically 5-iodo-2'-deoxyuridine (IUdR) radioiodinated with the Auger-electronemitting 123I or 125I, have been shown to produce extensive DNA damage in mammalian cell systems in vitro. Such nucleosides are cycle-dependent agents that are taken up by mitotically dividing cells in the S phase of the cell cycle. The degree of damage that occurs is related to the fact that these nucleosides bind covalently to DNA bringing the decaying Augerelectron-emitting radionuclide in close proximity to the genome. The use of these radiohalogenated nucleosides in vivo is associated with several problems. The first relates to their extremely short biologic half-life in blood (T1/2 of minutes in humans). The second involves achieving therapeutic ratios in tumor cells in the face of efficient hepatic dehalogenation. The third concerns the uptake of these radiopharmaceuticals by actively proliferating normal cell renewal systems, thus potentially causing toxic side effects. The fourth, one shared with other cycle-dependent drugs, relates to the matter of labeling the whole tumor cell population. To facilitate targeting to tumors, investigators have been examining the direct introduction of these agents into the targeted area or into an arterial blood supply that immediately precedes the target. For example, radiopharmaceutical administration could be intracavitary (bladder, spinal fluid, peritoneum), intralesional (brain tumor, breast mass) or intra-arterial (liver, pancreas). In all these situations, the following conditions must be met: (a) once within the vicinity of the tumor the agent can freely diffuse through the tissues and is selectively taken up by cancerous cells; (b) once the agent has left the target area it is converted quickly into a nontoxic form and/or excreted from the body; and finally, (c) the biologic behavior of the agent is not altered by repeated injections. We report herein our experience and that of others with [123I/125I/131I]IUdR in cultured cells, animal tumor-model systems, and patients. In vitro, DNA incorporation of 123I- and 125I-labeled IUdR leads to an exponential decrease in cell survival (no shoulder on the survival curve). However, the total number of decays needed to produce a given lethal effect with [123I]IUdR is approximately twice that required with [125I]IUdR. In vivo, the scintigraphic and antineoplastic capabilities of radioiodinated IUdR have been demonstrated in an intraperitoneal murine ovarian tumor model following intraperitoneal injection; in an intracerebral rat gliosarcoma model after intracranial administration; in an intrathecal rat gliosarcoma model after intrathecal infusion; and in a rat transitional cell bladder cancer model following intravesicular infusion. [123I]IUdR, [125I]IUdR, and/or [131I]IUdR have been administered to patients with brain, breast, colorectal, or gastrointestinal cancers (intratumorally); ovarian cancer (intraperitoneally); bladder cancer (intravesically); liver metastases from colorectal cancer (through the hepatic artery, permanent intra-arterial catheter). These studies have confirmed the observations made in animal models. The data indicate that 5-iodo-2'-deoxyuridine radiolabeled with an Auger electron emitter (123I or 125I) may be a useful agent for the scintigraphic diagnosis and/or therapy of neoplastic diseases that are accessible to direct radiopharmaceutical administration. This radiopharmaceutical should serve as a prototype for, and facilitate the development of, other radiolabeled nucleoside analogs. Further investigations are certainly warranted.     

Analysis of illumination-intensity-dependent j–V characteristics of ZnO/CdS/CuGaSe2 single crystal solar cells

Current–voltage characteristics of ZnO/CdS/CuGaSe₂ single crystal solar cells measured at room temperature are investigated depending on illumination intensity. The characteristics can be described using the two-diode model, indicating two current transport mechanisms acting in the cells. The first and dominant mechanism is recombination of carriers at the interface between CdS and CuGaSe₂. The second one is recombination in the depletion region, which has been found to have a small effect on the solar cell photovoltaic performance. Both the diode ideality factor and the saturation current density of the dominant diode increase under illumination. A model based on interface recombination can explain these results. This model allows the estimation of diffusion voltage, capture cross-section of holes at the interface and mobility of electrons in the CdS layer.     

Direction of Arrival Estimation using EM-ESPRIT with Nonuniform Arrays

This paper deals with the problem of the Direction Of Arrival (DOA) estimation with nonuniform linear arrays. The proposed method is based on the Expectation Maximization method where ESPRIT is used in the maximization step. The key idea is to iteratively interpolate the data to a virtual uniform linear array in order to apply ESPRIT to estimate the DOA. The iterative approach allows one to improve the interpolation using the previously estimated DOA. One of this method’s novelties lies in its capacity of dealing with any nonuniform array geometry. This technique manifests significant performance and computational advantages over previous algorithms such as Spectral MUSIC, EM-IQML and the method based on manifold separation technique. EM-ESPRIT is shown to be more robust to additive noise. Furthermore, EM-ESPRIT fully exploits the advantages of using a nonuniform array over a uniform array: simulations show that for the same aperture and with a smaller number of sensors, the nonuniform array presents almost identical performance as the equivalent uniform array.     

Fill factor losses in ZnO/CdS/CuGaSe2 single-crystal solar cells

Current–voltage characteristics of ZnO/CdS/CuGaSe₂ single-crystal solar cells with solar conversion efficiency values of η=3.5%, 6.0%, 6.7% and 9.7% were analyzed using the single diode equation. The effect of each of the achieved parameters on the fill factor was calculated. The calculations revealed that the fill factor reduction due to the series resistance remained below Δff=4.4% under illumination, while this effect would have been much higher if the illumination had not reduced the series resistance markedly. The calculation furthermore revealed that the fill factor reduction due to the shunt resistance remained below Δff=3.6% under illumination. This effect would have been negligible if the illumination had not also reduced the shunt resistance in all studied cells. The increase of the saturation current density under illumination has brought about considerably high fill factor losses (at least Δff=8.3%) in all studied cells. Already the dark saturation current density and the diode ideality factor in such cells have been found to be much higher than the ones in the cells based on CuInSe₂. This seems to be the most substantial restriction to the fill factor, and thus to the performance, of solar cells based on CuGaSe₂. An explanation for this different behavior seems to lie in the different band structures of these cells.     

5-[125I]iodo-2'-deoxyuridine in the radiotherapy of brain tumors in rats

Glial neoplasms of the human central nervous system have defied treatment, in part because of the limited selectivity of available cytotoxic agents. The thymidine analog 5-iodo-2'-deoxyuridine radiolabeled with the Auger electron emitter 125I (125IUdR) is highly toxic to dividing cells when it is deoxyribonucleic acid incorporated, but it is relatively innocuous when located outside the nucleus. Previous studies have shown that 125IUdR has significant antineoplastic potential against mammalian cells in vitro and direct administration of 125IUdR is effective therapy for ovarian ascites tumors in mice and neoplastic meningitis in rats. Studies using external gamma imaging and autoradiography have also shown that direct intratumoral administration of 123IUdR/125IUdR into intracerebral 9L gliosarcomas in rats results in selective uptake of the radionuclide into tumor cells. Based on these encouraging results, we have evaluated the therapeutic potential of 125IUdR in rats bearing intracerebral 9L gliosarcomas. METHODS: Iodine-125-IUdR was infused intracerebrally over a 2-day period into rats bearing 1-day-old 9L tumors and over a 6-day period into animals with 9-day-old 9L tumors; equimolar concentrations of 127IUdR were infused into control animals. Tumor growth was monitored by contrast-enhanced 1H MRI and animal survival was followed over time. RESULTS: Intracerebral tumors (3-7 mm) were readily detected by MRI. Tumor-bearing rats treated with 127IUdR succumbed within 17-24 days, whereas tumor-bearing animals treated with 125IUdR survived significantly longer, and 10%-20% of the animals were cured of tumors. CONCLUSION: These data substantiate the antineoplastic potential of 5-[125I]iodo-2'-deoxyuridine and indicate that it may be a useful agent for the therapy of solid tumors that are accessible to direct radiopharmaceutical administration.     

Effect of interface recombination on solar cell parameters

A model is presented for p–n hetero-junction solar cells in which interface recombination is the dominant diode current transport mechanism. The model explains the large diode ideality factor (n>2) and the increased saturation current density in terms of increased density of interface states N_ir. Furthermore, the model allows us to explain the non-translation between illuminated and dark J–V characteristics. The explanation is based on the assumption that, for high interface state density values, both the depletion layer width and the diffusion voltage in the p- and n-side of the junction are functions of N_ir. The interface recombination leads to lower values of the open-circuit voltage, short-circuit current density, and fill factor. These results are illustrated by numerical calculations of solar cell parameters and compared with experimental data achieved for ZnO/CdS/CuGaSe₂ single-crystal solar cells.     

Molecular and cellular radiobiological effects of Auger emitting radionuclides

Although the general radiobiologic principles underlying external beam therapy and radionuclide therapy are similar, significant differences in the biophysical and radiobiologic effects from the two types of radiation continue to accumulate. Here, I will address the unique features that distinguish the molecular and cellular radiobiological effects of Auger electron-emitting radionuclides consequent to (1) the physical characteristics of the decaying atom and its subcellular localisation, (2) DNA topology and (3) the bystander effect. Based on these experimental findings, I postulate that the ability of track structural simulations as primary tools in modelling DNA damage and cellular survival at the molecular level would be greatly enhanced when these contributions are factored in.     

Nerve growth factor (NGF)-mediated protection of neural crest cells from antimitotic agent-induced apoptosis: the role of the low-affinity NGF receptor

Prevention by nerve growth factor (NGF) of apoptotic death in neural cells has been variously ascribed to binding of NGF to its low-affinity (p75) or high-affinity (trkA) receptor or to a cooperative interaction between the two. In a series of studies using, in turn, neuroblastoma cell lines that express only p75, mutant NGF species that bind selectively to either p75 or trkA, and a polyclonal antibody that binds to the NGF-binding domain of p75, we demonstrate that NGF binding to p75 is both necessary and sufficient for the abrogation of apoptosis in neuroblastoma cells treated with antimitotic agents.     

Novel fluorescein-based flow-cytometric method for detection of lipid peroxidation

The novel property of fluorescein to detect peroxyl radicals is demonstrated. On the basis of this observation, a fluorescein-based, flow-cytometric method to directly and continuously detect free radicals generated in cell membranes during lipid peroxidation has been developed. 5- and 6-Carboxyfluorescein (5-/6-CF) free in solution and fluorescein-labeled polylysine lose their fluorescence gradually upon addition of a peroxyl-radical-generating system (thermal decomposition of 2,2'-azobis(2-amidinopropane) [AAPH]). 5-/6-CF retains its fluorescence when exposed to AAPH in the presence of the peroxyl radical scavenger Trolox. When 5-/6-CF free in solution is incubated with red blood cells exposed to cumene hydroperoxide (CH), a similar loss of fluorescence occurs due to lipid peroxidation on RBC membranes, which is preventable by pretreatment of the cells with Trolox or vitamin E. Undecylamine-fluorescein (C11-fluor), a lipophilic fluorescein conjugate, has been incorporated into the membranes of RBC. Upon addition of CH, a decrease in fluorescence is fluorometrically observed that is proportional to the amount of hydroperoxide added and inhibited by preincubation with Trolox or vitamin E. Flow-cytometric studies are then performed to demonstrate that C11-fluor can monitor free radicals generated during lipid peroxidation on a cell-by-cell basis. When exposed to CH, a time-dependent shift of the flow-cytometric profile toward lower values is observed that is inhibited by Trolox or vitamin E. This approach in conjunction with multiparametric flow cytometry may allow examination of the biologic significance of lipid peroxidation by correlation to other cellular end points on single cells.