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PubMed1993

Evidence of in vitro development of drug resistance to azidothymidine in T-lymphocytic leukemia cell lines (Jurkat E6-1/AZT-100) and in pediatric patients with HIV-1 infection.

Clinical reports indicate that the development of drug resistance to AZT after chronic administration is common. In order to study this phenomenon, the T-cell line Jurkat E6-1 was treated continuously in vitro with low, gradually increased, concentrations of azidothymidine (AZT). Initially, 1 microM AZT significantly retarded the cell line from reaching confluence. However, after 10 weeks the T-cell line was able to grow in 10 microM AZT without any evidence of growth inhibition. Subsequently, cell isolates could grow continuously in the presence of 20, 50, and 100 microM AZT without growth inhibition. These T-cell lines (Jurkat E6-1/AZT-10, Jurkat E6-1/AZT-20, Jurkat E6-1/AZT-50, and Jurkat E6-1/AZT-100) were tested for AZT anabolism using purified [3H]AZT, and the results were compared to the wild-type untreated Jurkat E6-1 cell line. Similar intracellular AZT anabolites concentrations were determined in all cell lines. However, a four- to sixfold lower cellular concentration of mono-, di-, and triphosphate anabolites of AZT was determined in the Jurkat E6-1/AZT-10 cell line after 1 microM AZT incubation and 6.5-fold lower after 10 microM AZT treatment. In general, a five- to sixfold reduction in the phosphorylation rates were estimated in the AZT resistant T-cell line. Pharmacology studies of [3H]AZT in the Jurkat E6-1/AZT-100 cell line showed a much lower level of activation of the pro-drug (28-fold), due to lack of thymidine kinase (TK) activity when compared to the Jurkat E6-1/AZT-10 T-cell line. A similar level of resistance was obtained at the thymidylate (dTMP) kinase level. Concurrently an additional mode of resistance (407-fold) was seen on the incorporation of the AZT triphosphate anabolite (AZTTP) into cellular DNA. The formation of this cell line in a period of < or = 4 months coincides with the evidence of the clinical development of "resistance" to AZT in patients who receive the drug continuously. In addition, these T-cell lines have been infected with HIV, and studies on the development of collaterally sensitive regimens are under way.

Adolescent↗

PubMed1995

Multiple drug resistance in Candida albicans.

By functional complementation of a PDR 5 (pleiotropic drug resistance) null mutant of S. cerevisiae, we have recently cloned and sequenced a multidrug resistance gene CDR 1 (Candida Drug Resistance). Transformation by CDR 1 of a PDR 5 disrupted host hypersensitive to cycloheximide and chloramphenicol resulted in resistance to these as well as other unrelated drugs. The nucleotide sequence of CDR 1 revealed that, like PDR 5, it encodes a putative membrane pump belonging to the ABC superfamily. CDR 1 encodes a protein of 169.9 kDa whose predicted structural organisation is characterised by two homologous halves, each comprising a hydrophobic region, with a set of six transmembrane stretches, preceded by a hydrophilic binding fold. We now have evidence to suggest that there are several PDR homologues present in C. albicans which display multidrug resistance and a collateral sensitivity pattern different from PDR 5 and CDR 1. The functions of such genes and their products in the overall physiology of C. albicans is not yet established.

Antifungal Agents↗

PubMedDate not supplied

Increased p21/WAF-1 and p53 protein levels following sequential three drug combination regimen of fludarabine, cytarabine and docetaxel induces apoptosis in human leukemia cells.

Combinations of nucleoside analog drugs, such as F-araA and ara-C, combined with Topoisomerase II inhibitors, such as anthracyclines, are synergistic against human leukemic T-cells and induce apoptotic cell death. Similarly, nucleoside analog drugs followed by mitotic inhibitors also have a synergistic effect. Sequence specific combinations of F-araA followed by ara-C and Taxotere (docetaxel) in CEM/0 cells showed a 2- to 3-fold synergism over the two drug (F-araA + ara-C) combinations and 2- to 4-fold synergism over Taxotere alone. This synergism was evident due to enhanced cellular apoptosis. In the CEM/ara-C/7A cell line, which is partially resistant to ara-C, the synergy observed with the triple drug combination was 9-fold greater than the F-araA plus araC combination, and 3-fold greater than Taxotere alone, making this three-drug regimen collaterally sensitive to ara-C. This study describes the mechanisms of the synergistic effect in regards to apoptosis achieved by three-drug regimens comprised of two nucleoside analog drugs and a mitotic inhibitor in comparison with the combination of two nucleotide analog drugs. The study also demonstrates that the possible biochemical mechanism of cellular toxicity and drug synergism is attributed to induction of apoptosis following drug treatment and the onset of the apoptotic cascade is primarily regulated by p21/WAF-I, which is transcriptionally activated by p53 following DNA damage. The anti-apoptotic protein, bcl-2, seemed to have no effect in inhibiting apoptosis following treatment with the two or three drug regimens in this in vitro leukemia model. The three-drug combination induced greater cellular apoptosis than the two-drug combination or Taxotere monotherapy. We conclude that the greater drug synergism observed in human leukemic cells, sensitive or resistant to ara-C, by Fludarabine + ara-C + Taxotere can be explained by the greater oligonucleosomal DNA fragmentation indicative of increased cellular apoptosis. The mechanism of this increased cytotoxic action is due to the upregulation of p53 and p21/WAF-1 with a down regulation of bcl-2. These studies are encouraging, and testing this three drug regimen in a clinical setting may result in improved antileukemic therapies.

Apoptosis↗

PubMed1992

Collateral resistance or sensitivity of human larynx carcinoma HEp2 cells resistant to cis-dichlorodiammineplatinum (II) or vincristine sulfate.

Human larynx carcinoma HEp2 cells in tissue culture were repeatedly treated with two chemotherapeutic agents which exhibit distinct mechanisms of action and which differ in mechanisms underlying resistance: cis-dichlorodiammineplatinum (II) (cis-DDP) and vincristine sulfate (VCR). Two schedules of resistance development were used: Acute (cells repeatedly treated with drug for 1 hour in serum-free medium: CA15 and VA15 cells), and continuous (repeatedly treated for 24 hours in complete medium: CK15 and VK15 cells). The sensitivity of cis-DDP resistant (CA15 and CK15 cells) and VCR resistant (VA15 and VK15 cells) sublines to cis-DDP VCR, methotrexate (MTX) and gamma rays was determined by survival assay. The results showed that all sublines became resistant to MTX. Cis-DDP resistant cells became cross-resistant to VCR too. Of VCR resistant sublines, only VK15 cells changed (increased) their sensitivity to cis-DDP. Resistant sublines (except CA15) became sensitive to gamma rays. The degree of resistance or collateral resistance/sensitivity depended on the chemotherapeutic agent used for selection and on the schedule of resistance development. The present data support the idea of complexity of resistance phenomenon. They also emphasize the difficulty and importance of judicious choice of agents that should be given in combined therapy of tumors.

Cell Survival↗

PubMed1985

Dopamine-sensitive alternation and collateral behaviour in a Y-maze: effects of d-amphetamine and haloperidol.

The degree of alternation of arm choice in a Y-maze was examined on 15-min tests over 4 days in rats treated (IP) with saline, amphetamine (0.5 or 2.0 mg/kg) or pretreated with haloperidol (0.08 mg/kg) in each condition prior to test. On day 1 amphetamine-treated animals chose arms at random, but from day 2-4 those receiving the higher dose perseverated their choice. Controls maintained alternation. These effects could be prevented by haloperidol pretreatment. Amphetamine treatment increased the frequency of rearing at the middle, choice-point of the maze more than at the end of an arm. The increase at the mid-point was suppressed by haloperidol pretreatment from day 1 and at the end of an arm from day 2. Amphetamine induced an increase in head-turning/"looking" that was suppressed by haloperidol from day 2. The effect of haloperidol in increasing the duration of an item of looking or rearing at the end of an arm also started later in testing. Two effects are postulated to have occurred: (i) a conflict on day 1 between novelty-controlled sensory or attentional effects that leads to an alternation of arm choice and amphetamine-induced dopaminergic activity that facilitates an alternation of behavioural responses. The result was random choice and increased rearing at the choice point. (ii) On days 2-4 the drug-induced effects on switching motor responses came to control behaviour.

Animals↗

PubMed2003

Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines.

Gemcitabine (2',2'-difluorodeoxycytidine) is a deoxycytidine analogue that is activated by deoxycytidine kinase (dCK) to its monophosphate and subsequently to its triphosphate dFdCTP, which is incorporated into both RNA and DNA, leading to DNA damage. Multidrug resistance (MDR) is characterised by an overexpression of the membrane efflux pumps P-glycoprotein (P-gP) or multidrug resistance-associated protein (MRP). Gemcitabine was tested against human melanoma, non-small-cell lung cancer, small-cell lung cancer, epidermoid carcinoma and ovarian cancer cells with an MDR phenotype as a result of selection by drug exposure or by transfection with the mdr1 gene. These cell lines were nine- to 72-fold more sensitive to gemcitabine than their parental cell lines. The doxorubicin-resistant cells 2R120 (MRP1) and 2R160 (P-gP) were nine- and 28-fold more sensitive to gemcitabine than their parental SW1573 cells, respectively (P<0.01), which was completely reverted by 25 micro M verapamil. In 2R120 and 2R160 cells, dCK activities were seven- and four-fold higher than in SW1573, respectively, which was associated with an increased dCK mRNA and dCK protein. Inactivation by deoxycytidine deaminase was 2.9- and 2.2-fold decreased in 2R120 and 2R160, respectively. dFdCTP accumulation was similar in SW1573 and its MDR variants after 24 h exposure to 0.1 micro M gemcitabine, but dFdCTP was retained longer in 2R120 (P<0.001) and 2R160 (P<0.003) cells. 2R120 and 2R160 cells also incorporated four- and six-fold more [(3)H]gemcitabine into DNA (P<0.05), respectively. P-glycoprotein and MRP1 overexpression possibly caused a cellular stress resulting in increased gemcitabine metabolism and sensitivity, while reversal of collateral gemcitabine sensitivity by verapamil also suggests a direct relation between the presence of membrane efflux pumps and gemcitabine sensitivity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Response of coronary microvascular collaterals to activation of ATP-sensitive K+ channels.

OBJECTIVE: Studies have suggested that collateral vessels of the coronary and hind-limb circulations are more sensitive to activation of ATP-sensitive K+ channels than are non-collateral vessels. The objective of the present study was to compare responses of microvascular non-collaterals, native collaterals and stimulated collaterals in the heart to three vasodilators which act through different mechanisms: activation of ATP-sensitive K+ channels with aprikalim, release of nitric oxide with acetylcholine, and endothelium-independent activation of soluble guanylate cyclase with nitroglycerin. METHODS: Collateral growth was stimulated by placing an Ameroid occluder on the proximal left circumflex artery in dogs. Non-collaterals, native collaterals and stimulated collaterals (100-220 microns in diameter) were isolated, cannulated on micropipettes and pressurized in vitro. Vessel diameters were measured using videomicroscopy. RESULTS: Dilation to aprikalim (10(-8)-10(-5) M), acetylcholine (10(-9)-10(-6) M) and nitroglycerin (10(-8)-3 x 10(-4) M) were similar in non-collateral, native collateral and stimulated collaterals. Dilation of native collaterals to aprikalim and acetylcholine was attenuated by glibenclamide (10 microM), an inhibitor of ATP-sensitive K+ channels, but not by tetraethylammonium (1 mM), a non-selective inhibitor of K+ channels. Dilation of native collaterals to acetylcholine but not aprikalim was also inhibited by nitro-L-arginine (10 microM), an inhibitor of nitric oxide synthase. CONCLUSION: These findings suggest that microvascular native and stimulated collaterals respond to activation of ATP-sensitive K+ channels and acetylcholine similar to non-collaterals of similar size. Thus, changes in reactivity of collaterals to activation of ATP-sensitive K+ channels are not related to changes in the ability of the vessels to respond to vasodilators but may primarily be determined by a change in the distribution of collateral vessel size.

Acetylcholine↗

PubMed1994

P2Y purinoceptor and nucleotide receptor-induced relaxation of precontracted bovine aortic collateral artery rings: differential sensitivity to suramin and indomethacin.

We have examined a series of adenine nucleotides and UTP for their ability to cause relaxation of precontracted bovine aortic collateral artery rings. The overall rank order of agonist potency for relaxation was 2-methylthioadenosine 5'-triphosphate (2MeSATP) > adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) > UTP > ADP > ATP. These responses were endothelium-dependent. Interaction studies showed that responses to the selective P2Y purinoceptor agonist 2MeSATP, and to ADP, were mediated by different receptors from those mediating responses to UTP. Suramin, a P2 purinoceptor antagonist that binds to diverse sites for ATP, produced a concentration-dependent shift in the agonist concentration-effect curve to 2MeSATP, with a pKB of 5.45 +/- 0.15 and a slope of 0.94 +/- 0.09. Suramin produced a small, nonsignificant shift in the UTP response curve and had little effect on responses to ATP. Indomethacin (2.8 x 10(-6) M) had no effect on concentration-effect curves to UTP but almost abolished the relaxations produced by 2MeSATP and ADP. The concentration-effect curves to ATP and ATP gamma S showed a significant (P < .05) rightward shift in the presence of indomethacin. These results suggest the presence of separate P2Y purinoceptor and nucleotide receptors mediating endothelium-dependent relaxations of bovine aortic collateral artery smooth muscle. ATP acts at both receptors, whereas ADP acts at only one (P2Y). The effects of indomethacin show that these receptors differentially modulate the release of cyclooxygenase-derived mediators of relaxation.

Adenosine Triphosphate↗

PubMed1991

Influence from stretch-sensitive receptors in the collateral ligaments of the knee joint on the gamma-muscle-spindle systems of flexor and extensor muscles.

In lightly alpha-chloralose anaesthetized cats, activity was recorded simultaneously from 2-4 primary muscle spindle afferents from triceps surae and/or posterior biceps and semitendinosus muscles. Increased tension in medial or lateral collateral ligament was found to evoke changes in the responses of the primary spindle afferents to sinusoidal stretching of their parent muscles. It is concluded that these changes were due to reflex actions of stretch/tension-sensitive receptors in the collateral ligaments on fusimotor neurones. Thus, receptor afferents from the collateral ligaments may contribute to the regulation of the activity in the gamma-motor-muscle-spindle system, and thereby also be of importance for the control of muscular stiffness and knee joint stability.

Animals↗

PubMed2000

Cytotoxic activity of several unrelated drugs on L1210 mouse leukemic cell sublines with P-glycoprotein (PGP) mediated multidrug resistance (MDR) phenotype. A QSAR study.

L1210/VCR-1 and L1210/VCR-2 cell lines are multidrug resistant (MDR) sublines obtained by adaptation of mouse leukemic cell line L1210 to vincristine and, the development of MDR in these cell lines has been found to be associated with an overexpression of P-glycoprotein (PGP). In the present work we studied the relationship between the structure of 15 cytotoxic active substances (drugs) and their cytotoxicities on L1210/VCR-1 and L1210/VCR-2 resistant cell lines. The resistance of these MDR cells to the respective drugs was expressed as the ratio of IC50 values obtained for resistant and sensitive cells. These values of resistance were correlated with the following physico-chemical constants of the test substances: binding energy, Ebind; total energy of the molecule, Esum; aromaticity, Kpi; molecular weight, Mw; acidobasic constant, pKa; partition coefficient in water/octanol two phase system, log(p). It has been found that according to the cytotoxic effects the tested drugs may be divided into three groups: (i) drugs with higher cytotoxicity to the resistant cell lines as to sensitive cells (collateral hypersensitivity); (ii) drugs exhibiting approximately similar effects on sensitive and resistant cell lines; (iii) drugs with weaker cytotoxicity to resistant cells than to sensitive cells. No direct correlations with any physico-chemical constant described above could be established for cell resistance to the drug studied. However, resistance values could be fitted by multiple exponential regression with all described physico-chemical constants implied as six independent variables. The latter procedure made us to conclude that the ability of a drug to be a substrate for PGP is connected with its fulfilling the following criteria: (i) flexible structure of its molecule; (ii) molecular weight lower than approximately 1,300 g/mol; (iii) nonprotonized character at pH 7.0.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1987

Clinical significance of early myocardial 99mTc-pyrophosphate uptake in patients with acute myocardial infarction.

Early 99mTc-pyrophosphate (PYP) scintigrams of 29 patients receiving coronary thrombolysis induced by urokinase, 3.9 +/- 1.2 hours after the onset of acute myocardial infarction (AMI), were evaluated. Intravenous 99mTc-PYP scintigraphy was performed 2.8 to 8.0 hours after the onset of AMI. All 19 patients with positive findings on early scintigrams had good recanalization, compared to only 3 of the 10 patients with negative findings. The seven patients with unsuccessful recanalization after coronary thrombolysis had total occlusion or subtotal occlusion with delayed washout of contrast material, and three of them had collaterals. The sensitivity, specificity, and predictive accuracy of positive results of early scintigraphy in predicting the presence of early reperfusion were 73%, 100%, and 90%, respectively. Patients with positive early scintigrams showed increasing regional ejection fraction and decreasing thallium defect scores from the acute stage to the chronic stage. These findings indicate that early 99mTc-PYP scintigraphy is a sensitive noninvasive technique for detecting early recanalization in infarcted vessels. The collateral flow or antegrade flow with delay is not enough to cause 99mTc-PYP uptake in a very early stage of AMI.

Aged↗

PubMedDate not supplied

Noninvasive detection of collateral flow to the infarct-related coronary artery in patients after myocardial infarction by Tl-201 tomographic imaging.

BACKGROUND: The determination of viability and perfusion within the infarct zone in post-myocardial infarction patients has both therapeutic and prognostic significance. Reversibility of thallium 201 uptake within the territory of the infarct-related coronary artery (IRA) as shown by single photon emission computed tomography (SPECT) is associated with a jeopardized but viable myocardium. We aimed to test the hypothesis that for post-myocardial infarction patients undergoing Tl-201 stress-redistribution SPECT, a scintigraphic pattern of distal reversibility without proximal reversibility within a defect corresponding to the IRA territory is a marker of collateral flow to the occluded culprit artery. METHODS AND RESULTS: We assessed Tl-201 SPECT imaging results of 78 patients with IRA occlusion as demonstrated by angiography 7 +/- 1 months after myocardial infarction. Angiography demonstrated the presence of collateral flow in 57 patients and its absence in 21 patients. Distal reversibility was present in 42 of the 57 patients with collateral flow (sensitivity, 74%) and was absent in 16 of the 21 patients without collateral flow (specificity, 76%). Collateral flow to the IRA was demonstrated in 42 of 47 patients with distal reversibility (group A) (positive predictive value, 89%) and absent in 16 of 31 patients with a fixed defect without reversibility (group B) (P <.001) (negative predictive value, 52%). CONCLUSIONS: In patients after myocardial infarction, a Tl-201 SPECT redistribution pattern of distal reversibility without proximal reversibility within a defect in the IRA territory is a noninvasive marker of collateral flow to the culprit artery with a high positive predictive value that may provide valuable information on patient management. A larger prospective study in an unselected patient population is needed to further evaluate the clinical value of this marker.

Adult↗

PubMed1997

Submodality-selective hyperalgesia adjacent to partially injured sciatic nerve in the rat is dependent on capsaicin-sensitive afferent fibers and independent of collateral sprouting or a dorsal root reflex.

We studied submodality dependence of sensory changes produced by unilateral ligation of the sciatic or the saphenous nerve in the rat. We focused especially on sensory changes in the skin area adjacent to the innervation area of the injured nerve. Moreover, we examined the roles of capsaicin-sensitive nociceptive fibers, collateral sprouting and a dorsal root reflex in sensory changes observed behaviorally. Assessment of sensory changes was performed by a pattern of behavioral tests: hot-plate test and hindlimb withdrawal responses induced by radiant heat, hot-water bath, innocuous mechanical stimuli, and noxious mechanical stimuli. In one group, the saphenous nerve ipsilateral to the sciatic ligation was topically treated with capsaicin (1%) at the time of the surgery. A proximal stump of a saphenous nerve strand was orthodromically stimulated to induce a dorsal root reflex (an antidromic volley) in nociceptive fibers of the saphenous nerve trunk. For visualization of plasma extravasation induced by a dorsal root reflex, a dye-labeling (Evans blue) technique was used. A collateral sprouting of nociceptive fibers of the uninjured saphenous nerve was evaluated by determining the plasma extravasation response induced by antidromic stimulation of the saphenous nerve. Three and 10 days following the sciatic constriction injury, the hindlimb withdrawal threshold evoked by noxious mechanical stimulation of the medial side of the paw (the innervation are of the intact saphenous nerve) was significantly decreased. There was no corresponding thermal hyperalgesia adjacent to the injured sciatic nerve. Chronic constriction of the saphenous nerve did not produce any significant hyper- or hypoalgesia to mechanical or thermal stimulation of the uninjured sciatic nerve area. Topical treatment of the ipsilateral (intact) saphenous nerve at the time of the sciatic nerve ligation completely prevented the development of mechanical hyperalgesia in the medial side of the paw (the innervation area of the saphenous nerve). No dorsal root reflex in nociceptive fibers mediating the adjacent hyperalgesia could be evoked. No collateral sprouting of the uninjured nociceptive fibers of the saphenous nerve was observed. The results indicate that the constriction injury of the sciatic nerve produced a selective hyperalgesia to mechanical stimulation in the innervation area of the neighboring saphenous nerve. At the peripheral level, the mechanical hyperalgesia adjacent to the innervation area of the injured nerve was mediated by capsaicin-sensitive nociceptive fibers. Collateral sprouting of nociceptive fibers from the uninjured to the injured innervation area did not contribute to the present sensory findings. The sciatic nerve injury did not induce a dorsal root reflex in nociceptive fibers innervating the hyperalgesic saphenous nerve area.

Animals↗

PubMed1994

[An evaluation of the hemodynamic efficacy of an extra-intracranial microanastomosis in unilateral occlusion of the internal carotid artery].

The physicians of the A. N. Bakulev Institute for Cardiovascular Surgery examined 64 patients with unilateral atherosclerotic occlusion of the internal carotid artery (ICA). TCDG and angiography were employed before and after establishment of EICMA. TCDG proved highly informative in assessment of collateral circulation (sensitivity 95.6%). Indications to EICMA should be based on overall account of initial stage of cerebrovascular insufficiency and collateral circulation. EICMA is indicated for patients with compensated and relatively compensated cerebrovascular insufficiency (transient ischemic attacks, minor apoplexy, dyscirculatory encephalopathy), residue sequelae of ischemic apoplexy stroke, baseline poor collateral circulation. Differentiated approach to EICMA establishment allows improved outcomes of the surgery and revision of common among angio-neurosurgeons attitude to the above surgery in ICA occlusion.

Adult↗

PubMed1981

Importance of coronary collateral circulation in interpreting exercise test results.

The importance of the coronary collateral circulation as a cause of false negative exercise tests was studied in 37 patients who had a 90 percent or greater isolated stenosis of the luminal diameter in one major coronary artery. Sixteen patients had large collateral vessels and 21 patients had either minimal or no collateral circulation. Myocardial scintigraphy was performed in 22 of the 37 patients. The final treadmill time was similar in both groups (521 +/- 192 versus 554 +/- 144 seconds [mean +/- standard error of the mean]). The presence and depth of S-T segment depression was not influenced by the degree of collateralization. The sensitivity of the exercise electrocardiogram was greater for patients with disease in the left anterior descending than in the right or left circumflex coronary arteries (95 versus 60 percent, p < 0.03). Among the 22 patients with thallium-201 scintigrams, myocardial perfusion defects were more common in patients without collateral circulation (100 versus 40 percent, p < 0.01) and involved more myocardial segments (p < 0.005). The overall sensitivity of exercise electrocardiography for the detection of single vessel stenosis 90 percent or greater was similar to that of myocardial scintigraphy (81 versus 73 percent). In conclusion, large intercoronary collateral vessels are not a cause of false negative exercise electrocardiograms in patients with single vessel disease but are a common cause of false negative scintigrams. Large collateral vessels may limit the quantity and location of myocardial ischemia, but exercise electrocardiography and thallium-201 scintigraphy may detect different aspects of ischemia.

Adult↗

PubMedDate not supplied

MDR hamster cells exhibiting multiple altered gene expression: effects of dexniguldipine-HCl (B859-35), cyclosporin A and buthionine sulfoximine.

An actinomycin D selected, multidrug-resistant (MDR) hamster CHO subline showed strong expression of the P-glycoprotein and sorcin genes together with several other alterations such as a: (i) reduced growth rate, (ii) lowered topoisomerase II, (iii) lowered glutathione-S-transferase-P gene expression, and (iv) the emergence of a 15.5 kDa protein. Besides high resistances to adriamycin, actinomycin D, and vincristine, we observed a lowered sensitivity towards bleomycin, a rather hydrophilic drug usually not involved in P-glycoprotein associated MDR. Moreover, the MDR subline showed a pronounced collateral (enhanced) sensitivity towards the sterically pure dihydropyridine anticancer drug dexniguldipine-HCl (B859-35) preventing its characterization for MDR modulation here. At a non-cytotoxic dose (10 microM) the immunosuppressive cyclic peptide cyclosporin A completely abolished the resistance to vincristine, partially reversed the resistance to teniposide and strongly enhanced the sensitivity towards bleomycin, while not influencing the drug sensitivities of the parental cell line. Buthionine sulfoximine (BSO), an agent depleting cellular glutathione levels, distinctly increased the sensitivity towards teniposide at nontoxic doses (50 microM) exclusively in the MDR subline, while it did not alter vincristine or bleomycin cytotoxicity.

Adenine Phosphoribosyltransferase↗

PubMed1986

Specific increase in sensitivity to serotonin of the canine hindlimb collateral arterial tree via the 5-hydroxytryptamine-2 receptor.

Evidence that platelet activation contributes to ischemia associated with atherosclerosis led us to examine the response of the limb collateral arterial tree to a platelet product, serotonin. In 23 anesthetized dogs we measured arterial diameter (angiography) and blood flow (133Xe transit) before or 2 weeks after superficial femoral artery ligation (SFAL). In normal hindlimbs blood flow increased after 5-hydroxytryptamine (5-HT) and there was a modest but measurable, dose dependent narrowing of 1- to 2-mm vessels, the major stem vessels for collateral blood flow. After SFAL, identical segments of these vessels responded to serotonin more: the slope relating dose and response became steeper (P less than 0.001), the threshold dose fell significantly (P less than 0.001), and calf blood flow fell. The vasodilator response to acetylcholine was reduced sharply after SFAL, but was still demonstrable. The 5-HT-2 serotonin antagonist, ketanserin, reversed serotonin induced spasm in the region served by collaterals (P less than 0.025). Responses to norepinephrine were not potentiated. A 5-HT-2 receptor dependent sensitization of collateral arterial vessels, and blunting of the normal vasodilator response, mediates a paradoxical decrease in perfusion induced by 5-HT in regions served by the collaterals.

Animals↗

PubMed2002

Color velocity imaging quantification in the detection of intracranial collateral flow.

BACKGROUND AND PURPOSE: The development of intracranial collateral circulation is associated with a lower risk of stroke. A noninvasive technique that can reliably detect the presence of intracranial collaterals would be a valuable factor in the assessment of risk in patients with occlusive cerebrovascular disease. METHODS: Color velocity imaging quantification was used to measure the blood flow volume of the common carotid and vertebral arteries in 40 patients with carotid occlusive disease. The blood flow volumes in these arteries were correlated with angiographic evidence of collaterals to establish the best cutoffs for detecting intracranial collateral circulation. RESULTS: A blood flow volume of either > or =370 mL/min in the common carotid artery or > or =120 mL/min in the vertebral artery was indicative of the presence of intracranial collaterals. The sensitivity and specificity for the common carotid artery were 92.3% [95% confidence interval (CI), 62.1 to 99.6] and 92.1% (95% CI, 77.5 to 97.9), respectively. The sensitivity and specificity for the vertebral artery were 75.0% (95% CI, 35.6 to 95.5) and 87.5% (95% CI, 66.5 to 96.7), respectively. CONCLUSIONS: Color velocity imaging quantification offers a noninvasive, accurate method for detecting the presence of intracranial collateral circulation and quantifying its magnitude. This technique would be a useful adjunct in screening or continuous monitoring of patients with severe carotid occlusive disease.

Aged↗