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Biomedical subjects

A Russo

Publications and source records attributed to A Russo.

At least 505 records · Page 28Linked to original sources
PubMed1989

Modification of SR 2508 sensitization in hypoxic V79 cells by manipulation of glutathione levels.

This series of experiments employed the hypoxic cell sensitizer SR 2508 in concentrations ranging from 0.1 to 10 mM and V-79 cells irradiated in air or made hypoxic in glass syringes, then irradiated with 15 MV X rays. Using a series of survival curves measured at the various concentrations, K curves relating sensitizer enhancement ratio (SER) to SR 2508 concentration were calculated with normal GSH levels or with depletion of GSH to 0% using 1 mM buthionine sulfoximine (BSO) or elevation to 200% of normal using 1 mM oxothiazolidine carboxylate (OTZ). Survival curves were fitted by computer, allowing calculation of standard errors for the SER values. The depletion of GSH by BSO sensitized hypoxic and aerated cells significantly and caused more than additive enhancement of SR 2508 sensitization in hypoxic cells. Elevation of GSH with OTZ protects cells irradiated in air or hypoxia and reduces the SER obtained with SR 2508. The results further support the importance of GSH levels in influencing sensitization by nitroimidazoles.

Animals↗
PubMed1989

Evaluation of nitroimidazole hypoxic cell radiosensitizers in a human tumor cell line high in intracellular glutathione.

Five nitroimidazole hypoxic cell radiosensitizers were evaluated in a human lung adenocarcinoma cell line (A549) whose GSH level was 8-fold higher than Chinese hamster V79 cells. One millimolar concentrations of Misonidazole (MISO), SR-2508, RSU-1164, RSU-1172, and Ro-03-8799 sensitized hypoxic A549 cells to radiation, with Ro-03-8799 giving the highest sensitizer enhancement ration (SER) (2.3). However, MISO, SR-2508 and Ro-03-8799 were less effective in this cell line than in V79 cells, presumably due to higher GSH content of the A549 cells. Increased hypoxic radiosensitization was seen with 0.1 mM Ro-03-8799 after GSH depletion by BSO as compared to 0.1 mM Ro-03-8799 alone (SER-1.8 vs 1.3). The combination of GSH depletion and 0.1 mM Ro-03-8799 was considerably more toxic than 0.1 mM or 1.0 mM Ro-03-8799 alone. This sensitivity was much greater than has been observed for SR-2508. These data show that Ro-03-8799 was the most efficient hypoxic cell radiosensitizer in a human tumor cell line considerably higher in GSH than the rodent cell lines often used in hypoxic radiosensitization studies. Thus, Ro-03-8799 may be a more effective hypoxic cell sensitizer in human tumors that are high in GSH.

Cell Line↗
PubMed1989

Superoxide reaction with nitroxide spin-adducts.

The reactions of superoxide radical with persistent nitroxide spin-adducts or with stable spin-labels were studied using ESR spectrometry. Superoxide radicals were produced enzymatically using xanthine - xanthine oxidase or chemically by dissolving potassium superoxide in DMSO. Hydroxyl and methyl spin-adducts of the spin-trap DMPO were performed by sonolysis and subsequently reacted with superoxide radical. Superoxide-induced depletion of DMPO--OH obeyed second order kinetics. Contrary to previously published mechanisms, the reaction requires neither transition metal ions nor thiols. The depleted spin-adducts could not be restored by reoxidation with ferricyanide or copper +H2O2; thus, the superoxide-mediated destruction does not result in a mere one-electron reduction product. Superoxide also depletes other DMPO spin-adducts including DMPO--CH3 and DMPO--H, but not PBN--CH3. In addition, some 5-membered ring stable nitroxides are depleted by superoxide in a pseudo-zero order reaction. In studying systems which generate O2- and OH, the superoxide-induced destruction of DMPO--OH may well lead to erroneous conclusions regarding the primary radicals produced. In particular this reaction might be operative under circumstances where elevated rates of superoxide production take place, such as during oxygen consumption "burst" in phagocytosis, degranulation, or paraquat intoxication.

Cyclic N-Oxides↗
PubMed1989

Photodynamic therapy of rabbit endometrial transplants: a model for treatment of endometriosis.

The potential of photodynamic therapy for endometriosis was evaluated by autotransplantation of endometrial tissue in 15 female virgin New Zealand white rabbits. After maturation, 14 animals were injected intravenously with 10 mg/kg of dihematoporphyrin ether (DHE) and, 24 hours later, transplants were exposed to 630 nm light at 100 to 210 mW/cm2. Sixteen transplants received 100 J/cm2, 10 transplants received 50 J/cm2; 13 untreated transplants served as controls. In the remaining animal that did not receive DHE, 3 transplants were irradiated with 100 J/cm2. Six days after treatment, transplants were harvested with the underlying musculature, and multiple sections were examined histopathologically. Complete endometrial epithelial destruction was seen in 13 of 16 transplants (81%) in the 100 J/cm2 group and in 6 of 10 transplants (60%) in the 50-J/cm2 group. Nearly complete endometrial epithelial destruction was seen in 2 other transplants in each group. No damage occurred in either the 3 transplants that received 100 J/cm2 without prior DHE or in the 13 transplants with DHE and no irradiation. The sensitivity of ectopic rabbit endometrial tissue encourages further evaluation of photodynamic therapy for the treatment of human endometrial disorders.

Animals↗
PubMed1989

Radiobiology and clinical application of halogenated pyrimidine radiosensitizers.

Halogenated pyrimidines (HP) represent a unique class of non-hypoxic cell radiosensitizers currently under clinical re-investigation. In order for halogenated pyrimidines to sensitize cells to radiation, they must be incorporated into cellular DNA. In the case of human tumors, which have in general rather long cell cycle times, this may require many days of continuous drug infusion to achieve adequate replacement of the DNA base thymidine with HP. In vitro studies support the relationship between the extent of radiosensitization and the percentage of thymidine replacement. Recent clinical studies evaluating the role of iododeoxyuridine (IdUrd) as a radiation sensitizer in large unresectable sarcomas have been extremely encouraging. To support and expand upon these positive clinical findings more information and research is needed regarding: (1) the mechanism of HP-induced radiosensitization; (2) the percentage of HP thymidine replacement in human tumors achievable and how it relates to treatment outcome; (3) the means of increasing HP incorporation in tumor and minimizing incorporation in normal tissues; (4) a better understanding of optimal timing between HP administration and radiation treatment; and (5) methods to evaluate which tumors are appropriate candidates for HP therapy. While presently limited to use in conventional high dose-rate X-ray therapy, laboratory studies suggest that HP might also be effective in low dose-rate brachytherapy and for selected high LET clinical beams. HPs probably will not be 'general' non-hypoxic cell radiosensitizers for all tumor types, but with appropriate tumor-type/anatomical site selection and refinement in their administration, HPs may prove beneficial in cancer treatment.

Bromodeoxyuridine↗
PubMed1989

The effectiveness of combination chemotherapy with cisplatinum and etoposide in the treatment of advanced non-small cell lung cancer.

Twenty-one patients with histologically proven advanced or disseminated non-small cell lung cancer were treated with cisplatinum 80 mg/m2 i.v. day 1 and etoposide (VP16) 80 mg/m2 i.v. day 1- greater than 3.15 patients were evaluable for response. One patient (6.6%) achieved a complete response, 4 (26.7%) a partial response and 6 (40.0%) a stabilization of disease. Four patients (26.7%) progressed. An improvement in performance status was obtained in more than 50% of cases. Responders had a mean survival of 345 + days, while non-responders 191.7 days. The treatment was generally well tolerated. In our opinion this combination regimen offers good palliation for patients affected by advanced and/or metastatic non-small cell lung cancer.

Aged↗
PubMed1989

Combination chemotherapy with cyclophosphamide, doxorubicin and vincristine in the treatment of stage III-IV small-cell lung cancer.

Twenty patients with histologically confirmed small-cell lung cancer were treated with cyclophosphamide 1000 mg/m2 i.v. on day 1, vincristine 1.4 mg/m2 i.v. day 1, and adriamycin 50 mg/m2 i.v. on day 1. This protocol was repeated every 21 days. Out of 17 evaluable patients 2 obtained a complete response (12%) with a mean duration of 11 months, 4 patients achieved a partial response with a mean duration of 6.3+ months, and 1 had a minimal response of 7.2 months. Two patients had a stabilization which lasted a mean of 4+ months, while 8 patients progressed. Although the mean survival was higher in responders than in non-responders, the difference in survival time was not statistically significant. The treatment was quite well tolerated with hematological toxicity in 78% of cases, oral and gastrointestinal toxicity in 83%, alopecia in 78%, and neurotoxicity in 16% of cases.

Aged↗
PubMed1989

Mechanisms involved in the Münsterberg "shifted chequerboard" illusion: an empirical test.

In the present work three alternative hypotheses proposed as explanations of the Münsterberg illusion are discussed: the Moulden and Renshaw 1979 hypothesis, which explains this effect using Helmholtz's 1856 "irradiation theory," the Gregory and Heard 1979 hypothesis, which proposes a mechanism of "border locking," and the McCourt 1982 hypothesis, which sustains a relation between this effect and brightness induction phenomena. To check these hypotheses, we took four measures, each one obtained by using a different pair of patterns mounted on circular displays which could be tilted by 360 degrees. The results do not support McCourt's hypothesis but, on the other hand, they seem to be partially in agreement, or at least not to be in disagreement, with the hypotheses both of Moulden and Renshaw and of Gregory and Heard.

Attention↗
PubMed1989

Halogenated pyrimidines as radiosensitizers for high-LET radiation.

The incorporation of iododeoxyuridine (IdUrd) into Chinese hamster cells was examined as a possible radiosensitizer for fission spectrum neutrons. Dose-response curves comparing both X rays and neutrons in the same cell line with the same IdUrd replacement showed a similar radiation enhancement for IdUrd incorporation. Enhancement ratios at the 1% survival level were 1.8 for X rays and 1.5 for fission spectrum neutrons. While the mechanism of this enhancement in the response for fission neutron radiation is unclear, these positive data should support further exploration to determine if halogenated pyrimidine incorporation results in sensitization for neutron energies employed in therapy.

Animals↗
PubMed1988

A novel metal-free low molecular weight superoxide dismutase mimic.

2-Ethyl-1-hydroxy-2,5,5-trimethyl-3-oxazolidine (OXANOH), the one-electron reduction product of the stable nitroxide radical, 2-ethyl-2,5,5-trimethyl-3-oxazolidinoxyl (OXANO), is reportedly oxidized by superoxide, and its oxidation has been proposed as a method for assaying superoxide. We find that superoxide can both reduce OXANO and oxidize OXANOH. The respective rate constants, k1 and k2, were determined using two superoxide-generating systems (xanthine oxidase/xanthine as well as ionizing radiation). OXANOH oxidation and OXANO reduction are both inhibitable by superoxide dismutase, pH-dependent (4.5-9.3), and result in a steady state distribution of [OXANO] and [OXANOH], independent of their initial concentrations, i.e. the OXANO/OXANOH couple exhibits a metal-independent superoxide dismutase-like function. Thus it provides a prototype for future development of improved low molecular weight superoxide dismutase mimics which will also function in cellular hydrophobic (aprotic) compartments such as membranes.

Hydrogen-Ion Concentration↗
PubMed1988

Role of the ventromedial hypothalamus in the regulation of adenohypophyseal immunoreactive dynorphin in the rat.

In this study, we have examined the role of the dorsomedial (DMH), ventromedial (VMH) and arcuate (ARH) nuclei of the hypothalamus in the control of hypothalamic and pituitary immunoreactive (ir) dynorphin (Dyn) A and ir-Dyn B in the rat, by evaluating the effect of discrete, bilateral radiofrequency lesions in these structures. Lesions limited to the VMH reduced the content of ir-Dyn in the anterior pituitary but not in the neurointermediate lobe or in the hypothalamus. Gel chromatographic analysis of anterior pituitary extracts confirmed that ir-Dyn is mainly associated with high molecular weight forms containing Dyn A and Dyn B in their sequence. Anterior pituitary extracts of VMH-lesioned rats displayed a clearly lower proportion of these forms. Destruction of the DMH affected only the hypothalamic content of ir-Dyn; ablation of the ARH did not cause any significant change. Our results suggest that ablation of the VMH may disrupt critical neuronal connections to the median eminence originating in this nucleus or crossing it and participating in control of the adenohypophyseal pool of ir-Dyn.

Animals↗
PubMed1988

Branching axons from subcoeruleus area project to the nucleus raphe pontis and hypothalamic zona incerta, as studied with the double fluorescent retrograde tracing technique.

In this study we utilized a double retrograde axonal tracing technique to investigate the possible existence of collateralized axonal projections of subcoeruleus area neurons to both raphe pontis nucleus and hypothalamic zona incerta. Following microinjections of fluorescent tracers (Fast blue (FB) and Diamidino yellow (DY] within raphe pontis and zone incerta, substantial numbers of double-labeled branched neurons have been found within the subcoeruleus area.

Amidines↗
PubMed1988

Hydroxyl radical production by stimulated neutrophils reappraised.

Release of active oxygen species during the human neutrophil respiratory burst is thought to be mandatory for effective defense against bacterial infections and may play an important role in damage to host tissues. Part of the critical bacterial and host tissue damage has been attributed to hydroxyl radicals produced from superoxide and hydrogen peroxide. Because of the short life time of the very reactive hydroxyl radical, direct study of hydroxyl radical production is not possible; therefore, indirect detection methods such as electron spin resonance (ESR) coupled with appropriate spin-trapping agents such as 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) have been used. Superoxide production during the oxidative burst has been unambiguously demonstrated. Recent reports claim that hydroxyl radicals are not made during neutrophil stimulation and offer as an explanation the presence of granular components that interfere with hydroxyl radical production. When using the spin-trap agent DMPO, absence of the relatively long-lived adducts DMPO-OH and DMPO-CH3 has been assumed to be prima facie evidence for lack of hydroxyl radical participation. We show that high superoxide flux produced during stimulation of human neutrophils rapidly destroys both DMPO-OH and DMPO-CH3. In accord with previous implications, our results provide an alternative explanation for the absence of .OH adduct in spin-trapping studies and corroborate results obtained using other methods that implicate hydroxyl radical production during neutrophil stimulation.

Cyclic N-Oxides↗
PubMed1988

212Bismuth linked to an antipancreatic carcinoma antibody: model for alpha-particle-emitter radioimmunotherapy.

For comparison of cytotoxicity from alpha-particle irradiation with that from conventional x-irradiation, 212Bi, an alpha-emitting radionuclide, was attached to a monoclonal antibody that recognizes a cell surface antigen on human pancreatic carcinoma cells. For a given level of survival, the 212Bi-antibody complex was found to be approximately 20 times more efficient in cell killing than x-irradiation and 5 times more cytotoxic when compared with the cytotoxicity of an antigen-negative cell line or an isotype-matched control antibody. High linear energy transfer radioimmunotherapy using alpha emitters linked to monoclonal antibodies may be useful in vivo and in vitro for selectively killing target cell populations, especially those resistant to other forms of treatment.

Antibodies, Monoclonal↗