cis-Amminedichloro(2-methylpyridine) platinum(II) (AMD473), a novel sterically hindered platinum complex: in vivo activity, toxicology, and pharmacokinetics in mice

A novel sterically hindered platinum complex, AMD473 [cis-amminedichloro(2-methylpyridine) platinum(II)], designed primarily to be less susceptible to inactivation by thiols, has shown in vitro activity against several ovarian carcinoma cell lines. Notably, AMD473 has shown activity in vitro in human carcinoma cells that have acquired cisplatin resistance due to reduced drug transport (41M/41McisR) or enhanced DNA repair/increased tolerance of platinum-DNA adducts (CH1/CH1cisR). In this study, we show that AMD473, at its maximum tolerated dose of 35-40 mg/kg i.p. administration, produced marked in vivo antitumor activity against a variety of murine (ADJ/PC6 plasmacytoma, L1210 leukemia) and human ovarian carcinoma xenograft models, including several possessing acquired resistance to cisplatin [ADJ/PC6cisR, L1210cisR, CH1cisR, and HX110 (carboplatin-resistant)]. In the ADJ/PC6 model, an increased therapeutic index was noted following oral as opposed to i. p. administration. In a head-to-head comparison using CH1cisR xenografts and equitoxic doses (q7dx4 schedule), comparative growth delays were as follows: AMD473, 34 days; cisplatin, 10.4 days; carboplatin, 6.4 days; and JM216 (p.o. administration), 3.5 days (in a previous experiment, the trans-platinum complex JM335 induced a growth delay of 5.4 days against this model). In this model, oral activity was also noted with a growth delay of 34 days at 400 mg/kg every 7 days (total of four doses). In addition, AMD473 showed promising activity against CH1 xenografts that had regrown following initial treatment with cisplatin (additional growth delay of 30 days over that observed for retreatment with cisplatin). Across the whole panel of cisplatin-sensitive to cisplatin-resistant human ovarian carcinoma xenografts, AMD473 showed improved or at least comparable activity to that observed for an equitoxic dose (4 mg/kg) and schedule of cisplatin. Platinum pharmacokinetics showed that following i.v. administration of 20 mg/kg AMD473 in saline to Balb/c- mice bearing murine plasmacytoma (ADJ/PC6), a biexponential decay was observed in the plasma with a rapid distribution t1/2alpha of 24 min followed by a slow elimination t1/2beta of 44 h. Platinum accumulated in various organs with platinum tissue to plasma area under the curve ratios of 8.6 for liver and kidney, 5.7 for spleen, 3.7 for heart, 5.2 for lung, and 5 for tumor. The plasma and tissue concentration time curve following i.p. administration was similar to that observed following i.v. administration, with a bioavailability of 89%. When AMD473 was given p.o., the platinum absorption was rapid (K01 of 30 min) and the bioavailability was 40%. A less than proportional increase in area under the curve and Cmax was noted in tissue, plasma, and plasma ultrafiltrate following increasing oral doses of AMD473. In vitro, with AMD473, the rate of binding to different plasma proteins was approximately half of that of cisplatin. Following administration of 45 mg/kg i.p. in oil, 33% of the administered platinum was eliminated in the urine after 24 h, and 40% was eliminated after 72 h. Fecal recovery represented 13% of the administered dose after 3 days. Similar results were observed following oral and i.v. administration of 20 mg/kg, but significantly more was excreted in the feces (over 50% of the administered dose) following oral administration of 400 mg/kg, showing that absorption might be a limiting factor by this route of administration. The dose-limiting toxicity for AMD473 in mice was myelosuppression, and no renal toxicity was observed. The promising antitumor activity of AMD473, together with its lack of nephrotoxicity and favorable pharmacokinetic profile, suggests that AMD473 is a good candidate for clinical development. AMD473 is entering Phase I clinical trials under the auspices of the United Kingdom Cancer Research Campaign in 1997.     

Peri-infarct angiographic behavior of "non-culprit" coronary infarct lesions]

Because systemic factors, such as lipoproteins, autoantigens, infectious agents, may facilitate plaque rupture, thrombus formation and coronary occlusion, the question may arise of whether thrombosis be only a local plaque event or the consequence of an acute activity of the entire coronary tree. Taking changes at the narrowest point of non culprit lesions as reflecting progression or regression of the disease when > 0.27 mm, early (within a few days) and late (within 1 month) coronarographic findings in 23 patients with first infarction were compared with those of patients with stable angina, in whom coronary angiography was performed for diagnostic purposes and was repeated 1 month later, before angioplasty. Sixteen infarction patients had progression, 4 had regression, 1 had both, and 2 had steadiness; corresponding values in stable angina group were 2 (p < 0.001), 1 (NS), 0 (NS) and 20 (p < 0.001). In the infarction group, 17 out of the 45 non culprit lesions progressed and 5 regressed; corresponding figures in stable angina group were 2 (p < 0.001) and 1 (p < 0.05). Three of the infarction patients developed interim angina at rest that was associated with progression of a culprit lesion in each of them. These results support the hypothesis that in a number of cases infarction may not reflect an arbitrary plaque event but rather a systemic coronary disease activity with maximal expression at the level of the offending plaque.     

Peripheral pain mechanisms

A promising new treatment for glioma involves Auger electron emitters such as 125I or 123I conjugated to deoxyuridine (IUdR). However, the presence in tumour deposits of non-proliferating cells with clonogenic potential poses a major limitation to this cycle-specific therapy. We have used multicellular tumour spheroids derived from the human glioma cell line UVW to study [125I]IUdR-targeted radiotherapy in aggregates containing cells in different proliferative states. Autoradiographic identification of labelled cells indicated that nuclear incorporation of [125I]IUdR decreased markedly with increasing size of spheroid. IUdR incorporation was maximal in the surface layer of cells and decreased with depth within spheroids. Radiopharmaceutical uptake corresponded closely to the regions of cell cycling as indicated by staining for the nuclear antigen Ki67. The uptake of drug was enhanced by increasing the duration of incubation from 52 h to 104 h. These observations suggest that significant sparing of non-cycling malignant cells would result from treatment delivered as a single injection of radiolabelled IUdR. To achieve maximal therapeutic effect. IUdR should be administered by multiple injections, by slow release from biodegradable implants or by slow-pump delivery.     

In situ optical control and stabilization of the curing process of holographic gratings with a nematic film-polymer-slice sequence structure

We report on the realization of what we believe to be a new holographic setup for the fabrication of polymer liquid-crystal polymer-slice diffraction gratings, which utilizes an optical-feedback-driven nanopositioning technique. We have increased the stability of the interference pattern by means of a simple piezomirror used in a feedback configuration to keep constant the phase of the interferometer. The feedback system is driven by a proportional, integral, derivative control software, and the stability degree is controlled by the reference signal coming from a standard test grating. A preliminary experimental characterization indicates that good control and stabilization of parasitic fluctuations of the interference pattern are obtained.     

Phase-Change Perovskite Microlaser with Tunable Polarization Vortex

Metasurfaces supporting optical bound states in the continuum (BICs) are emerging as simple and compact optical cavities to realize polarization-vortex lasers. The winding of the polarization around the singularity defines topological charges which are generally set by the cavity design and cannot be altered without changing geometrical parameters. Here, a subwavelength-thin phase-change halide perovskite BIC metasurface functioning as a tunable polarization vortex microlaser is demonstrated. Upon the perovskite structural phase transitions, both its refractive index and gain vary substantially, inducing reversible and bistable switching between distinct polarization vortexes underpinned by opposite topological charges. Dynamic tuning and switching of the resulting vector beams may find use in microscopy imaging, particle trapping and manipulation, and optical data storage.     

A Cyclometalated Iridium (III) Complex as a Microtubule Probe for Correlative Super-Resolution Fluorescence and Electron Microscopy

The visualization of microtubules by combining optical and electron microscopy techniques provides valuable information to understand correlated intracellular activities. However, the lack of appropriate probes to bridge both microscopic resolutions restricts the areas and structures that can be comprehended within such highly assembled structures. Here, a versatile cyclometalated iridium (III) complex is designed that achieves synchronous fluorescence–electron microscopy correlation. The selective insertion of the probe into a microtubule triggers remarkable fluorescence enhancement and promising electron contrast. The long-life, highly photostable probe allows live-cell super-resolution imaging of tubulin localization and motion with a resolution of ≈30 nm. Furthermore, correlative light–electron microscopy and energy-filtered transmission electron microscopy reveal the well-associated optical and electron signal at a high specificity, with an interspace of ≈41 Å of microtubule monomer in cells.     

Potentiation of tumour necrosis factor-mediated cell killing by VP16 on human ovarian cancer cell lines. In vitro results and clinical implications

Synergism between recombinant human tumour necrosis factor (rHuTNF) and DNA topoisomerase II inhibitor VP16 during the killing of cells has been studied in six human ovarian cancer cell lines (A2774, A2780, SW626, IGROV-1, SKOV3, Pa1) and a cervical carcinoma cell line (Me180). Studies were performed using an assay of colony formation inhibition (drug treatment for 1 h) and a growth inhibition assay (continuous exposure for 20 h). Concomitant treatment of cells with VP16+rHuTNF enhanced cell killing in all the cell lines tested--an effect observed in both short- and long-term cytotoxicity assays. This study suggests that the activity of VP16 in ovarian cancer cell lines might be enhanced by rHuTNF in in vitro models.     

Auto-Calibrated Gaze Estimation Using Human Gaze Patterns

We present a novel method to auto-calibrate gaze estimators based on gaze patterns obtained from other viewers. Our method is based on the observation that the gaze patterns of humans are indicative of where a new viewer will look at. When a new viewer is looking at a stimulus, we first estimate a topology of gaze points (initial gaze points). Next, these points are transformed so that they match the gaze patterns of other humans to find the correct gaze points. In a flexible uncalibrated setup with a web camera and no chin rest, the proposed method is tested on ten subjects and ten images. The method estimates the gaze points after looking at a stimulus for a few seconds with an average error below \(4.5^{\circ }\). Although the reported performance is lower than what could be achieved with dedicated hardware or calibrated setup, the proposed method still provides sufficient accuracy to trace the viewer attention. This is promising considering the fact that auto-calibration is done in a flexible setup , without the use of a chin rest, and based only on a few seconds of gaze initialization data. To the best of our knowledge, this is the first work to use human gaze patterns in order to auto-calibrate gaze estimators.     

Lipid composition of meat and backfat from Casertana purebred and crossbred pigs reared outdoors

The study aimed to evaluate, with regard to the human nutrition, the lipid profile of meat and backfat from gilts and barrows of the Italian autochthonous genotype Casertana and its crossbreed (Casertana×Large White) slaughtered at two different live weights. Meat from the Casertana cross was nutritionally comparable to that from the purebreed and both would be considered healthy, irrespective of sex and weight, due to the relatively low levels of intramuscular lipids and cholesterol. Muscle cholesterol was considerably lower in the heavy pigs than in the light ones and, as weight increased, cholesterol decreased but only in gilts. Females supply meat with higher polyunsaturated fatty acids (PUFA) and slightly lower saturated fatty acids (SFA) respect to barrows and, thus, higher PUFA/SFA ratio. Casertana crossbreds can represent a good alternative to pure Casertana, mainly in the production of Colonnata lard, due to the better fatty acid profile of the subcutaneous adipose tissue. From the nutritional point of view, the optimal slaughtering weight was about 150kg for both genotypes. Heavy pigs, compared to the light ones, produced loin with lower atherogenic and thrombogenic indexes, lower SFA/unsaturated fatty acids ratio, and higher PUFA/SFA ratio.