Search PubMed⌕ Search

Biomedical subjects

A Krishan

Publications and source records attributed to A Krishan.

At least 73 records · Page 4Linked to original sources
PubMed1985

Reversal of resistance to rhodamine 123 in adriamycin-resistant Friend leukemia cells.

Pleiotropic resistance to rhodamine 123 (Rho-123) in Adriamycin (ADM)-resistant Friend leukemia cells was circumvented by cotreatment with 10 microM verapamil. Increased cytotoxicity corresponded to higher intracellular Rho-123 levels. The verapamil-induced increase of drug accumulation in resistant cells is accounted for at least in part by the blockage or slowing of Rho-123 efflux from these cells. In contrast, accumulation and consequent cytotoxicity of Rho-123 in sensitive cells are not increased by verapamil. Similar results were obtained when ADM was used in this cell system. These results suggest that the efflux system for Rho-123 and ADM in sensitive cells is either reduced or absent. Although Rho-123 accumulates specifically in mitochondria and ADM mainly in the nucleus, the loss of these two different classes of compounds from resistant cells appears to occur via a similar or common mechanism. The similarities in drug transport between Rho-123 and ADM may have important implications when applied to an in vivo environment.

Animals↗
PubMed1985

Effect of amphotericin B on Adriamycin transport in P388 cells.

In Adriamycin-sensitive and -resistant P388 cells, coincubation with amphotericin B causes a marked increase in Adriamycin retention, as determined by laser flow cytometry. P388/S cells were generally more affected than were P388/R cells. Preincubation with amphotericin B had a greater effect on Adriamycin retention than did co- or postincubation. In splenocytes, bone marrow, and ascites from mice, enhanced Adriamycin retention was seen in all the tissues. However, bone marrow cells showed heterogeneous response, with some populations being more sensitive than others.

Amphotericin B↗
PubMed1985

Flow cytometric studies on modulation of cellular adriamycin retention by phenothiazines.

Phenothiazines (chlorpromazine and trifluoperazine) enhance the cellular retention and cytotoxicity of adriamycin in P388/S and P388/R cells. Effects on the resistant cells are more pronounced than those on the sensitive cells. Multiparametric flow-cytometric determination of cellular Adriamycin fluorescence shows that the phenothiazine effects are not uniform in a cell population, and cells in later part of the cell cycle traverse (S and G2/M), mitogen-stimulated lymphocytes (as compared to nonstimulated lymphocytes), and ascites (as compared to splenocytes) have greater sensitivity to phenothiazine effects on Adriamycin retention.

Animals↗
PubMed1984

Cell cycle related phenothiazine effects on adriamycin transport.

In P388 murine leukemic cells, the pheno-thiazine tranquilizer, chlorpromazine, causes a marked increase in intracellular drug retention. Laser excited flow cytometry shows that in log phase cultures this increase in drug retention is not uniform but confined to a sub-population. In cell cycle phase enriched populations of P388 cells obtained by centrifugal elutriation, the phenothiazine enhanced adriamycin retention is seen predominantly in cells in the late S, G2/M part of the cell cycle.

Animals↗
PubMed1984

Experimental pharmacology of auromomycin in L1210 tumor cells in vitro and in vivo.

The antibiotic protein auromomycin (AUR) is composed of a chromophore and an apoprotein. The in vitro cytotoxic activity of AUR is associated with the chromophore, whereas the apoprotein is not cytotoxic. Exposure to AUR blocks cell cycle traverse in G2-M phase. Both AUR and the chromophore exhibit antitumor activity against murine L1210 leukemia, both in vitro and in vivo. Similarly, neocarzinostatin and its chromophore also show antitumor activity against L1210 tumor cells in vitro and in vivo. AUR and neocarzinostatin apoproteins have no antitumor activity. The pharmacokinetics of 125I-labeled AUR in L1210 tumor-bearing mice shows a triexponential drug decay and initial rapid clearance of drug from the blood. The distribution of AUR-associated radioactivity into various tissues is rapid, and at the end of 24 hr, there is little drug accumulation in the tissues. During the first hr, greater than 50% of the administered drug is eliminated in the urine. As the chromophores alone possess antitumor activity, the effect of these antitumor proteins in cancer chemotherapy might be significantly increased by the administration of protein preparations containing biologically active and stable chromophores.

Animals↗
PubMed1983

Cytokinetic and cytogenetic effect of agricultural chemicals on human lymphoid cells in vitro. II. Organochlorine pesticides.

Human lymphoid cells of LAZ-007 cell line, incubated with 10(-4) to 10(-6) molar of eight different organochlorine pesticides had dose related cytotoxicity, mitotic depression and cell cycle traverse inhibition. In cultures incubated with 10(-4) M concentrations, M1 metaphases were as high as 13% (Dicofol) as compared to less than 1% in the controls. The frequency of M3 metaphases in cultures incubated with 10(-6) M concentrations ranged from 11% (Chlordane) to 15% (Endosulfan) compared to 17% in control cultures. Statistically significant increase in SCE frequency was seen in cells exposed to Chlordane, Dicofol, Endosulfan and Toxaphene. On metabolic activation with rat liver microsomal S-9 enzymes, Chlordane, Dicofol and Tetradifon induced SCE frequency was higher than that of nonactivated cultures.

Animals↗
PubMed1983

Correlation of in vitro clonogenic assay data with in vivo growth delays and cell cycle changes of a human melanoma xenograft.

We have reported previously that, in a human melanoma xenograft line, plating efficiency and drug sensitivity in vitro were enhanced under hypoxic conditions. In the present study, we show that the in vitro chemosensitivity data using clonogenic assays at 5% oxygen also correlate better with the drug-induced in vivo growth delay. Tumors implanted in bilaterally symmetrical locations grew at different rates, and response to chemotherapy was also variable. Cell cycle changes in the xenograft, as monitored by flow cytometry, suggest that major changes in cell cycle traverse occur when a drug is active in vitro and also causes in vivo growth delay. These studies indicate the usefulness of the nude mouse human xenografts to study correlations between soft agar clonogenic assays, in vivo growth delay, and cell cycle traverse in response to chemotherapeutic manipulation.

Animals↗
PubMed1982

Tubulin as a major cell surface protein in human lymphoid cells of leukemic origin.

Surface-exposed proteins of vinblastine-sensitive human lymphoid cell line of leukemic origin (CCRF-CEM) were examined by the lactoperoxidase-catalyzed iodination and two-dimensional polyacrylamide gel electrophoresis methods. Spots which comigrate with bovine brain tubulin and rabbit muscle actin were prominently labeled in the whole membrane but not in the high-speed supernatant fraction of the disrupted cells. Mild trypsinization of labeled cells removed the iodinated tubulin and actin without significantly affecting the protein staining pattern. Iodination of normal human lymphocytes resulted in no labeling of the tubulin or actin. The presence of surface-exposed tubulin in this leukemic cell line suggests a possible mechanism for their enhanced sensitivity to the cytotoxic action of vinblastine.

Cell Line↗
PubMed1982

Intracellular adriamycin levels and cytotoxicity in adriamycin-sensitive and adriamycin-resistant P388 mouse leukemia cells.

Adriamycin (ADR) (NSC-123127) uptake and retention in ADR-sensitive P388 leukemia (P388/S) and ADR-resistant P388 leukemia (p388/R) cells were compared by fluorometry and laser flow cytometry (FCM) and were correlated with cytotoxic effects. Drug levels in P388/R cells treated in vitro with ADR (1-10 micrograms/ml) were twofold to fourfold lower than were levels in similarly treated P388/S cells FCM analysis of P388/S and P388/R cells exposed in vitro to ADR showed qualitative and quantitative differences in ADR fluorescence profiles of drug-treated cells (1-5 micrograms/ml) but not of the isolated nuclei (0.5- 10 micrograms/ml). Drug-induced perturbations in cell cycle traverse and chromosome aberrations were seen in P388/S but not in P388/R cells treated with 0.5-5 micrograms ADR/ml in vitro or 4-8 mg ADR/kg in vivo. The role of FCM in rapidly comparing and quantitating cellular ADR fluorescence profiles of ADR-sensitive and ADR-resistant tumors was demonstrated.

Animals↗
PubMed1982

Effect of oxygen concentration on the growth and drug sensitivity of human melanoma cells in soft-agar clonogenic assay.

Tumor cells from a human melanoma xenograft show better colony growth and plating efficiency in soft agar when incubated in a 5% O2 atmosphere that at a higher concentration of 20% O2. Exposure to low drug concentrations under a 20% (but not 5%) O2 atmosphere stimulated plating efficiency. Enhanced sensitivity (4- to 20-fold) to a variety of chemotherapeutic agents was seen in cells incubated under low but not the higher O2 concentration. These studies suggest the important role of O2 concentration in tumor colony growth, plating efficiency, and drug cytotoxicity for human solid tumors in vitro.

Agar↗
PubMed1981

Comparative effects of adriamycin and N-trifluoroacetyladriamycin-14-valerate on cell kinetics, chromosomal damage, and macromolecular synthesis in vitro.

N-Trifluoroacetyladriamycin-14-valerate differs from Adriamycin in its rapid intracellular transport and lack of fluorescent binding to nuclei or chromosomes. Both of these anthracyclines cause inhibition in the incorporation of labeled precursors into nucleic acids, extensive chromosomal damage, and arrest of cell cycle traverse in G2. In human lymphoid cells, N-trifluoroacetyladriamycin-14-valerate, unlike Adriamycin, does not show cell cycle phase-specific or proliferation-related cytotoxic effects. In an L1210 soft-agar assay, both Adriamycin and N-trifluoroacetyladriamycin-14-valerate show no enhanced sensitivity of mid-S-phase cells to their cytotoxic action.

Animals↗
PubMed1981

DNA replication of X-irradiated human lymphocytes.

Human peripheral blood lymphocytes are well-differentiated cells. Ordinarily, they do not divide and are considered to be in the G0 stage of the cell cycle. These cells can be stimulated to undergo DNA replication in culture by mitogens such as phytohemagglutinin. In the present study, we have examined cellular and biochemical events that occur after exposure of lymphocytes to X-irradiation. Irradiation with up to 100 rads, prior to stimulation with phytohemagglutinin, did not interfere with DNA replication. At later periods, DNA replication was inhibited proportionally to the amount of radiation. In comparison to DNA synthesis, the effect of X-irradiation on RNA and protein synthesis in phytohemagglutinin-stimulated lymphocytes was less marked. Furthermore, X-rays did not inhibit either the induction or the continual synthesis of DNA polymerase-alpha or -beta in response to phytohemagglutinin. Kinetic studies with different nucleotide substrates suggest that cellular pools of nucleotides are not significantly altered by X-irradiation. Thus, the inhibition of DNA synthesis in irradiated cells is likely to be due to damage to the cellular DNA template. The inhibition of DNA synthesis was accompanied by accumulation of cells in the G2 and M stages of the cell cycle, suggesting that inhibition of DNA replication by X-irradiation is a postmitotic event.

Cell Cycle↗
PubMed1980

Laser flow cytometric studies on the intracellular fluorescence of anthracyclines.

We have used a laser flow cytometer to excite and quantitate the intracellular fluorescence of cells exposed in vitro and in vivo to various anthracyclines. In cells exposed to Adriamycin (ADR), intracellular drug fluorescence appeared slowly and reached a peak after 4 hr of incubation. Cells incubated with 10 micrograms/ml were 5 times more fluorescent than were cells incubated with 1 microgram/ml. Cells exposed to daunomycin were 2 to 4 times more fluorescent than were cells similarly exposed to ADR, and the intracellular appearance of daunomycin fluorescence was much more rapid. Cells exposed to N-trifluoroacetyladriamycin and carminomycin had higher amounts of intracellular fluorescence (2 to 4 times), and peak values were reached much more rapidly than in cells exposed to ADR. In cells exposed to rubidazone, fluorescence increased 2- to 4-fold with increased drug concentration and length of exposure. In contrast, nogalamycin fluorescence reached a peak after 60 min of incubation, and a 10-fold increase in drug concentration increased fluorescence only 2-fold. In animals given injections of ADR (4 mg/kg) and sacrificed after 3 hr, drug fluorescence could be detected in tumor and spleen cells. In contrast, fluorescence in heart nuclei was barely recognizable. However, incubation of isolated nuclei in ADR (1 microgram/ml) showed that bone marrow and heart nuclei had greater amounts of ADR fluorescence (2- to 3-fold) than did spleen or liver nuclei similarly treated. The use of laser flow cytometry for monitoring intracellular anthracycline transport, binding, and efflux is demonstrated.

Antibiotics, Antineoplastic↗
PubMed1980

Effect of 2,3-dihydro-1 H-imidazo[1,2-b]pyrazole on the proliferation of mouse leukemic and normal cells in vivo.

Administration of 2,3-dihydro-1 H-imidazo[1,2-b]pyrazole (IMPY; NSC 51143), 250 to 500 mg/kg, in Day 5 L1210 and P388 (ascites) tumor-bearing mice did not consistently prolong the life span of tumor-bearing animals. Flow cytometry and autoradiographic studies showed that, after 12 to 18 hr of a single IMPY injection, both P388 and L1210 tumor cells were synchronized in S phase. In contrast, IMPY inhibited cellular proliferation in both bone marrow and duodenal crypts during the first 24 hr. and a recovery was detectable only after 36 hr, returning to pretherapy values by 72 hr. Preliminary data indicate that this differential response of normal versus tumor cells to IMPY can be exploited to maximize chemotherapeutic efficacy in scheduled chemotherapy with cycle-specific agents.

Animals↗
PubMed1980

Effect of cholesterol content on antitumor activity and toxicity of liposome-encapsulated 1-beta-D-arabinofuranosylcytosine in vivo.

1-beta-D-Arabinofuranosylcytosine (ara-C) was encapsulated in anionic multilamellar liposomes prepared with different lecithin: cholesterol (L:C) ratios. The chemotherapeutic activity of encapsulated ara-C was compared with comparable doses of ara-C in 0.85% saline solution (single- and multiple-dose schedules) in mice bearing L1210 (i.p.) leukemia. Maximum survival was obtained in animals given injections of ara-C (40 mg/kg) encapsulated in liposomes with a L:C ratio of 1:1. The effect of L:C ratio on survival was not pronounced in multiple-dose schedules. Multiple doses (every 4.5 hr for 3 separate injections) of 40 mg/kg with L:C ratios of 1:1 and 1:0.5 were toxic, resulting in 83 and 50% mortality, respectively, of mice by Day 7. This study shows that drug efflux and in vivo antitumor activity and toxicity of encapsulated ara-C is influenced by the cholesterol content of the liposomal lipid bilayer.

Animals↗