Nanofocused synchrotron X-ray absorption studies of the intracellular redox state of an organometallic complex in cancer cells.

Synchrotron nanoprobe X-ray absorption (XAS) studies of a potent organo-osmium arene anticancer complex in ovarian cancer cells at subcellular resolution allow detection and quantification of both OsII and OsIII species, which are distributed heterogeneously in different areas of the cells.

Specimen preparation for "block face" scanning electron microscopy (BFSEM). An energy-dispersive X-ray spectroscopy study

In this paper we describe a SEM block-face technique in which block faces of large dimensions can be examined in a high-resolution SEM under high vacuum. The results of different tissue contrast methods have been studied and, in addition to osmium, potassium permanganate has been used as a staining medium for the first time in BFSEM. The study also examined the effects of uranyl acetate and phosphotungstic acid. The following organs of adult albino rats were examined: colonic mucosa, spinal ganglion, anterior pituitary gland and exocrine pancreas.Six preparation protocols, referred to here as treatments, were applied and evaluated according to three criteria: 1st the visual quality of the digital images, 2nd the measurements of the signal-noise ratio (SNR) of the digital images with and without beam deceleration (BD), and 3rd the X-ray microanalysis of samples, treated according to the 6 proposed protocols, demonstrating the presence and relative quantity of the elements used to stain the cellular structures, enabling visualisation with the electron microscope. In conclusion, it can be said that treatments with osmium produced better results than those containing potassium permanganate. Treatments with the addition of thiocarbohydrazide (TCH) considerably increased the osmium deposits (ligand effect) and proved highly effective. Finally, it should be noted that the method proposed, called here 2D BFSEM, can be very useful not only in histology but also in histo-pathology, for example in the study of biopsies and - last but not least - in embryology: all these are situations in which it is important to avoid a loss of material due to preparation exigencies

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Mirror-image organometallic osmium arene iminopyridine halido complexes exhibit similar potent anticancer activity.

Four chiral Os(II) arene anticancer complexes have been isolated by fractional crystallization. The two iodido complexes, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 2, (S)-ImpyMe: N-(2-pyridylmethylene)-(S)-1-phenylethylamine) and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 4, (R)-ImpyMe: N-(2-pyridylmethylene)-(R)-1-phenylethylamine), showed higher anticancer activity (lower IC50 values) towards A2780 human ovarian cancer cells than cisplatin and were more active than the two chlorido derivatives, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 1, and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 3. The two iodido complexes were evaluated in the National Cancer Institute 60-cell-line screen, by using the COMPARE algorithm. This showed that the two potent iodido complexes, 2 (NSC: D-758116/1) and 4 (NSC: D-758118/1), share surprisingly similar cancer cell selectivity patterns with the anti-microtubule drug, vinblastine sulfate. However, no direct effect on tubulin polymerization was found for 2 and 4, an observation that appears to indicate a novel mechanism of action. In addition, complexes 2 and 4 demonstrated potential as transfer-hydrogenation catalysts for imine reduction.

In vivo tumour and metastasis reduction and in vitro effects on invasion assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model.

We have compared the organometallic arene complexes [(eta(6)-biphenyl)M(ethylenediamine)Cl](+) RM175 (M=Ru(II)) and its isostructural osmium(II) analogue AFAP51 (M=Os(II)) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6x more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231 cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo.

Low-energy electron emitters for targeted radiotherapy of small tumours.

The possibility of using electron emitters to cure a cancer with metastatic spread depends on the energy of the emitted electrons. Electrons with high energy will give a high, absorbed dose to large tumours, but the absorbed dose to small tumours or single tumour cells will be low, because the range of the electrons is too long. The fraction of energy absorbed within the tumour decreases with increasing electron energy and decreasing tumour size. For tumours smaller than 1 g, the tumour-to-normal-tissue mean absorbed dose-rate ratio, TND, will be low, e.g. for 131I and 90Y, because of the high energy of the emitted electrons. For radiotherapy of small tumours, radionuclides emitting charged particles with short ranges (a few microm) are required. A mathematical model was constructed to evaluate the relation between TND and electron energy, photon-to-electron energy ratio, p/e, and tumour size. Criteria for the selection of suitable radionuclides for the treatment of small tumours were defined based on the results of the TND model. In addition, the possibility of producing such radionuclides and their physical and chemical properties were evaluated. Based on the mathematical model, the energy of the emitted electrons should be < or = 40 keV for small tumours (< 1000 cells), and the photon-to-electron energy ratio, p/e, should be < or = 2 to achieve a high TND. Using the selection criteria defined, five low-energy electron emitters were found to be suitable: 58Co, 103mRh, 119Sb, 161Ho, and 189mOs. All of these nuclides decay by internal transition or electron capture, which yields conversion and Auger electrons, and it should be possible to produce most of them in therapeutic amounts. The five low-energy electron-emitting radionuclides identified may be relevant in the radiation treatment of small tumours, especially if bound to internalizing radiopharmaceuticals.

Pharmacomodulations on new organometallic complexes of Ir, Pt, Rh, Pd, Os: in vitro and in vivo trypanocidal study against Trypanosoma brucei brucei.

New organometallic complexes have been synthesized by association of an active organic molecule with a metallic element such as Pt, Rh, Ir, Pd, Os. Their trypanocidal activity was studied in vitro and in vivo against T. b. brucei. The more active compounds were pentamidine derivatives. The Ir- COD-pentamidine complex, and Iridium (I) cationic and organometallic complex showed and in vitro activity at 60 micrograms/l. Moreover, all infected mice were cured by this compound subcutaneously administered in a single dose at 0.5 mg/kg (0.317 mumol/kg). In the same conditions, pentamidine cured all the mice at 5 mumol/kg. Ir-COD-pentamidine (or P1995) was 16 fold more efficient than pentamidine. Since the chemotherapeutic index of this molecule was 7.5 fold higher than those of pentamidine, P1995 can be considered as a potential trypanocidal drug of the future.

Knee arthroscopy after yttrium or osmic acid injection.

This study presents the macroscopic and histologic results of 35 knee arthroscopies performed on patients with rheumatoid arthritis, some months after an yttrium or osmic acid intraarticular injection. The procedure was most often performed after a failure of the injection or a relapse of synovitis. Arthroscopy provides an understanding of the cause of synoviorthesis failure--insufficient action of the product on the synovitis or its poor diffusion, fibri-nonecrotic deposits, or cartilaginous lesions--and may be used both diagnostically and therapeutically.

[Results more than five years after osmic acid synoviorthesis of the rheumatoid knee]. / Résultats à plus de cinq ans des synoviorthèses a l'acide osmique du genou rhumatoïde.

Osmic acid synoviorthesis is an adjuvant form of local treatment for rheumatoid arthritis, the value of which has been demonstrated by a large number of studies over some 30 years. However, it is widely considered that the stability of the results of this type of synoviorthesis is less satisfactory than that obtained with isotope synoviorthesis and that osmic acid may damage the articular cartilage. The authors analyzed the results of a retrospective study of 90 rheumatoid knees treated by this method with a follow-up of more than 5 years (mean period 9 years). With such a follow-up, a satisfactory clinical result was seen in 44.5 p. cent of cases and radiological evaluation of the knees treated showed no worsening in initial signs in an identical percentage of cases. Best results were obtained in joints where there was little radiological damage and in cases of inflammatory or only moderately progressive arthritis, good results may also be hoped for in more severe or advanced cases. The good overall quality of the results obtained with a mean follow-up of 9 years would be in favour of the value of osmic acid synoviorthesis in the local treatment of rheumatoid arthritis.

Osmium tetroxide in antigen-induced arthritis: failure to inhibit joint destruction.

Antigen induced arthritis (AIA) was elicited in 28 adult rabbits using ovalbumin. All animals developed an intensive monarthritis manifested by local heat and swelling. Two, 7 and 21 days later, respectively, 0.3 ml of 1 per cent OsO4 was injected into the arthritic knees of three groups of 9 rabbits. The rabbits were killed 1, 3 and 6 months later. No modifying influence on the severe to complete cartilage destruction was evident. One group of 8 rabbits received only OsO4 and the cartilage of these animals remained intact after 6 months.

Synovial fluid hydroxyproline fractions before and after osmic acid treatment in rheumatoid arthritis.

Synovial fluid total, dialysable and non-dialysable hydroxyproline were determined in patients with Rheumatoid Arthritis before intra-articular osmic acid injection and on days 2 and 4 after this local treatment. On day 2 the increase in dialysable hydroxyproline paralleled the increase in non-dialysable hydroxyproline. Patients with the highest pre-treatment dialysable hydroxyproline levels also had the highest levels of this fraction on day 2 suggesting that articular damage proceeds after osmic acid injection. However, on day 4 dialysable hydroxyproline levels were consistently lower than before the treatment; the same pattern was observed with non-dialysable hydroxyproline, except for all the joints but one, where effusion recurred 6-12 months after osmic acid treatment. This study suggests that the determination of synovial fluid non-dialysable levels 4 days after osmic acid injection may provide a clue to the prediction of recurrent joint effusion and possibly justify a complementary injection either with osmic acid or with a beta-emitting isotope.

Osmic acid versus yttrium-90 in rheumatoid synovitis of the knee.

The effectiveness of osmic acid and yttrium-90 in the treatment of synovitis of the knee in rheumatoid arthritis is compared in 126 patients followed-up for 3 years. Ninety-one knees were injected with osmic acid and eighty-four knees with yttrium-90. Osmic acid appeared to be more effective than yttrium-90 throughout the period of the follow-up but the difference only reached statistical significance (p less than 0.05) at 3 years. Both therapies were well tolerated by patients and should be considered as an alternative to operative synovectomy.

Intra-articular osmic acid in rheumatoid arthritis: five years' experience.

Two hundred and one patients (305 knees) with rheumatoid arthritis received intra-articular osmic acid in one or both knees. Assessment was based on pain relief, warmth, tenderness, size and presence of effusion, degree of synovial thickening and range of pain-free movement. Satisfactory results were obtained in 61% at one year gradually reducing to 22% over a five-year period. If only those knees with none or minimal joint damage were considered, then a satisfactory result was obtained in a higher percentage, 74% at one year and 38% at five years.

[Radiological opacities after intra-articular injection of osmic acid. Relationship with the injection site (author's transl)]. / Opacités radiologiques après synoviorthèse du genou à l'acide osmique. Relation avec le site d'injection.

Abnormal radiological opacities are sometimes observed after intra-articular injection of osmic acid. These opacities are radio-opaque because osmium is a heavy metal (atomic number = 76). They are usually found near the suprapatellar pouch which is the usual injection site. A parasynovial injection (or back flow from the joint cavity) of some of the osmic solution, followed by concentration and fixation of the osmic deposits at this level, seems to be the cause of these radiological opacities. This could be the reason for the poor clinical results encountered in some cases of osmic acid therapy followed by such deposits.

[Arthroscopic study after failure of synoviorthesis (author's transl)]. / Etude arthroscopique après échec de synoviorthèses.

Arthroscopy of the knee, including synovial biopsy under direct vision, was performed in 22 patients (21 cases of arthritis, 1 of osteoarthrosis), treated 15 days to 12 months previously by osmic or isotopic synoviorthesis. The aspects seen after the 16 failures were compared with those seen after good results (4 cases) and after recurrences (2 cases). In arthritis, failure was due either to persistent synovitis, to synovial necrosis or to a combination of the two. Arthroscopy is useful since the discovery of inflammatory lessions justifies repeat synoviorthesis, whilst necrosis indicates the need for articular lavage.