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PubMedDate not supplied

Analysis of cellular sensitization with cisplatin-induced apoptosis by glucose-starved stress in cisplatin-sensitive and -resistant A431 cell line.

BACKGROUND: Most solid tumors show resistance to current chemotherapy. This drug resistance can be associated with stress conditions, such as glucose starvation, low pH and hypoxia. These conditions are not observed in normal tissues. These tumor specific conditions commonly cause the glucose-regulated stress response of cancer cells. This stress response leads to induction of resistance to multiple anticancer drugs, such as etoposide, doxorubicin, camptothecin and vincristine. An examination was made of the effect of the glucose-regulated protein (GRP)-inducing conditions on cellular sensitivity to cisplatin (CDDP), which is a widely used drug against solid tumors. MATERIALS AND METHODS: We used CDDP resistant subline A431/CDDP2 from human epidermoid carcinoma cell line A431 as previously established. Glucose-starved response showed GRP78 protein by Western blotting. We generated the glucose-starved condition by exposing cells to 2-deoxyglucose (2-DG) and examined cellular sensitivity to CDDP. We next examined CDDP induced apoptosis in glucose-starved condition. Furthermore, we determined the JNK1/SAPK and caspase-3 protein levels by Western blotting. RESULTS: The glucose-starved condition was up-regulate GRP78 in the parent A431 cell (A431/P). On the other hand, in A431/CDDP2, GRP78 levels were not changed. The GRP78 inducing stress condition led to cellular sensitization to CDDP in A431/P cells only. DNA fragmentation of A431/P treated with 2-DG increased CDDP-induced apoptosis. A431/CDDP2 was not different with CDDP induced apoptosis in glucose-starved stress condition. The reduction of CDDP-induced apoptosis under glucose-starved stress condition was influenced by JNK1/SAPK and caspase-3 proteins. CONCLUSION: These results indicated that the glucose-starved stress condition was associated with increased sensitivity to CDDP in the up-regulated GRP78 cells. Furthermore, the reduction of CDDP-induced apoptosis can be considered as one of the CDDP resistant mechanisms in a glucose-starvation condition.

Antimetabolites↗
PubMed2001

Effects of Ca2+ sensitizers on contraction, [Ca2+]i transient and myofilament Ca2+ sensitivity in diabetic rat myocardium: potential usefulness as inotropic agents.

The purpose of the present study was to investigate the effects of Ca2+ sensitizers EMD 57033, MCI-154, and EGIS-9377 in cardiac preparations from streptozotocin-induced diabetic rats. In enzymatically dissociated ventricular myocytes loaded with the Ca2+ probe indo 1, these Ca2+ sensitizers caused an increase in cell shortening without a significant effect on the intracellular Ca2+ ([Ca2+]i) transient. The contractile responses were substantially similar in myocytes from diabetic and age-matched control rats. In contrast, the contractile and [Ca2+]i responses to pimobendan and isoproterenol were significantly less in diabetic myocytes. The Ca2+ sensitivity of tension in beta-escin-skinned trabeculae from diabetic hearts was not significantly different from that of controls. The effect of EMD 57033 on myofilament responsiveness to Ca2+ was identical in control and diabetic preparations. The slower time course of relaxation observed in diabetic papillary muscles was further prolonged in the presence of EMD 57033. However, the extent of the increase in relaxation produced by EMD 57033 did not differ between control and diabetic muscles, and the detrimental effect on resting tension was less pronounced in the two groups. In anesthetized rats, echocardiography showed that intra-duodenal administration of EMD 57033 increased left ventricular systolic function without affecting variables of diastolic filling in both groups. Taken together, the present results suggest that Ca2+ sensitizers, unlike conventional inotropic agents, have the potential to increase in force of contraction to the same extent in nondiabetic and diabetic myocardium, possibly without exaggerating extremely the impairment of diastolic function in diabetes.

Actin Cytoskeleton↗
PubMed2000

Effect of MCI-154, a calcium sensitizer, on calcium sensitivity of myocardial contractile system in endotoxemic rats.

AIM: To investigate the effect of MCI-154 on calcium sensitivity of myocardial contractile system in endotoxemic rats. METHODS: Skinned right ventricular papillary muscles from endotoxemic rats were prepared by saponin 500 mg/L. Forces of the skinned muscles were recorded when they were activated sequentially by different concentrations of Ca2+ with or without cardiotonic agents. The tension-pCa relationship and pCa50 of the skinned fibers were taken as the index of Ca2+ sensitivity of myocardial contractile system. RESULTS: The maximal Ca(2+)-activated tension (Tmax) was lower, and pCa50 was reduced in endotoxemia group as compared with those in sham control group. Milrinone 50 mumol/L could not counteract the above abnormalities. However, after MCI-154 10 mumol/L was added, the Tmax and pCa50 were increased to an extent similar to that of sham control group and significantly higher than those of endotoxemia group and endotoxemia + milrinone group. Furthermore, such effects of MCI-154 were concentration-dependent. CONCLUSION: The Ca2+ sensitivity of cardiac contractile system in endotoxemic rats is decreased. MCI-154 can reverse the decreased sensitivity and increase Tmax of myocardial muscles from endotoxemic rats.

Animals↗
PubMed2002

The dual AngII/AVP receptor gene N119S/C163R variant exhibits sodium-induced dysfunction and cosegregates with salt-sensitive hypertension in the Dahl salt-sensitive hypertensive rat model.

BACKGROUND: Essential hypertension is a prevalent complex polygenic disease and a major risk factor for cardiovascular disease, the leading cause of death in developed countries. Because of its complex and multifactorial nature, its genetic determinants still remain largely unknown. The Dahl salt-sensitive hypertensive rat model exhibits impaired sodium handling, which is hypothesized to play a key role in the pathophysiology of polygenic hypertension. Thus, genes associated with renal regulation of salt and water balance are a priori likely candidates for a causative role in hypertension pathogenesis. The functional properties and renal-specific expression of the recently characterized AngII/AVP receptor suggest a putative modulator role in tubular sodium and fluid reabsorption. Based on these observations, we investigated the potential involvement of the AngII/AVP receptor in salt-sensitive hypertension. MATERIALS AND METHODS: We performed cosegregation analysis of the AngII/AVP receptor locus with salt-sensitive hypertension in an F2 (Dahl S X Dahl salt-resistant [R]) hybrid male cohort characterized for blood pressure by radiotelemetry after 8 weeks of high salt challenge. Further molecular analysis was done to identify putative AngII/AVP receptor molecular variants that could account for the AngII/ AVP receptor involvement in salt-sensitive hypertension pathogenesis. RESULTS: The AngII/AVP receptor was mapped to rat chromosome 1, 1.7 cM centromeric to the D1Rat188 marker by radiation hybrid mapping analysis. Quantitative trait locus (QTL) analysis detected a highly significant linkage of the AngII/AVP receptor locus with high blood pressure (LRS = 13.8, p= 0.0002). Molecular characterization of the Dahl S and Dahl R AngII/AVP receptor cDNAs revealed two amino acid substitutions in the Dahl S AngII/AVP receptor (N119S, C163R) when compared to the Dahl R AngII/AVP receptor. These mutations are associated with an increased receptor affinity for both ligands (AVP and AngII) and an enhanced G(s)-coupling by the receptor resulting in increased activation of adenylate cyclase with concomitant increase in cAMP production. CONCLUSIONS: The observed molecular dysfunction in the Dahl S AngII/AVP receptor is consistent with increased tubular sodium and fluid reabsorption observed in Dahl S rats. Interestingly, the AngII/AVPr locus is within the narrowed chromosome 1 QTL region for blood pressure detected in different rat intercross linkage analyses. Altogether, the data strongly suggest that the AngII/AVP receptor is a hypertension susceptibility gene in the Dahl S rat model, as well as raises the hypothesis that it too underlies the chromosome 1 blood pressure QTL identified in other hypertension rat models.

Allosteric Regulation↗
PubMed2003

[Thermo-sensitive period and critical temperature of fertility transition of thermo-photo-sensitive genic male sterile wheat].

The thermo-sensitive period and the critical temperature of fertility transition of C49S, a principal thermo-photosensitive genic male sterile line in two-line hybrid wheat, was studied in the growth chambers for controlling temperature and photoperiod. The seeds were sown on different time for some years. The results showed that the thermo-sensitive period in fertility expression of C49S was from PMC formation stage to mature pollen stage, and there were two most sensitive stages to temperature on fertility expression. One was the PMC meiosis stage, and the other was the middle microspore stage. The critical temperatures evoking a complete male sterility were the mean minimum temperature at PMC meiosis stage (Tmin1), the mean temperature at microspore stage (T2) and the mean minimum temperature at microspore stage (Tmin2) lower than 8.5 degrees C, 13.5 degrees C and 10.5 degrees C, respectively. The critical temperatures keeping a nearly normal male fertility Tmin1 and T2 and Tmin2 were higher than 11.5 degrees C, 15.0 degrees C and 12.5 degrees C, respectively. The value as well as the conditions and the risks of thermo-photo-sensitive genic male sterile line of wheat applied to hybrid wheat were evaluated in this paper.

Environment, Controlled↗
PubMedDate not supplied

Factors contributing to adriamycin sensitivity in human xenograft tumors: the relationship between expression of the MDR1, GST-pi and topoisomerase II genes and tumor sensitivity to adriamycin.

To study the factors contributing to tumor sensitivity to adriamycin (ADR) in vivo, the relationship between mRNA expression of the MDR1, GST-pi and topoisomerase II genes and tumor response to ADR was examined in six human xenograft tumors derived from two esophageal, two gastric and two colon cancers. A significant tumor response to ADR was observed in two esophageal xenograft tumors of six tumor lines, and one gastric tumor partially responded to ADR. mRNA expression of the MDR1 and GST-pi genes was elevated in five tumor lines including three ADR responsive tumors, whereas mRNA expression of the topoisomerase II gene was detected in all six tested tumor lines. Topoisomerase II mRNA expression levels in ADR responsive tumors were higher compared with those of ADR unresponsive tumors. No significant relationship between mRNA expression of the MDR1 and GST-pi genes and ADR sensitivity was found. In contrast, topoisomerase II mRNA expression was significantly correlated with tumor sensitivity to ADR (p less than 0.01). Moreover, topoisomerase II mRNA expression was significantly correlated with the growth fraction (S-phase fraction) in the cell cycle kinetics (p less than 0.01). These results indicate that topoisomerase II mRNA expression in association with the high growth fraction may be an important in vivo factor to contribute to ADR sensitivity in human tumors.

Animals↗
PubMed1992

Influence of the xanthine derivate HWA 138 on endotoxin-related coagulation disturbances: effects in non-sensitized vs D-galactosamine sensitized rats.

We have evaluated the effects of the xanthine derivate HWA 138 in rat endotoxemia in order to 1) prevent coagulation disturbances and other endotoxin-induced physiological abnormalities and 2) to reduce mortality. We performed two studies using two different models (sensitized vs non-sensitized rats) with a similar mortality but different severity of coagulation disturbances: a) LPS (15 mg/kg) alone or with HWA 138 (80 mg/kg) as a treatment modality 30 min pre LPS, b) galactosamine (500 mg/kg) simultaneously with LPS (100 micrograms/kg) with or without HWA 138 (80 mg/kg) pretreatment. Experiments c) and d) employed D-galactosamine and/or LPS similar to experiments a) and b), while HWA 138 was applied simultaneously. We found significant 1) amelioration of life-threatening coagulation disturbances in non-sensitized rats, 2) prevention of liver dysfunction in sensitized rats, 3) reduction of TNF formation in both models, and 4) improvement of survival in all groups receiving HWA 138. Our data indicate protective effects of HWA 138 against clotting disturbances either directly via reduced LPS-induced formation of procoagulant activity or indirectly via reduced TNF formation.

Animals↗
PubMed2003

Fast synaptic currents in Drosophila mushroom body Kenyon cells are mediated by alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors and picrotoxin-sensitive GABA receptors.

The mushroom bodies, bilaterally symmetric regions in the insect brain, play a critical role in olfactory associative learning. Genetic studies in Drosophila suggest that plasticity underlying acquisition and storage of memory occurs at synapses on the dendrites of mushroom body Kenyon cells (Dubnau et al., 2001). Additional exploration of the mechanisms governing synaptic plasticity contributing to these aspects of olfactory associative learning requires identification of the receptors that mediate fast synaptic transmission in Kenyon cells. To this end, we developed a culture system that supports the formation of excitatory and inhibitory synaptic connections between neurons harvested from the central brain region of late-stage Drosophila pupae. Mushroom body Kenyon cells are identified as small-diameter, green fluorescent protein-positive (GFP+) neurons in cultures from OK107-GAL4;UAS-GFP pupae. In GFP+ Kenyon cells, fast EPSCs are mediated by alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors (nAChRs). The miniature EPSCs have rapid rise and decay kinetics and a broad, positively skewed amplitude distribution. Fast IPSCs are mediated by picrotoxin-sensitive chloride conducting GABA receptors. The miniature IPSCs also have a rapid rate of rise and decay and a broad amplitude distribution. The vast majority of spontaneous synaptic currents in the cultured Kenyon cells are mediated byalpha-bungarotoxin-sensitive nAChRs or picrotoxin-sensitive GABA receptors. Therefore, these receptors are also likely to mediate synaptic transmission in Kenyon cells in vivo and to contribute to plasticity during olfactory associative learning.

Animals↗
PubMed2005

Sensitivity of primary R5 HTV-1 to inhibition by RANTES correlates with sensitivity to small-molecule R5 inhibitors.

In approximately 50% of HIV-1 subtype B-infected individuals, progression to AIDS is preceded by the emergence of CXCR4-using (X4) variants, whereas the rest progress to AIDS in the presence of CCR5-using (R5) variants only. In a previous study, we showed that during disease progression in the presence of R5 variants only, HIV-1 variants emerge with a decreased sensitivity to inhibition by RANTES, a natural ligand of CCR5 that inhibits cellular entry of R5 variants. This observation was of potential clinical relevance as HIV-1 small-molecule R5 entry inhibitors are a new class of drugs that, in analogy to RANTES, target the binding and subsequent entry of HIV into the target cell. Here we show that R5 HIV-1 sensitivity to RANTES correlates with sensitivity to the R5 small-molecule inhibitor AD101. HIV-1 small-molecule entry inhibitors are a new class of drugs that target the binding and subsequent entry of HIV into the target cell. Furthermore, we found that R5 variants obtained from individuals who later developed X4 variants were less sensitive to AD101 inhibition compared with R5 variants obtained from individuals who never developed X4 variants. These results may have implications for the evaluation of R5 inhibitors in future clinical trials.

CCR5 Receptor Antagonists↗
PubMed1991

Involvement of pertussis toxin-sensitive G-proteins in the hormonal inhibition of dihydropyridine-sensitive Ca2+ currents in an insulin-secreting cell line (RINm5F).

Adrenaline inhibits insulin secretion via pertussis toxin-sensitive mechanisms. Since voltage-dependent Ca2+ currents play a key role in insulin secretion, we examined whether adrenaline modulates voltage-dependent Ca2+ currents of the rat insulinoma cell line, RINm5F. In the whole-cell configuration of the patch-clamp technique, dihydropyridine- but not omega-conotoxin-sensitive Ca2+ currents were identified. Adrenaline via alpha 2-adrenoceptors inhibited the Ca2+ currents by about 50%. Somatostatin which also inhibits insulin secretion was less efficient (inhibition by 20%). The hormonal inhibition of Ca2+ currents was not affected by intracellularly applied cAMP but blocked by the intracellularly applied GDP analog guanosine 5'-O-(2-thiodiphosphate) and by pretreatment of cells with pertussis toxin. In contrast to adrenaline and somatostatin, galanin, another inhibitor of insulin secretion, reduced Ca2+ currents by about 40% in a pertussis toxin-insensitive manner. Immunoblot experiments performed with antibodies generated against synthetic peptides revealed that membranes of RINm5F cells possess four pertussis toxin-sensitive G-proteins including Gi1, Gi2, Go2, and another Go subtype, most likely representing Go1. In membranes of control but not of pertussis toxin-treated cells, adrenaline via alpha 2-adrenoceptors stimulated incorporation of the photo-reactive GTP analog [alpha-32P]GTP azidoanilide into pertussis toxin substrates comigrating with the alpha-subunits of Gi2, Go2, and the not further identified Go subtype. The present findings indicate that activated alpha 2-adrenoceptors of RINm5F cells interact with multiple G-proteins, i.e. two forms of Go and with Gi2. These G-proteins are likely to be involved in the adrenaline-induced inhibition of dihydropyridine-sensitive Ca2+ currents and in other signal transduction pathways contributing to the adrenaline-induced inhibition of insulin secretion.

Animals↗
PubMed1976

Repartition and drug sensitivity of dopamine and L-isoproterenol-sensitive adenylate cyclases in rat brain homogenates.

The characteristics of dopamine, 1-isoproterenol, and d-LSD stimulated adenylate cyclases were studied in homogenates of fresh or frozen tissues. In rat striatum, when the assay was done in the presence of 1 mM MgSO4, dopamine (10(-4) M) stimulated the enzyme activity by 3.5-fold. This effect was completely blocked by fluphenazine (10(-5) M; Ki = 9 X 10(-9) M) and by phentolamine (Ki = 3 X 10(-7) M). d-LSD stimulated the adenylate cyclase activity (Km = 1.4 X 10(-7) M) by interacting with the dopaminergic receptors. Maximal adenylate cyclase stimulation by d-LSD was 1.4-fold; as a matter of fact, this compound acted as a partial agonist on the dopaminergic receptors. l-Isoproterenol (Km = 10(-6) M) activated an adenylate cyclase present in rat striatum homogenates through a receptor distinct from the dopaminergic receptor; this stimulation was not affected by addition of fluphenazine or phentolamine but suppressed by dl-propranolol (10(-4) M). The topographical distributions of dopamine adenylate cyclase activity and endogeneous dopamine content were examined in homogenates prepared from discs punched out from serial frozen (-7 degrees C) slices of the striatum. A 4.8-fold progressive decrease in the amount of cyclic AMP produced in the presence of dopamine (10(-4) M) was observed from the rostral to the caudal part of the structure. The d-LSD-sensitive adenylate cyclase followed a similar distribution. It should be noted that the topographic distribution of endogeneous dopamine is quite comparable to the distribution of the dopamine-sensitive adenylate cyclase, suggesting that this enzyme is an integral part of the dopamine synapses. We also reported that the frontal cortex contains a dopamine-sensitive adenylate cyclase. In conclusion, we trust that the micromethod described for adenylate cyclase assay will be of some use in the study of the precise topographic distribution of catecholamine sensitive adenylate cyclases in different structures of brain.

Adenylyl Cyclases↗
PubMed1989

Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity to N-methyl-aspartate neurotoxicity.

The endogenous excitotoxin, glutamate (Glu), acting at the N-methyl-aspartate (NMA) subtype of Glu receptor, is thought to play a major role in hypoxic/ischemic neuronal degeneration. In the present study, the sensitivities of the developing rat CNS to hypoxic/ischemic neuronal degeneration and to the neurotoxic action of NMA were compared at various postnatal ages. In the hypoxic/ischemic experiments, ischemia was produced by unilateral common carotid artery ligation and hypoxia by subjecting the pups to a partial vacuum. Keeping the duration of the hypobaric episode constant at 75 min for all age groups, we observed that the vulnerability of the immature brain to hypobaric/ischemic damage increased during the early neonatal period (days 2-4), reached a peak at day 6 and then diminished progressively with increasing age. In the second part of the study, NMA was microinjected unilaterally into the head of the caudate nucleus at various postnatal ages (2-80 d). In the early neonatal period (days 2-6), injections of relatively small doses of NMA (6-15 nmol) produced a dose-dependent widespread excitotoxic reaction throughout the forebrain with peak sensitivity being observed on day 6. The cytotoxic reaction to NMA was identical in appearance and time course to that induced by hypobaric/ischemic methods. With increasing age, the excitotoxic response to a given dose of NMA decreased progressively and the lesions became more strictly confined to the injection site. Cell populations most sensitive to NMA toxicity in the 2-10 d period closely correlated with those most vulnerable to hypoxia/ischemia, and sensitivity to both types of injury reached a peak at 6 d. These findings reinforce other evidence linking an excitotoxic mechanism and the NMA subtype of Glu receptor to hypoxic/ischemic brain damage and suggest that there may be a period during development when NMA receptors are hypersensitive to excitotoxic stimulation, thus rendering the neurons possessing such receptors hypervulnerable to hypoxic/ischemic damage.

Air Pressure↗
PubMed1989

Immunotherapy with dog and cat allergen preparations in dog-sensitive and cat-sensitive asthmatics.

Standardized dog and cat allergen preparations with defined allergen composition were used for immunotherapy (IT) in dog-sensitive and/or cat-sensitive adult patients. Seventeen patients completed 1 year of IT. Eleven patients were treated with dog allergen, five with cat allergen, and one with both dog and cat allergen. The treatment was well tolerated, with increased subjective tolerance. After 3 months of IT there was a significant decrease in conjunctival (p less than .05) and skin sensitivity (p less than .05). Specific IgE decreased significantly within 1 year as assayed by RAST and IgE-crossed radioimmunoelectrophoresis. Specific IgG increased in all patients. The results indicate that IT with potent and standardized dog and cat allergens influence the sensitivity to these allergens.

Allergens↗
PubMed1987

Interactions of target-sensitive immunoliposomes with herpes simplex virus. The foundation of a sensitive immunoliposome assay for the virus.

Interactions between target-sensitive (TS) immunoliposomes and herpes simplex virus (HSV) were investigated. Target sensitivity of phosphatidylethanolamine (PE) immunoliposomes is a result of the ability of acylated monoclonal anti-HSV glycoprotein D (gD) to stabilize the bilayer phase of PE, whereas by itself, PE does not form stable liposomes (Ho, R. J. Y., Rouse, B. T., and Huang, L. (1986) Biochemistry 25, 5500-5506). Upon binding of these immunoliposomes to HSV antigen-containing gD, destabilization of PE immunoliposomes was observed. By encapsulating either a self-quenching fluorescent dye, calcein, or alkaline phosphatase inside the liposomal compartment, the HSV-induced destabilization of TS immunoliposomes was shown to be target-specific. Neither Sendai, Semliki Forest, nor Sindbis virus could significantly destabilize the TS immunoliposomes. Moreover, HSV-induced liposome destabilization could be inhibited by free anti-gD (the same antibody used in TS immunoliposomes) but not by monoclonal anti-HSV glycoprotein B, indicating that the interaction was antigen-specific. Destabilization could also be induced by binding to truncated gD (tgD), but only when in a multivalent form immobilized on latex beads. Truncated gD is a cloned, 312-amino acid fragment of HSV-gD that lacks the transmembrane segment. Preincubation of soluble tgD with the TS immunoliposomes failed to induce destabilization and, in addition, abolished the tgD-bead-induced destabilization. This finding strongly indicated that multivalent binding is essential for TS immunoliposome destabilization. Using alkaline phosphatase encapsulated in the liposomes, TS immunoliposomes could be used to detect HSV in fluid phase with 50% signal recorded at 5 microliters of 3.2 x 10(3) pfu/ml; at least 10-fold more sensitive than the standard double-antibody sandwich enzyme-linked immunosorbent assay. The interactions described here may be useful in designing a homogeneous and sensitive immunoliposome assay.

Animals↗
PubMed1978

Antibody responses to contact sensitizing agents. Effect of sensitized cells.

Lymphocytes from mice immunized by painting with the contact sensitizing agent picryl chloride have been shown to produce regulatory effects on the DNA synthesis and contact sensitivity responses of normal mice painted with picryl chloride. This report describes the effect of these cells on antibody responses of normal mice to picryl chloride. Lymph node cells taken 5--7 days after painting increased early IgM antibody responses of normal mice to picryl chloride. Spleen cells were not effective. The increase was mediated by T cells as judged by anti-theta treatment and nylon wool filtration and could not be produced by killed, irradiated or allogeneic cells. A similar activity could be demonstrated in cells from mice painted with another contact sensitizing agent, oxazolone. The effect was strictly specific and cells from mice painted with picryl chloride or oxazolone would only increase responses to picryl chloride or oxazolone, respectively, even when presented with a mixture of the two antigens. The cel-s increasing antibody production were different from T cells previously shown to mediate contact sensitivity and T cells shown to regulate DNA synthesis in that they could not be generated in adult-thymectomized mice.

Animals↗
PubMed1986

[Sensitivity test of anticancer agents by subrenal capsule assay (SRC assay). II--Determination of tumor sensitivity by percentage inhibition of DNA protein].

Subrenal capsule assay(SRC assay) has been reported to be an effective and rapid method for predicting the tumor sensitivity of individual patients to anti-cancer agents. In order to establish a more objective method of determining sensitivity in SRC assay the DNA content was measured by the schmidt-Thannhauser-Schneider method and the protein content was estimated using Bio-Rad protein assay, after removal of a tumor implanted in the subrenal capsular space of ddY mice. Percentage inhibition of DNA/protein had a high correlation with that of relative increase of tumor weight, although three groups treated with mitomycin-C, 5-fluorouracil and cyclophosphamide indicated different values of tumor sensitivity. From these results, the percentage inhibition of DNA/protein seems to be more objective than microscopic measurement for predicting tumor sensitivity.

Animals↗
PubMed1988

Demonstration of a [K+,Cl-]-cotransport system in human red cells by its sensitivity to [(dihydroindenyl)oxy]alkanoic acids: regulation of cell swelling and distinction from the bumetanide-sensitive [Na+,K+,Cl-]-cotransport system.

A screening of several families of compounds on NEM-stimulated K+ efflux in human red cells allowed us to select a [(dihydroindenyl)oxy] alkanoic acid (DIOA) as the first potent inhibitor of this K+ flux (IC50 of 10(-5) M) without side effects on the bumetanide-sensitive [Na+,K+,Cl-]-cotransport system. Incubation of human red cells in hypotonic media (179 mosm) increased cell volume (by 18-20%) and provoked the appearance of a DIOA-sensitive K+ efflux of 4.48 +/- 0.83 mmol.(liter of cells X hr)-1 (mean +/- SD of nine experiments). This DIOA-sensitive K+ efflux exhibited a Michaelian-like dependence on the Cl- concentration of the incubation media (freely equilibrated with intracellular Cl-) with an apparent dissociation constant of 39.6 +/- 14.7 mM and a maximal rate of 4.7 +/- 0.9 mmol.(liter of cells X hr)-1 (mean +/- SD of five experiments). The chloride effect was mediated by intracellular and not by extracellular Cl-, as expected for an outward [K+,Cl-]-cotransport. The above properties of DIOA-sensitive K+ efflux clearly confirm that human red cells have a [K+,Cl-]-cotransport system that regulates cell swelling. The regulatory response to hypotonic media was also strongly depressed by cytochalasin B at a concentration of 1 mM, suggesting that the activating signal is probably transduced by the cytoskeleton.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1976

Hapten-specific responses to contact sensitizers. Use of fluorodinitrobenzene to elicit migration inhibition and macrophage agglutination factors from lymph node cells of contact-sensitive guinea-pigs.

Hapten-specific sensitivity of guinea-pigs sensitized to dinitrophenyl (DNP) contactants and to DNP-protein conjugates was investigated by skin test and by antigen-induced elaboration of migration inhibition (MIF) and macrophage agglutination factors (MAF) From lymph node cells. The delayed contact reaction was highly specific for low doses of contactant and markedly less so for conjugates; lymph node cells elaborted both lymphokines in response to brief exposures to dinitrofluorobenzene (DNFB) or prolonged exposures to DNP conjugates. Elicitation of MAF by DNFB or DNP conjugate was inhibited in the presence of DNP glycine; the activity of MAF induced by DNP conjugate (but not that induced by DNFB) was inhibited in the presence of DNP-glycine as well. These results suggest that contact sensitivity to DNP conjugates reflect two different types of hapten-specific cellular sensitivity mediated by populations of cells with different antigen receptors and possibly, functionally different lymphokines.

Animals↗