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At least 19 recordsLinked to original sources
PubMed1988

Effects of U-71,184 and several other CC-1065 analogues on cell survival and cell cycle of Chinese hamster ovary cells.

CC-1065 is a very potent antitumor antibiotic which selectively binds in the minor groove of DNA with alkylation at N-3 of adenine. Since therapeutic doses of CC-1065 caused delayed deaths in mice, analogues were synthesized, some of which had significant antitumor activity. The effects of several of these analogues on inhibition of CHO cell survival, cell progression, and their phase-specific toxicity are reported. CC-1065, U-66,664, U-66,819, U-66,694, and U-71,184 all have a left hand segment with an intact cyclopropyl group but have different tail segments. Lethality of these compounds after 2 h drug exposure was in the following order (50% lethal dose in nM in parentheses): CC-1065 (0.06) greater than U-71,184 (1.3) greater than U-66,694 (3.2) greater than U-68,819 (171) greater than U-66,664 (greater than 1200). In general, these compounds did not inhibit progression from G1 to S but slowed progression through S and blocked cells in G2-M. The phase-specific toxicity of U-71,184 and U-66,694 was different from that of CC-1065. CC-1065 was most cytotoxic to cells in M and early G1 and toxicity decreased as cells entered late G1 and S. In contrast, U-66,694 and U-71,184 were most toxic to cells in late G1. The biochemical and cellular effects of U-71,184 were then studied in detail since it was the most active among these analogues. After a 2-h exposure to 3 ng/ml U-71,184, 90% cell kill or growth inhibition was observed whereas 100 ng/ml was needed for similar inhibition of DNA and RNA synthesis. This discrepancy between the doses suggested that inhibition of nucleic acid synthesis may not be causally related to lethality. Further studies showed that when drug was removed after 2 h exposure, DNA synthesis continued to be inhibited whereas RNA and protein synthesis reached levels higher than the control. Therefore, it is likely that at cytotoxic doses the low level of inhibition of DNA synthesis combined with the stimulation of RNA and protein synthesis leads to unbalanced growth and cell death.

Animals↗
PubMed1975

The effect of an hypoxic cell sensitizer on tumour growth delay and cell survival. Implications for cell survival in situ and in vitro.

A comparison has been made of the effects of the 2-nitroimidazole Ro-07-0582 on tumour growth delay after irradiation and tumour cell survival in vitro after irradiation in vivo. This compound has previously been shown to be a specific sensitizer of hypoxic cells. A dose of 1 mg/g body weight gave an enhancement ratio of 2-2 for both growth delay and cell survival in a system where high pressure oxygen has been shown to have no effect. However, while the hypoxic fraction in the tumour was estimated to be less then 10% from the growth delay curves, the survival curves gave a value in excess of 50%. This discrepancy probably reflects differences in the response of cells left in situ or removed and assayed in vitro.

Animals↗
PubMed1978

Effects of chartreusin on cell survival and cell cycle progression.

Chartreusin was lethal to both L1210 and P388 cells in culture with 90% of the cells being killed after a 24-hr exposure to 1.1 and 2.6 microgram/ml, respectively. The lethality of the drug increased in direct proportion to dose and exposure time. Both L1210 and Chinese hamster ovary cells in S phase were more sensitive to the lethality of the drug than were their corresponding non-S-phase cells. L1210 cells were partially synchronized by exposing an asynchronous culture to [methyl-3H]thymidine (20 Ci/mmol) and Colcemid for 3 hr. Synchronous culture of Chinese hamster ovary cells was established by planting mitotic cells. The progression of cells through the cell cycle was studied with flow microfluorometry both in the presence of the drug and after the drug had been washed off. In the presence of chartreusin the progression of mitotic cells into G1 was not affected. The movement of G1 cells into S was slower, and the movement of G2 cells into mitosis was blocked. When the drug was removed, the G2 to M block persisted for at least 4 hr but the progression of G1 cells to S was no longer inhibited.

Animals↗
PubMed1992

Social controls on cell survival and cell death.

Programmed cell death occurs in most animal tissues at some stage of their development, but the molecular mechanism by which it is executed is unknown. For some mammalian cells, programmed death seems to occur by default unless suppressed by signals from other cells. Such dependence on specific survival signals provides a simple way to eliminate misplaced cells, for regulating cell numbers and, perhaps, for selecting the fittest cells. But how general is this dependence on survival signals?

Animals↗
PubMed1978

In situ lymphoid cells of mouse mammary tumors. III. In vitro stimulation of tumor cell survival by lymphoid cells separated from mammary tumors.

Lymphoid cells were isolated by isokinetic gradient centrifugation from mouse mammary tumors and evaluated for their ability to affect tumor cell survival with the microcytotoxicity assay. In all experiments stimulation of the growth or survival of tumor cells was seen. This stimulation was not seen with separated lymphoid cells treated with anti-lymphocyte serum and complement. The lymphoid cells separated from tumors were more stimulatory than were lymph node cells; even toxic to the tumor cells, the separated tumor-associated lymphoid cells were markedly stimulatory. The gradient procedure had no effect on the activity of sensitized lymph node cells, but it did separate cytotoxicity and stimulation into different fractions.

Animals↗
PubMed1989

Sister-chromatid exchanges (SCEs), cell survival and mutation in HeLa s3 cells with different sensitivity to alkylating agents; evidence that SCE induction and cell survival or mutation induction are dissociable.

We previously isolated N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-resistant cells, MR from HeLa S3 Mer- cells. In the present study, we have isolated 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant cells, ACr. The MR cells had only a little O6-methylguanine-DNA methyltransferase (MT) activity, while the ACr cells had increased MT activity and also became resistant to the cytotoxic effect of MNNG. We compared the induction of sister-chromatid exchanges (SCEs), cell survival and mutation in these HeLa S3 cells with different sensitivity to MNNG. The ACr cells were much more resistant than the parental HeLa S3 Mer- cells to cytotoxicity, mutagenicity and SCE induction by MNNG, showing a positive correlation between SCE induction and cell killing or mutation. In contrast, this positive relationship was not observed between HeLa S3 Mer- and MR cells. These results suggest that O6-methylguanine (O6-MeG) is involved in the induction of the biological effects of MNNG such as cytotoxicity, mutagenicity and SCEs, and also indicate that SCE induction does not always correlate with cell killing and mutation.

Alkylating Agents↗
PubMed1992

The RBE-LET relationship for rodent intestinal crypt cell survival, testes weight loss, and multicellular spheroid cell survival after heavy-ion irradiation.

This report presents data for survival of mouse intestinal crypt cells, mouse testes weight loss as an indicator of survival of spermatogonial stem cells, and survival of rat 9L spheroid cells after irradiation in the plateau region of unmodified particle beams ranging in mass from 4He to 139La. The LET values range from 1.6 to 953 keV/microns. These studies examine the RBE-LET relationship for two normal tissues and for an in vitro tissue model, multicellular spheroids. When the RBE values are plotted as a function of LET, the resulting curve is characterized by a region in which RBE increases with LET, a peak RBE at an LET value of 100 keV/microns, and a region of decreasing RBE at LETs greater than 100 keV/microns. Inactivation cross sections (sigma) for these three biological systems have been calculated from the exponential terminal slope of the dose-response relationship for each ion. For this determination the dose is expressed as particle fluence and the parameter sigma indicates effect per particle. A plot of sigma versus LET shows that the curve for testes weight loss is shifted to the left, indicating greater radiosensitivity at lower LETs than for crypt cell and spheroid cell survival. The curves for cross section versus LET for all three model systems show similar characteristics with a relatively linear portion below 100 keV/microns and a region of lessened slope in the LET range above 100 keV/microns for testes and spheroids. The data indicate that the effectiveness per particle increases as a function of LET and, to a limited extent, Z, at LET values greater than 100 keV/microns. Previously published results for spread Bragg peaks are also summarized, and they suggest that RBE is dependent on both the LET and the Z of the particle.

Animals↗
PubMed1978

Irreversibly sickled cells and red cell survival in sickle cell anemia: a study with both DF32P and 51CR.

For 25 subjects with sickle cell anemia the mean red cell life span measured with Di-isopropylfluorophosphite-32P (DF32P) was 17.32 +/- 4.51 days. Performed simultaneously, the half life (T1/2 of radioactively-labelled chromium 51Cr) was 10.11 +/- 2.82 days (14 subjects). Eight additional subjects, or more than 30 per cent of those studied using both red cell tags, had 51Cr red cell survival curves better described by two exponents than by one, apparently due to two different rates of 51Cr elution from the red cells. This finding limits the value of quantitative data obtained by this procedure. A negative correlation was found between the mean red cell life span measured with DF32P-tagged cells and the proportion of irreversibly sickled cells in venous or capillary blood. A similar negative correlation was found between the red cell half survival time measured with 51Cr-tagged cells and the proportion of irreversibly sickled cells. These data are compatible with the view that repeated sickling and, in particular, the formation of irreversibly sickled cells play a distinct role in the pathogenesis of hemolysis in sickle cell anemia.

Anemia, Sickle Cell↗
PubMed1990

Effects of variation in glutathione peroxidase activity on DNA damage and cell survival in human cells exposed to hydrogen peroxide and t-butyl hydroperoxide.

The selenium-dependent glutathione peroxidase activities of two human cell lines, the colon carcinoma HT29 and the mesothelioma P31, cultured in medium containing 2% serum, increased from 195 to 541 and from 94 to 361 units/mg of protein respectively after supplementation with 100 nM-selenite. The catalase activity remained unchanged by this treatment. The effects of the obtained variation in glutathione peroxidase activities were investigated by exposing cells to H2O2 and t-butyl hydroperoxide. Selenite supplementation resulted in a decrease in H2O2-induced DNA single-strand breaks in both HT29 and P31 cells. A small, but significant, decrease in the number of DNA single-strand breaks for low doses (10-50 microM) of t-butyl hydroperoxide was found only in P31 cells and not in HT29 cells. We could detect neither induction of double-strand breaks (detection limit approx. 1000 breaks per cell) nor DNA-protein cross-links after exposing the cells to the two peroxides. In spite of the apparent protective effect of increased glutathione peroxidase activity on DNA single-strand break formation, there were no differences between selenite-supplemented and non-supplemented cells in cell survival after exposure to peroxide.

Catalase↗
PubMed1991

Criteria and techniques for analysing cell survival data.

Cell survival was studied by analyzing the inactivation probability density function and its fundamental parameters. Mean D, variance sigma 2 and mode Dmode were evaluated and a set of equations relating these parameters to the usual parameters of the multitarget, multihit and linear-quadratic models Do and n, alpha and beta, kappa and lambda are reported. The multihit equation used was an extension of the usual equation, to allow parameter kappa to assume values that are not necessarily integers. In the multitarget curve, the mode of inactivation probability density function, proved to be the quasi-threshold dose Dq = Do ln(n). Relative variance, degree of asymmetry and degree of peakedness can be calculated from the shape parameters n in the multitarget model, kappa in the multihit model, and alpha/square root of beta in the linear-quadratic model. From an analysis of eight published cell survival sets of data, on C3H10T1/2 cells exposed to low LET radiations, it was found that D, sigma, and SF2 are the parameters which exhibit the least variation from experiment to experiment and the least variation in selecting the range of data available for estimation.

Analysis of Variance↗
PubMed1991

Ethanol potentiates doxorubicin-induced inhibition of cell survival in cultured Chinese hamster ovary cells.

Doxorubicin is an antineoplastic drug which undergoes oxidation-reduction cycling and produces toxicity to some cancer cell lines. Since oxidation-reduction cycling requires reducing equivalents and because ethanol metabolism via alcohol dehydrogenase (ADH) increases NADH, the effect of ethanol on doxorubicin toxicity was examined in cultured cells. Since some cells exhibit resistance to anthracyclines such as doxorubicin, two different Chinese hamster ovary cell lines were used, one sensitive (AUX B1) and one resistant (CHRC5) to doxorubicin. Studies were designed to determine if ethanol could decrease resistance to doxorubicin. Cells were treated for 24 h with doxorubicin in the presence or absence of ethanol, and the number of live cells was estimated spectrophotometrically. Ethanol (60-150 mM) potentiated the doxorubicin-induced decrease in cell number in both cell lines. In AUX B1 cells the concentration of doxorubicin required for half-maximal inhibition of cell survival was reduced 20-fold by ethanol, and a completely nontoxic concentration of doxorubicin decreased the number of surviving cells to 30% in the presence of ethanol. Addition of ethanol to the medium also increased doxorubicin-induced inhibition of cell survival in CHRC5 cells, but the effect was less dramatic than in AUX B1 cells. The effect of ethanol on cell number was concentration related; the half-maximal response was observed with about 1 mM ethanol. The hypothesis that ethanol potentiates doxorubicin toxicity by generation of NADH during metabolism by ADH was strengthened by the observations that both cell lines possess ADH activity (30-400 units/10(12) cells) and that ethanol (0.1-0.5 mM) increased NADH fluorescence 15-80% over basal values in cultured cells. Further, the effect of doxorubicin on cell number was also potentiated by another substrate for ADH, 2-ethylhexanol. Desferrioxamine, an iron chelator, increased survival in cells treated with doxorubicin plus ethanol by up to 60% (half-maximal effect, 1 mM), and (+)-catechin, a radical scavenger, abolished the decrease in cell number due to doxorubicin plus ethanol at concentrations greater than 0.1 mM. Allopurinol, an inhibitor of xanthine oxidase with radical scavenging properties, diminished the effect of doxorubicin plus ethanol on cell number by 60% (P less than 0.05). Taken together, these data are consistent with the hypothesis that ethanol potentiates toxicity due to doxorubicin by providing reducing equivalents for oxidation-reduction cycling which produce toxic reduced oxygen species.

Alcohol Dehydrogenase↗
PubMed1990

Relationship between pyrimidine dimers, 6-4 photoproducts, repair synthesis and cell survival: studies using cells from patients with trichothiodystrophy.

Trichothiodystrophy is a genetic disease which in the majority of cases studied is associated with a deficiency in the ability to repair UV damage in cellular DNA. Three categories of UV response have been identified. In type 1 the response is completely normal, whereas type 2 cells are deficient in excision-repair, with properties indistinguishable from those of XP complementation group D. Type 3 cells have normal survival following UV-irradiation and normal rates of removal of cyclobutane pyrimidine dimer sites. Nevertheless repair synthesis is reduced by 50% in these cell strains and this is associated with a marked reduction in the repair of 6-4 photoproducts from cellular DNA. The present results show that 50% or more of repair synthesis at early times after irradiation of normal primary human fibroblasts is attributable to repair of 6-4 products. They also suggest that repair of cyclobutane dimers is crucial for cell survival.

Cell Survival↗
PubMed1985

Effects of 9-OH-ellipticine on cell survival, macromolecular syntheses, and cell cycle progression in sensitive and resistant Chinese hamster lung cells.

In an effort to understand the mechanism of action of the DNA-intercalating antitumor agent 9-hydroxyellipticine (9-OH-E), we have examined the effects of this drug on the cell survival, macromolecular syntheses, and cell cycle progression in sensitive and resistant cells. Our results show that 9-OH-E toxicity on sensitive and resistant cells involves different mechanisms of action: the drug toxicity in the sensitive cells appears to result from lethal lesions mediated through the interaction of the drug with an intracellular protein, independently of any effect of the drug on the macromolecular syntheses; in the resistant cells, the cell death occurs concomitantly with the inhibition of these syntheses. Cell cycle progression analysis after 9-OH-E treatment showed that, in the sensitive cells, the drug is inducing a G1 and a G2 block, which are both released in the presence of 1 mM caffeine, without any effect on the 9-OH-E toxicity. In the resistant cells, a G2 block was also observed but only when the cells were resuming their growth after about a 30- to 40-h growth arrest. Caffeine release of this block, which again had no effect on 9-OH-E toxicity, was only observed when it was added from 40 to 60 h after 9-OH-E treatment, when the cells resumed their growth. Finally in the sensitive cells, cycloheximide exerted an inhibitory effect on 9-OH-E toxicity when it was added before and during the cell exposure to the drug. This effect was interpreted as indicating that 9-OH-E toxicity in the sensitive cells relies on a protein which is not induced by the drug but has to be present in the cells when the drug is added. The possible implication of DNA topoisomerases in 9-OH-E toxicity mechanism is discussed.

Alkaloids↗
PubMed1989

Radiation damage to glucose concentrating capacity and cell survival in kidney tubule cells: effects of fractionation.

The glucose concentrating capacity of cultured LLC-PK1 kidney epithelial cells has been measured after single and fractionated doses of X-rays. Steady-state glucose concentrating capacity (ratio of glucose concentration inside to outside cell) can be measured using radiolabelled analogues of glucose which are actively transported but not metabolized. These cells can be stimulated to increase their glucose concentrating capacity (up-regulation) by a reduction in the glucose concentration of the growth medium. However, after X-ray irradiation the cells have a reduced capacity to respond to up-regulation. This effect can be measured 7 days after irradiation and before radiation-induced cell killing affects the cell population. The previously reported radiosensitivity of this function to single doses of X-rays (in the range 1-16 Gy) was confirmed. Surprisingly, no significant sparing of this effect could be measured by fractionation of the X-ray dose into two or four fractions. However, the cells showed a significant fractionation effect if clonogenic survival was measured using the standard cell survival assay. These early effects have different fractionation response from the later phases of tissue damage, measured months to years after irradiation, which do show sparing due to fractionation and are thought to be mainly due to changes in cell survival. The lack of sparing by fractionation to the functional damage may suggest a different target from that which determines cell survival. These results support the hypothesis that radiation damages cellular functions, separately from cell replication.

Biological Transport↗
PubMed1990

Dose-rate dependent stochastic effects in radiation cell-survival models.

When cells are subjected to ionizing radiation the specific energy rate (microscopic analog of dose-rate) varies from cell to cell. Within one cell, this rate fluctuates during the course of time; a crossing of a sensitive cellular site by a high energy charged particle produces many ionizations almost simultaneously, but during the interval between events no ionizations occur. In any cell-survival model one can incorporate the effect of such fluctuations without changing the basic biological assumptions. Using stochastic differential equations and Monte Carlo methods to take into account stochastic effects we calculated the dose-survival relationships in a number of current cell survival models. Some of the models assume quadratic misrepair; others assume saturable repair enzyme systems. It was found that a significant effect of random fluctuations is to decrease the theoretically predicted amount of dose-rate sparing. In the limit of low dose-rates neglecting the stochastic nature of specific energy rates often leads to qualitatively misleading results by overestimating the surviving fraction drastically. In the opposite limit of acute irradiation, analyzing the fluctuations in rates merely amounts to analyzing fluctuations in total specific energy via the usual microdosimetric specific energy distribution function, and neglecting fluctuations usually underestimates the surviving fraction. The MOnte Carlo methods interpolate systematically between the low dose-rate and high dose-rate limits. As in other approaches, the slope of the survival curve at low dose-rates is virtually independent of dose and equals the initial slope of the survival curve for acute radiation.

Cell Survival↗
PubMed1978

Excision of hydrocarbon-DNA adducts and consequent cell survival in normal and repair defective human cells.

Survival curves for normal human cells and xeroderma pigmentosum variant cells (XP4BE) after ultraviolet radiation were indistinguishable. In comparison, cells from xeroderma pigmentosum complementation group A (XP12BE) were very sensitive to ultraviolet radiation. Complementation group C (XP2BE) cells were almost as sensitive as group A cells. These survival phenomena parallel to known unscheduled DNA synthesis responses of these cells to ultraviolet radiation, which, compared with normal cells, are: XP4BE, 100%; XP2BE, 20%; XP12BE, 2%. The relative capacities of these cells to excise 7-bromomethylbenz[a]anthracene-DNA adducts and to survive treatment with the carcinogen were similar to the responses to ultraviolet irradiation, except that the XP2BE cell line both excised and survived this damage far better than anticipated from its response to ultraviolet irradiation. Moreover, whilst in the normal cells and variant cells the ratio of hydrocarbon-adenine adduct to hydrocarbon-guanine adduct remaining in DNA decreased notably with excision, this ratio did not change significantly with excision in the XP2BE cell line. The relationship between greater excision capacity and increased cell survival in the experiments with the chemical carcinogen indicates that the unexcised damage is responsible for the cell-killing action of this agent. The different relative repair and survival responses of these cell lines to ultraviolet irradiation on the one hand, and to 7-bromomethylbenz[a]anthracene chemical carcinogen treatment on the other, indicate that in at least one of these cell lines (XP2BE), and possibly in all the lines, different cellular mechanisms are involved in the repair of DNA damage resulting from ultraviolet irradiation and that resulting from the chemical carcinogen treatment.

Benz(a)Anthracenes↗