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Biomedical subjects

R Sridhar

Publications and source records attributed to R Sridhar.

At least 19 recordsLinked to original sources
PubMed1994

Dipyridamole modulates multidrug resistance and intracellular as well as nuclear levels of doxorubicin in B16 melanoma cells.

Simultaneous occurrence of resistance to many chemotherapeutic agents, termed multidrug resistance (MDR), is a complex phenotype. MDR occurs due to several reasons, including over-expression of a 170-kDa membrane-bound protein, called P-glycoprotein (P-gp), which apparently participates in active drug efflux. Multidrug-resistant cells also frequently exhibit an altered pattern of intracellular drug distribution, resulting in a reduction in the nuclear level of drugs such as doxorubicin (DOX). In this study, the effect of dipyridamole (DP) on drug resistance and on intracellular as well as nuclear levels of DOX in multidrug-resistant melanoma cells has been examined. For this purpose, drug-sensitive murine melanoma cells (B16V) and their multidrug-resistant variant cells, (B16VDXR; selected for resistance to DOX) which over-produce P-gp, were employed. B16VDXR cells were cross-resistant to several anti-cancer agents including etoposide (VP-16) and mitoxantrone (Mitox). DP (10 microM) significantly potentiated the cytotoxicity of DOX, VP-16 and Mitox towards multidrug-resistant B16VDXR cells but not in parental drug-sensitive B16V cells. The presence of DP resulted in a 3.7-fold increase in the total cellular level and a 4.2-fold increase in the nuclear content of DOX in the resistant cells. Isobologram analysis indicates that DP at several pharmacologically relevant concentrations synergistically potentiates the activity of DOX in B16VDXR cells.

Animals↗
PubMed1993

Iodine-131 treatment of hyperthyroidism in a patient on dialysis for chronic renal failure.

A 7- to 8-cm diffuse toxic goiter with associated symptoms of hyperthyroidism developed in a 38-year-old black female undergoing regular hemodialysis for renal failure. Our treatment of choice was an ablative dose of radioactive iodine in the form of sodium iodide (Na-131I). To our knowledge, this is only the 4th documented case of hyperthyroidism in a patient with renal failure. Detailed monitoring of 131I radioactivity in the blood, thyroid gland and the dialysate demonstrated that there was no radiation hazard to personnel involved in the patient management.

Adult↗
PubMed1992

Effects of verapamil on the acute toxicity of doxorubicin in vivo.

BACKGROUND: Studies indicating that verapamil substantially enhances doxorubicin levels in certain drug-resistant tumor cells have led to the use of verapamil in combination with doxorubicin in animal and clinical studies of multidrug-resistant tumors. These studies have shown this drug combination to be associated with severe toxic effects. It is important to determine whether verapamil modulates the dose-limiting and potentially lethal cardiotoxicity of doxorubicin and to elucidate possible mechanisms. PURPOSE: The aims of this study were to evaluate the in vivo effects of verapamil on (a) doxorubicin-stimulated cardiac lipid peroxidation and cardiac damage, (b) doxorubicin-induced animal mortality, and (c) biodistribution of doxorubicin to the heart. METHODS: Male (BALB/c x DBA/2)F1 mice were treated with a high dose of doxorubicin (15 mg/kg, injected intraperitoneally), verapamil (25 mg/kg, injected intraperitoneally), or combinations of the two. Lipid peroxidation was determined using the 2-thiobarbituric acid assay for malonaldehyde. Light microscopy was used for histopathologic examination of cardiac tissue. A fluorometric assay procedure was employed to determine doxorubicin levels in the heart. RESULTS: Verapamil was an effective inhibitor of peroxidative damage to myocardial lipids following a high dose of doxorubicin (15 mg/kg, injected intraperitoneally). However, mice treated with verapamil and doxorubicin had a lower survival rate and a higher initial peak concentration of doxorubicin in the heart than those treated with doxorubicin alone. They also demonstrated a higher incidence and severity of degenerative changes in cardiac tissue. CONCLUSIONS: Our findings suggest that verapamil effectively inhibits doxorubicin-mediated lipid peroxidation in vivo but that cardiac lipid peroxidation is not the major limiting mechanism underlying doxorubicin-induced toxicity. A possible explanation for the excess mortality and cardiac injury in mice treated with verapamil plus doxorubicin is that verapamil alters the pharmacokinetics of doxorubicin. IMPLICATIONS: Further studies are necessary for development of safer protocols and/or drug combinations to treat multidrug-resistant tumors. We are currently studying treatment of tumor-bearing animals with a cumulative dosage regimen of doxorubicin in the presence and absence of verapamil.

Animals↗
PubMed1992

Potentiation of cytotoxicity of mitoxantrone toward CHO-K1 cells in vitro by dipyridamole.

Dipyridamole (DP), a clinically used vasodilator and an antiplatelet compound, augmented the activity of the anticancer drug mitoxantrone (MXN) toward chinese hamster ovary (CHO-K1) cells in culture. Clonogenic assays indicated that DP (1.0, 2.5, and 5.0 microM) decreased the survival of cells treated with MXN (5 to 25 nM) in a dose-dependent manner. Further, DP (1 and 5 microM) decreased the MXN concentration required for 50% inhibition of cell growth from 3.2 to 1.8 and from 3.0 to 0.5 nM, respectively, over a period of 3 days. DP (10 microM) increased the accumulation of MXN by 1.8-fold in exponentially growing cells exposed to MXN. The enhanced levels of MXN in CHO-K1 cells in the presence of the chemosensitizer may account for the potentiation of MXN-cytotoxicity by DP.

Animals↗
PubMed1991

Attenuation of daunorubicin-augmented microsomal lipid peroxidation and oxygen consumption by calcium channel antagonists.

Daunorubicin (20 microM) stimulated NADPH-dependent microsomal lipid peroxidation about 2-fold over control values and enhanced the rate of oxygen utilization by microsomes. The calcium channel blockers tested inhibited daunorubicin-augmented lipid peroxidation and O2 consumption to varying degrees. Inhibition of daunorubicin-stimulated lipid peroxidation was found to be dose dependent; the IC50 (drug concentration producing 50% inhibition of lipid peroxidation) values for verapamil, nifedipine and diltiazem were approximately 150 microM, 200 microM, and 600 microM respectively. Our in vitro studies suggest that calcium channel antagonists may modulate the free radical-mediated, cardiotoxic effects of daunorubicin.

Animals↗
PubMed1990

Theoretical calculations on calcium channel drugs: is electron transfer involved mechanistically?

Theoretical studies were done on calcium channel drugs in order to gain insight into the mode of action. Empirical force field calculations with nifedipine, a calcium channel antagonist, indicate that the E-conformation at the ring juncture is lower in energy than the Z-conformation. This energy difference is only 0.2 kcal/mol when the esters in the 3- and 5-positions of the dihydropyridine (DHP) ring are both synperiplanar (sp, sp). Molecular orbital calculations on the ground and excited states in the Z-conformation with the esters in the (ap, sp) conformation show a low lying excited state with substantial intramolecular electron transfer (ET) character. This excited state is only 1.8 eV higher in energy than the ground state and corresponds to a transfer of approximately 0.3 electron from the DHP ring to the nitrobenzene moiety. We suggest that ET may play an important role in the mechanism of action, either intramolecular or, as previously proposed, intermolecular, along with lipophilicity and steric effects.

Calcium Channel Blockers↗
PubMed1989

Inhibition of rat heart and liver microsomal lipid peroxidation by nifedipine.

Lipid peroxidation in rat heart and liver microsomes was induced by an NADPH-generating system or by ascorbate in the presence of an ADP-iron complex. Microsomal lipid peroxidation, as measured by malonaldehyde formation, was inhibited by nifedipine over a wide range of concentrations (47 microM to 6 mM). Nifedipine also decreased the oxygen consumption of cardiac and hepatic microsomes in a concentration-dependent manner. These results indicate that nifedipine may perturb microsomal electron transport systems. Nifedipine may have the potential to alter the sensitivity of cardiac and hepatic membranes to peroxidative damage.

Animals↗
PubMed1987

Superoxide dismutase-like activities of copper(II) complexes tested in serum.

The superoxide dismutase-like activities of a series of coordination complexes of copper were evaluated and compared to the activities of bovine erythrocyte superoxide dismutase (superoxide: superoxide oxidoreductase, EC 1.15.1.1) in serum using the nitroblue tetrazolium chloride (NBT)-reduction assay and electron paramagnetic resonance (EPR) spectroscopy. A 40% inhibition was observed for the initial rate of the NBT reduction by superoxide dismutase in serum, but more than 40% inhibition was achieved with CuSO4, Cu(II)-dimethylglyoxime, Cu(II)-3,8-dimethyl-4,7-diazadeca-3,7-dienediamide, Cu2[N,N'-(2-(O-hydroxy-benzhydrylidene)amino)ethyl]2-1,2-ethane dia mine), Cu(II)-(diisopropylsalicylate)2, Cu(II)-(p-bromo-benzoate)2, Cu(II)-(nicotinate)2 and Cu(II)-(1,2-diamino-2-methylpropane)2. The electron paramagnetic resonance technique of spin trapping was used to detect the formation of superoxide (O2-.) and other free radicals in the xanthine-xanthine oxidase system under a variety of conditions. Addition of the spin trapping agent 5,5-dimethylpyrroline 1-oxide (DMPO) to the xanthine-xanthine oxidase system in fetal bovine serum produced the O2-.-spin adduct of DMPO (herein referred to as superoxide spin adduct, DMPO-OOH) as the well known short-lived nitroxyl whose characteristic EPR spectrum was recorded before its rapid decay to undetectable levels. The hydroxyl radical (HO.) adduct of the spin trap DMPO (herein referred to as DMPO-OH) was detected to a very small extent. When CuSO4, or the test complexes of copper, were added to the xanthine-xanthine oxidase system in serum containing the spin trap, the yield of DMPO-OOH was negligible. In addition to their superoxide dismutase-like activity, CuSO4 and the copper complexes also behaved as Fenton-type catalysts as seen by the accumulation of varying amounts of the hydroxyl spin adduct DMPO-OH. Both the Fenton-type catalysis and the superoxide dismutase-like action of these compounds were lost when a chelator such as EDTA was included in the xanthine-xanthine oxidase incubation mixture. Addition of superoxide dismutase instead of the copper compounds to this enzyme system abolished the formation of superoxide adduct DMPO-OOH, and no hydroxyl adduct DMPO-OH was detected. This effect of superoxide dismutase remained unaltered by EDTA.

Animals↗
PubMed1987

Changes in cyclic nucleotide profiles in proliferating multi-cell spheroids.

The intracellular concentration of cyclic adenosine 3':5'-mono-phosphate (cAMP) has been shown to be related to each developmental phase of the cell cycle. Highest levels of this nucleotide are evident during the S-phase (the DNA synthetic phase) which has also been shown to be radiation-sensitive. The relationship between the levels of cyclic nucleotides, cAMP and guanosine 3':5'-monophosphate (cGMP), and the proliferation of cells in a tumor model system was investigated using V79-171b Chinese hamster lung cells grown both as monolayer and as three dimensional cell clusters (spheroids). The spheroid which is more radiation-resistant than its monolayer counterpart, has been used by many radiobiologists as an in vitro tumor model. Our results indicate that the yin-yang hypothesis of a opposing regulatory relation between the two different classes of cyclic nucleotides only held true for monolayer cultures (both exponential and plateau phase) but could not be demonstrated in the tumor model where the levels of both nucleotides increased directly with the diameter of the growing spheroid mass.

Animals↗
PubMed1986

In vivo spin trapping of free radicals generated in brain, spleen, and liver during gamma radiation of mice.

Spin trapping techniques combined with electron spin resonance spectroscopy were used to capture and detect free radicals generated in vivo during exposure to ionizing radiation. Tissue extracts of mice given an intraperitoneal or intragastric dose of the spin trap, alpha-phenyl-t-butyl nitrone prior to exposure to gamma radiation (2 to 5 Gy), contained a radical adduct with hyperfine splitting constants characteristic of spin adducts of carbon-centered lipid radicals. Considerably more radicals were trapped in tissues when the trap was given 3 h before radiation as compared to 30 min before exposure. The radicals observed may either be secondary species resulting from an attack on cellular components by products of water radiolysis, or primary radicals resulting from direct interaction of the radiation with biological molecules. The results indicate that the spin trapping agent is able to penetrate well into animal tissues, and to capture radical species under conditions where the latter would be expected to occur.

Animals↗
PubMed1981

A new technique of depositing phospholipid bilayers on quartz surfaces: its use in membrane spin-label studies.

We have developed a new improved technique termed the parallel-beam spattering (PBS) method for depositing phospholipid bilayers on quartz surfaces. This technique involves atomizing the phospholipid mixture with a stream of nitrogen gas and passing this atomized mixture through two orifices separated by a distance to achieve a parallel beam of atomized particles before deposition on the quartz plate. A static electric field can easily be applied to the quartz surface. Also a goniometer of new design has been constructed to allow precise positioning of the deposited phospholipid bilayers with reference to the magnetic field. We have utilized the PBS method to deposit phosphatidylcholine/nitroxyl labeled cholestane mixtures on quartz plates and have found that hydrated bilayers of these mixtures yield ESR spectra with essentially the same characteristics as those obtained using more conventional techniques. The distinct advantage of the new technique for depositing bilayers is that there is no spectral anomaly present which usually is present when the more conventional method of depositing bilayers is used. The spectral anomaly is apparently caused by a portion of the bilayers aligned in directions not directly parallel to the quartz surface. For precision work the spectral anomaly is unacceptable. It is not observed with the new PBS method which has yielded highly reproducible results.

Electron Spin Resonance Spectroscopy↗
PubMed1980

Deuterium oxide protects against hyperthermic cell death: evidence for role of interfacial water.

Tissue culture cells incubated at 43 degrees C show a dramatic decrease in cell survival compared with cells incubated at lower temperatures; the effect is termed hyperthermic cell death (HCD). Replacing water in the culture medium with deuterium oxide produces a dose-dependent reduction in HCD. On the basis of this and other evidence it is concluded that the mechanism of HCD involves a hydration-dependent phase transition in membrane lipids.

Animals↗
PubMed1979

Cytotoxicity of glucose analogues in V79 multicell spheroids.

2-Deoxy-D-glucose (2DG) and 5-thio-D-glucose (5TG) are glucose antimetabolites that are known to be selectively toxic to hypoxic cells grown as single cells or as monolayer cultures. These analogues were toxic to Chinese hamster V79 cells grown as multicell spheroids even under aerobic conditions. When spheroids, 500- to 600-microns diameter, were exposed to 7.5 mM of these chemicals for 3 days, the number of clonogenic cells per spheroid dropped to 50% for 5-thio-D-glucose and 20% for 2-deoxy-D-glucose, relative to control values. Survivals were reduced to less than 1% when the experiment was repeated in glucose-free medium. Scanning electron photomicrographs of spheroids treated with 7.5 mM of either analogue showed extensive damage to the outer cells. The cell killing observed was much more than could be predicted on the basis of the hypoxic fraction known to be present in these spheroids. The crowded tumor-like environment may make the cells vulnerable to the cytotoxic action of glucose analogues and other glycolytic inhibitors.

Animals↗
PubMed1978

Application of alkaline sucrose gradient sedimentation to the study of DNA damage and its repair in mammalian cells treated with methylmethanesulfonate and 4-nitroquinoline-1-oxide.

KB cells and L cells were treated with methylmethanesulfonate (MMS) or 4-nitroquinoline-1-oxide (4 NQO) and the resulting damage to DNA and its repair were examined by sedimentation in an alkaline sucrose gradient. The sedimentation profiles obtained were found to be the resultant of a complex interrelationship between drug dosage, duration of the lysis period and the repair capacity of the cells. A systematic study of these variables was made which led to a plausible and useful interpretation of the sedimentation profiles. Both drugs produce two kinds of DNA modifications which show up as a single-strand breaks but affect the sedimentation profile in characteristic ways. One of these modifications which is quite alkali-labile can be studied using a 30-min lysis period. The other modification is less alkali-labile and can be studied using a long lysis period. Both KB cells and L cells can repair the former type of damage but only KB cells can repair the latter type of damage.

4-Nitroquinoline-1-oxide↗
PubMed1978

Effect of radiosensitizing agents on electron transport systems.

Experiments have been carried out to study the interaxtion between chemical radiosensitizing agents and model electron transport systems. Using an NAD(P)H:O2 oxidoreductase enzyme as such a model, it was demonstrated that radiosensitizers can act as intermediates in the transfer of electrons from NADH to O2, even in the presence of classical inhibitors of electron transport, with anefficiency related to both their redox potentials and their radiosensitizing abilities. This work which was further confirmed in mammalian mitochondria and microsomes as well as in a cultured cell system indicated that these sensitizers can accept electrons from a variety of organelle systems. This action was shown to be related to the concentration of reduced pyridine nucleotides present both in vivo and in vitro. Of the electron-affinic agents tested, those whose redox potential was more negative than -0.39 V may possibly serve as better radiotherqpeutic mediators.

Animals↗