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Biomedical subjects

R Gorodetsky

Publications and source records attributed to R Gorodetsky.

At least 19 recordsLinked to original sources
PubMed1999

Late effects of dose fractionation on the mechanical properties of breast skin following post-lumpectomy radiotherapy.

PURPOSE: Late radiation-induced skin effects were studied in a multicenter project using our new sensitive noninvasive viscoelasticity skin analyzer (VESA). METHODS AND MATERIALS: Skin viscoelasticity and anisotropy were examined quantitatively in symmetric areas of both breasts in healthy women and in 110 breast cancer patients who underwent lumpectomy and radiotherapy. These parameters were evaluated by the VESA measurement of the speed of elastic wave propagation in the skin; higher VESA readings correspond to higher skin stiffness. Effect of radiation was estimated by comparison of the data recorded in the irradiated versus nonirradiated breast of the same patient. RESULTS: Skin viscoelasticity and anisotropy were similar in contralateral areas of the breasts in healthy controls as well as in the nonirradiated breasts of the patients. With age, skin viscoelasticity decreased and anisotropy increased similarly in both breasts. Radiotherapy, by a total radiation dose in the range of 45-50 Gy given with 1.8 Gy/fraction (fx) resulted in a similar minor, but still statistically significant, increase of skin stiffness relative to control. The effect was more pronounced when a dose of 50 Gy was given in a higher dose/fraction of 2.5 Gy. CONCLUSION: We found that the increase in dose of radiation per fraction had much more impact on the development of late skin effects than elevation in the total dose given.

Adult↗
PubMed1999

Fibrin microbeads (FMB) as biodegradable carriers for culturing cells and for accelerating wound healing.

We have developed biodegradable fibrin-derived microbeads as potent cell carriers. The fibrin-derived microbeads, 50-200 microm in diameter, were tested for their attachment to a wide range of cell types. Fibrin-derived microbeads were shown to be greatly haptotactic to cells (such as endothelial cells, smooth muscle cells and fibroblasts), which respond to fibrinogen in contrast to keratinocytes and different cell lines derived from leukocytic lineage. The cells on fibrin-derived microbeads could be maintained for more than 10 d and achieved a high density. 31P-nuclear magnetic resonance was employed to monitor phosphate metabolism in cells, with densities on the order of 100 million cells per g of fibrin-derived microbeads. The 31P-nuclear magnetic resonance adenosine triphosphate and phosphocreatine signals, equivalent to the signal obtained with perfused normal skin, indicated that metabolism of cells on fibrin-derived microbeads was responsive to oxygenation and nutrients. Light, fluorescent, and confocal laser microscopy revealed that the porous fibrin-derived microbeads accommodate up to 200-300 cells due to their high surface area which minimized contact inhibition. Cells could degrade the fibrin-derived microbeads and be transferred to seed culture flasks without trypsinization. In a pig skin wound healing model, fibrin-derived microbeads + fibroblasts were transplanted into full thickness punch wounds. This procedure was compared with other treatment modalities, such as the addition of human platelet-derived growth factor BB or fibrin-derived microbeads alone. By the third day after wounding, only the wounds in which fibroblasts on fibrin-derived microbeads were added showed significant formation of granulation tissue. Based on the above, we project many uses of our novel fibrin-derived microbead technology for cell culturing, wound healing and tissue engineering.

Animals↗
PubMed1999

Evaluation of skin viscoelasticity and anisotropy by measurement of speed of shear wave propagation with viscoelasticity skin analyzer.

Skin viscoelasticity was evaluated by a fast, noninvasive assay based on the measurement of the speed of elastic shear wave propagation in the skin by a new portable and user-friendly viscoelasticity skin analyzer. The range of speed of elastic shear wave propagation measured by viscoelasticity skin analyzer allows the evaluation of the stiffness of a wide spectrum of artificial materials as well as the viscoelasticity of skin of laboratory animals and human subjects. The directional nature of the measurement enables to monitor the anisotropy of the materials tested. The speed of elastic shear wave propagation was shown to have a positive correlation with the stiffness of the material tested. In symmetric contralateral areas of intact skin in rabbit ears, similar viscoelasticity and anisotropy were observed. Twenty-four hours after the induction of local edema by croton oil, skin stiffness and anisotropy were significantly increased. In healthy human subjects of both sexes significant variations in skin stiffness and anisotropy were observed in three different skin areas along the forearms, but the speed of elastic shear wave propagation was similar in the symmetric contralateral areas. Age (17-65 y) seemed to have a limited effect on the viscoelasticity of the forearm skin. Hydrating creams decreased the stiffness of the forearm skin for only approximately 3 h. The stiffness and anisotropy of the skin of the breasts in female volunteers (20-86 y) increased with age, but the speed of elastic shear wave propagation was similar in symmetric contralateral areas in the same individuals. Based on these results, we propose the application of the viscoelasticity skin analyzer in experimental and clinical practice for quantitative evaluation of skin condition.

Administration, Topical↗
PubMed1999

Measurement of breast skin viscoelasticity and a pilot study on the potential radioprotective effect of a zinc-based cream.

Radiation-induced late skin effects were studied in patients with breast cancer in relation to different protocols of fractionated radiotherapy in three different medical centres, in Israel, the UK and the USA. The mechanical properties of skin were evaluated in breasts of healthy volunteers, and non-irradiated and irradiated breasts of patients, using a newly developed viscoelasticity skin analyser (VESA). The increase of the dose of radiation per fraction was found to have more impact on the development of radiation-induced late skin effects than the elevation of the total dose given. In addition, a pilot study on the possible radioprotective effect of external application of a cream containing zinc oxide on radiation-induced early skin changes in patients with breast cancer was initiated. Non-invasive measurement of trace elements and zinc pharmacokinetics in the skin of healthy controls following the application of the zinc oxide cream were performed by unique diagnostic X-ray spectrometry (DXS). Application of the cream, followed by thorough skin cleansing, significantly increased the amount of residual zinc in the skin, but continuous daily treatment did not cause further build-up of the dermal zinc level. The radioprotective effect of the zinc oxide cream on the skin is now being studied.

Administration, Cutaneous↗
PubMed1998

Combination of cisplatin and radiation in cell culture: effect of duration of exposure to drug and timing of irradiation.

Responses to the combination of cisplatin (CDDP) and radiation in experimental and clinical studies have been reported to vary from high radiosensitization to clear sub-additivity. We examined the combined effect of CDDP with ionizing radiation in both murine mammary adenocarcinoma (EMT-6) and human ovarian carcinoma (OV-1063) cells with special reference to the duration of CDDP exposure and timing of irradiation. Cell survival was measured with a colorimetric assay of cell density. The nature of interaction of cisplatin and radiation was evaluated using isobolograms and a combination index (CI). Exposure of both cell lines to CDDP for 24 hr before irradiation yielded an additive or slightly sub-additive response only if the exposure was extended for a few more hours after irradiation. In EMT-6 cells, the combination of radiation with subsequent continuous as well as short-term (4 to 6 hr) CDDP treatment was found to have a clear sub-additive effect; dose escalation of each modality reduced the additional effect of the other. The sub-additive effect may be explained by a radiation-induced arrest of cells in late S phase, which was dose- and time-dependent. Post-radiation exposure to CDDP further increased the S-phase arrest. In contrast, a 2 hr post-radiation drug exposure resulted in a supra-additive combined effect. Our results stress the crucial role of the timing and the doses of both modalities as well as the duration of post-radiation drug exposure on their combined effect.

Adenocarcinoma↗
PubMed1998

Haptotactic and growth stimulatory effects of fibrin(ogen) and thrombin on cultured fibroblasts.

We tested the ability of purified, ultraviolet C virally inactivated components of human fibrin sealant (FS) to modulate the chemotaxis, adherence, and proliferation of cultured cells. A fibrin clot formed on a near-confluent layer of human fibroblasts (HFs) recruited cells from the surrounding area. Thrombin (Thr) enhanced HF proliferation by a factor of 1.5 to 1.8, whereas fibrinogen (Fib) exerted only a minimal proliferative effect. We developed a new cell haptotactic/attachment assay by using Thr and Fib covalently bound to Sepharose beads (SBs). The kinetics of cell binding were approximately equivalent for beads coated with either protein. Uncoated SBs or fibrinogen-bound SBs (Fib-SB) pretreated with plasmin did not attract HFs. AlphaThr-SB induced a positive migratory response that was not affected by blocking its proteolytic site, whereas gammaThr-SB elicited no response. X irradiation of HFs at a dose of 6 Gy showed that the migratory response of HF is independent of proliferation, as confirmed by a bromodeoxyuridine uptake assay. Several types of cultured cells (murine fibroblasts, smooth muscle cells, aortic endothelial cells, and murine mammary carcinoma cells) also attached to Fib-SB. By contrast, human keratinocytes, human ovarian carcinoma cells, murine macrophage-like cells, leukemic cells, and murine mast cells did not attach. Our results provide some mechanistic insights into the haptotactic and proliferative effects of Fib and Thr on different cells.

Animals↗
PubMed1998

Chronic graft-versus-host disease treated with UVB phototherapy.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Immunosuppressive treatment regimens carry the potential of causing severe morbidity and mortality, so that additional modes of therapy with fewer side-effects are clearly needed. Five cGVHD patients (sclerodermoid cGVHD in two patients, lichenoid cGVHD in one patient and intraoral cGVHD in two patients), who had not responded to standard immunosuppressive drugs, were treated with adjuvant UVB phototherapy. The patient with lichenoid cGVHD experienced complete clearing of cutaneous lesions, whereas both patients with sclerodermoid cGVHD experienced significant relief of pruritus, but showed no change of the sclerodermoid skin lesions. Intraoral lesions cleared in one patient. The effects of UVB phototherapy were furthermore documented by measurement of skin viscoelasticity and mouth opening. No side-effects were encountered. This preliminary study suggests that UVB phototherapy is useful as an adjuvant therapeutic modality in intraoral and cutaneous lichenoid cGVHD.

Adolescent↗
PubMed1998

Paclitaxel-induced modification of the effects of radiation and alterations in the cell cycle in normal and tumor mammalian cells.

The cytotoxicity of paclitaxel (taxol) is associated mainly with block in G2/M phase, the most radiosensitive phase of the cell cycle. Nevertheless, taxol-induced modification of the effects of radiation may vary from clear sensitization to subadditivity. Therefore, this effect was studied in relation to drug-induced alterations in the distribution of cells in the phases of the cell cycle in tumor cells (EMT-6 and OV-1063) and normal skin fibroblasts. Cell survival was evaluated with two colorimetric assays. The cell cycle was evaluated by FACS analysis of doubly-labeled cells. The radiosensitivity of the different cells studied was similar, apart from the less radiosensitive human fibroblasts. However, their dose- and time-dependent sensitivity to taxol varied significantly. After 24 h exposure of EMT-6 cells to taxol (IC50 approximately 20 nM), the fraction of cells in G2/M phase increased, the fraction in S phase decreased, and the proportion of possibly apoptotic cells with subdiploid and subtetraploid DNA content increased; this coincided with radiosensitization. In OV-1063 cells (IC50 approximately 3 nM), the drug-induced G2/M-phase block was most pronounced, but the combined effect with radiation was merely additive. In human fibroblasts (IC50 approximately 35 nM), a minimal G2/M-phase block with no change in the S phase and a massive elevation of apoptotic cells with subdiploid DNA content was accompanied by a subadditive combined effect with radiation. Six hours of exposure to taxol increased the fraction of cells in S phase in both nonsynchronized and S-phase-synchronized human fibroblasts (G1 phase approximately 65%, S phase approximately 13%). This was accompanied by a pronounced subadditive effect of the combined treatment. However, in G1-phase synchronized human fibroblasts (G1 phase > or =90%, S phase approximately 3%), only the fraction of cells in G2/M phase was slightly elevated, with a merely additive response to the combined treatment. The differences in the response to the combined treatment between slowly and rapidly proliferating cells in relation to modifications in the cell cycle are discussed.

Animals↗
PubMed1997

Conformational studies of paclitaxel analogs modified at the C-2' position in hydrophobic and hydrophilic solvent systems.

The conformations of two paclitaxel analogs modified at the C-2' position, 2'-deoxypaclitaxel and 2'-methoxypaclitaxel, were studied in hydrophobic and hydrophilic solvent systems by a combination of NMR spectroscopy, CD measurements, and molecular modeling. Both analogs have hydrophobic and hydrophilic conformations that resemble those of paclitaxel itself in the same media. Since the two have diminished biological activities in a number of bioactivity assays and the hydrogen-bonding capability of the 2'-hydroxyl group has been eliminated, we postulate that this group is involved in hydrogen bonding with tubulin and plays an important role in molecular recognition. The results of this study are in agreement with our earlier report on paclitaxel 2'-acetate, an analog in which the 2'-hydroxyl group hydrogen-bonding capacity has also been eliminated.

Animals↗
PubMed1995

Reduction of the systemic toxicity of cisplatin by intra-arterial hepatic route administration for liver malignancies.

Cisplatin (CDDP) administration by the intra-arterial hepatic route (i.a.h.) in patients with primary or metastatic liver malignancies could enhance the anti-tumor activity of the drug and reduce its systemic toxicity. The aim of the present study was to compare Pt pharmacokinetics and the toxicity of the circulating drug after i.a.h. versus intravenous (i.v.) administration. CDDP pharmacokinetics was followed-up in 11 i.a.h. courses given to 7 patients with liver malignancies and compared with 19 i.v. courses in 15 patients with cancer of different origins. The Pt level in blood was monitored by sensitive atomic absorption spectrometry. The dose given was in the range of 25-80 mg/m2/treatment. For analysis and for comparison purposes, the data from both CDDP treatments were normalized to a standard dose of 35 mg/m2. The mean peak Pt level for i.a.h. treatment was found to be about half of the mean peak value for i.v. administration with a similar dose-independent bi-exponential rate of elimination i.a.h. CDDP treatment was relatively well tolerated with no symptoms of either nephro- or neurotoxicity. For in vitro evaluation of peripheral CDDP toxicity, a sensitive ovarian carcinoma cell line, OV-1063, was used. A cytotoxic effect was recorded only within 2 hr following high-dose i.v. CDDP treatment. A substantial fraction of the drug given by the i.a.h. route was found to be extracted by the liver in the first passage, with reduced drug level in the peripheral blood plasma relative to the dose given. This may explain the apparent diminution of side-effects following i.a.h. CDDP treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Plasma platinum elimination in a hemodialysis patient treated with cisplatin.

The pharmacokinetics of intravenously administrated cisplatin (CDDP) were studied in a patient with meduloblastoma receiving regular hemodialysis for chronic renal failure. The patient received four CDDP infusions of 25 mg/m2 in two courses and underwent hemodialysis before each treatment and in intervals of 48 h thereafter with blood sampling at the beginning and the end of each hemodialysis. The data obtained were compared with the pharmacokinetic data from follow-up studies of 19 CDDP treatments in 15 patients suffering from various malignancies with no renal failure where a biexponential pharmacokinetic curve was recorded. The data of platinum (Pt) elimination of the patient receiving hemodialysis resembled the curve of those who had not, but following the second CDDP treatment in each course the peak Pt level in plasma was doubled, with a somewhat slower rate of elimination.

Adult↗
PubMed1994

The effect of immunosuppression by total-body irradiation on the pharmacodynamics of centrally active drugs in rats.

The aim of this investigation was to assess whether immunosuppression induced by total-body irradiation (TBI) affects the pharmacodynamics of centrally acting drugs. Female Sabra rats were exposed to a single dose of gamma irradiation (5.3 Gy). Four days later, when both the cellular and the humoral immune responses were impaired, they received an i.v. infusion of either phenobarbital (0.8 mg/min), ethanol (16.3 mg/min), pentylenetetrazol (PTZ; 0.618 mg/min), or theophylline (as aminophylline; 2 mg/min). The infusion was stopped at the onset of the pharmacologic end point--loss of righting reflex for the depressant agents or maximal seizures for the stimulant drugs--and the concentrations of the neuroactive drugs at that point were determined. In the ethanol experiment, blood samples were also taken upon awakening. The radiation-induced immunosuppression significantly decreased the CNS sensitivity to the depressant action of both phenobarbital and ethanol as indicated by the higher CSF phenobarbital concentrations required to induce sleep in the irradiated rats versus controls (156 +/- 4 vs 133 +/- 5 mg/L, respectively; P < 0.05), and the higher serum ethanol concentrations at the onset and offset of sleep in the immunosuppressed group versus control values (4.6 +/- 0.2 and 1.68 +/- 0.01 vs 3.79 +/- 0.17 and 1.32 +/- 0.9 mg/mL, respectively; P < 0.04). Exposure to TBI did not alter the pharmacodynamics of the two convulsant drugs (theophylline and PTZ).

Animals↗
PubMed1993

Noninvasive follow-up of platinum pharmacokinetics in the skin of patients on cisplatin chemotherapy.

BACKGROUND: Treatment with high-dose cisdiammine-dichloroplatinum (II) (cisplatin, cDDP) often is associated with late complications, predominated by peripheral neuropathy. Pt deposition in different tissues may play a key role in the induction of many of these effects. Main topics of interest include the relationship between cDDP doses given during treatment and the long-term pharmacokinetics of the drug complexes in normal tissues and blood. Noninvasive examination of Pt in tissues during and after cDDP treatment are needed to clarify these points. METHODS: A novel, high-sensitivity diagnostic x-ray spectrometry (DXS) method was used for the fast, noninvasive analysis of Pt in external tissues of patients with cancer treated with courses of cDDP. The Pt in a small skin area was excited by a monochromatic soft x-ray beam (14.6 KeV) and the spectral L lines emitted from the tissue were detected. A limit of detection below 1 microgram/g wet weight was reached. The pharmacokinetics of Pt in blood was investigated in parallel with the use of high-sensitivity, flameless atomic absorption spectrometry (AAS). RESULTS: Follow-up of Pt concentrations in the skin of patients with cancer by DXS before cDDP treatment, during treatment, and up to 4 months after its completion, showed prolonged Pt deposition that corresponded to the net cumulative doses of the drug. Pt clearance from the skin fitted a monoexponential curve with a half-life of about 30 days. In comparison, the pharmacokinetics of total Pt in plasma showed a much faster, biexponential clearance with half-lives of 41 minutes and 5.2 days, respectively. CONCLUSIONS: The amount of nonspecific Pt deposition in the tissues was found to depend on the total doses administered, the time interval between the courses, and the slow rate of clearance. Noninvasive measurements of tissue Pt levels may serve as a major tool in the evaluation of the induction of late cDDP complications.

Cisplatin↗
PubMed1993

Platelet multielemental composition, lability, and subcellular localization.

Diagnostic X-ray spectrometry (DXS), based on X-ray fluorescence, was used to quantitate directly the multiple elemental composition of washed, intact human platelets (n = 16), with the following results: K = 3.08 +/- 1.00 mg/g, Ca = 1.18 +/- 0.29 mg/g, Zn = 35 +/- 9 micrograms/g. These values show that washed platelets contain significant pools of K, Ca, and Zn, the latter some 30-60-fold higher than plasma levels. Dialysis of whole platelets against cation exchange resin (Chelex-100) did not extract Ca(II) and Zn(II) sequestered within whole cells. To identify the subcellular locale of the elements, platelet lysate was subjected to 30-70% sucrose gradient ultracentrifugation and subcellular enriched fractions were obtained. Fractions were analyzed by DXS (for elements), electron microscopy (for dense granules), and subcellular markers fibrinogen and von Willebrand factor. In contrast to Ca and K, which accumulate in the dense granules and the cytoplasm, respectively, Zn appears to be distributed in the alpha-granules (40%) and the cytoplasm (60%). The subcellular distribution of Zn(II) is discussed within the context of the sensitivity of platelet response to the availability of Zn(II) and the platelet release reactions following stimulation.

Absorption↗
PubMed1993

Packaging zinc, fibrinogen, and factor XIII in platelet alpha-granules.

Zinc(II) accumulated by platelets has profound effects on platelet activity. This study is focused on the distribution of Zn(II) between human platelet subcellular compartments. After incubation with 86Rb+ and platelet lysis, the organelles were separated by sucrose density gradient centrifugation. Fibrinogen served as a marker for alpha-granules. 86Rb+ and factor XIII served as markers for the cytoplasmic fractions. Zn(II) was found to be distributed between the cytoplasm and the alpha-granules, with variations between different individual units. The total platelet Zn concentration and its relative subcellular distribution were dependent on its extracellular level. Incubation of platelets with 100 microM Zn(II) resulted in a twofold increase of its level in the cytoplasm and by one order of magnitude in the alpha-granules. In addition to the anticipated factor XIII activity in the cytoplasmic pool fraction, we found thrombin-inducible factor XIII activity within the alpha-granules. Immunoblotting confirmed the presence of both the a and b subunits of plasma factor XIII (a2b2 form) in the alpha-granules. As fibrinogen is not synthesized in the platelet, we propose that by virtue of their mutual binding, fibrinogen, Zn(II) and plasma factor XIII-a2b2 are simultaneously taken up into the alpha-granules by endocytosis, presumably through the vehicle of the GPIIb/IIIa fibrinogen receptor. A rationale for co-packaging these components within the alpha-granules is that Zn(II) inhibits factor XIII activity and thereby prevents the premature cross-linking of the concentrated fibrinogen prior to platelet activation and secretion. By contrast, cytoplasmic Zn(II) may increase platelet responsiveness to agonists due to its interaction with cytoplasmic modulators of platelet activity.

Blood Platelets↗
PubMed1993

In vivo anti-inflammatory effects of the M20 IL-1 inhibitor: II. Effects on serum reactants.

We have previously described an IL-1 Inhibitor derived from the M20 myelomoncytic cell line. This line also secretes several molecules of IL-1. We have shown that this factor is specific to IL-1 in vitro, as well as in vivo. In vitro IL-1 induced proliferative responses of mouse thymocytes, human T cells and fibroblasts and IL-1 stimulated PGE2 secretion from fibroblasts, were all inhibited by the M20 IL-1 Inhibitor. In vivo, the IL-1 Inhibitor reduced parameters of acute inflammation such as fever, leukocytosis and local inflammation. This study describes additional effects of the M20 IL-1 Inhibitor on inflammatory serum reactants. Levels of corticosterone and fibrinogen were increased by injection of IL-1, and decreased by the IL-1 Inhibitor. IL-1 reduced zinc and iron plasma levels and elevated copper plasma levels. The M20 IL-1 Inhibitor reversed these changes in a dose dependent manner. Similar effects produced by IL-6 and TNF were unaffected by the M20 IL-1 Inhibitor. Our results indicate that the M20 IL-1 Inhibitor acts specifically on IL-1 induced responses in vivo. Therefore we conclude that this IL-1 Inhibitor has a great potential as an anti-inflammatory agent.

Animals↗
PubMed1992

A long-term follow-up of metallic intraocular foreign bodies, employing diagnostic x-ray spectrometry.

We describe 10 eyes harboring metallic intraocular foreign bodies (IOFBs) for 9 to 46 years that had undergone diagnostic x-ray spectrometry to measure metal dissolution 9 years before this study. Findings from the present clinical and laboratory examinations, including perimetry, electroretinography, electrooculography, and diagnostic x-ray spectrometry examinations are reported. Deterioration in visual acuity consequent to metal dissolution of the IOFB was found in only one eye. Visual fields and electrophysiologic performances deteriorated in two other eyes for reasons that were probably unrelated to IOFB dissolution. Visual functions remained stable during the follow-up period in seven eyes, although excess copper levels were demonstrated in one of them. Eight of 10 eyes retained visual acuity of 6/24 or better. Diagnostic x-ray spectrometry confirmed siderosis in one patient and ruled out metallosis in the two patients with deteriorated vision for reasons that were unrelated to metallosis. The favorable outcome of this series of patients may influence one to consider a more conservative approach in the decision to remove IOFBs. A careful, life-long follow-up might be considered with periodic electroretinographic and diagnostic x-ray spectrometry examinations; the IOFB should be promptly removed if and when metallosis with damage to visual functions is demonstrated.

Adult↗