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PubMed1995

Saturation reversal of the multidrug pump using many reversers in low-dose combinations.

Multidrug resistance in cancer cells, in cell culture and in the clinic, is often associated with a membrane protein (the multidrug resistance pump or P-glycoprotein) that pumps out anti-cancer drugs as fast as they enter the cell. This pump is blocked by a range of well-known pharmaceuticals that reverse drug resistance. We have investigated whether effective reversal of drug resistance could be achieved by using many reversers together, each at a low dose relative to its maximal tolerated plasma level. We measured in cell culture, using resistant P388 cells in suspension, the extent of reversal of the accumulation of two labeled cytotoxins (vinblastine and daunomycin). We fitted the data to a modified Michaelis-Menten equation and extracted the half-inhibition constants for 18 reversers acting on the pump. We measured also the reversal of resistance in a cell growth assay using incorporation of labeled thymidine. We showed that these drugs in groups of up to 18 together, each drug being at a low dose, in many cases well-tolerated in humans, had additive effects so that the combination was as effective as any of the drugs present singly. This was the case both for reversal of cell accumulation and for the effects of cytotoxins on cell growth. Our data show that a low-dose multidrug approach to saturation reversal of the multidrug pump is feasible in cell culture and provide the initial experimental basis for the development of an effective regime of such combination reversal therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Intrinsic properties of reverse transcriptase in reverse transcription. Associated RNase H is essentially regarded as an endonuclease.

The intrinsic properties of reverse transcriptase in reverse transcription were studied using a synthetic, partial ovalbumin mRNA with a synthetic DNA oligonucleotide annealed to the 3'-end of the RNA as a model substrate. With or without concomitant cDNA synthesis, the RNase H activity of avian myeloblastosis virus (AMV)-reverse transcriptase cleaved the substrate at a site which would leave a hybrid of between 7 and 14 base pairs between the 3' termini of the RNA and DNA oligonucleotide. Variability in the exact size of the hybrid probably reflects some weak base preference for cleavage by the enzyme. These short hybrids can be recognized as substrates by Escherichia coli RNase H and can be utilized by reverse transcriptase as sites for continuation of cDNA synthesis. Substrates with 5'-triphosphorylated termini, 3'-OH, 3'-phosphate, 3'-end hairpin structures and 20 base pair hybrids on the middle region of long RNA more than 300 bases or on circular RNA were all cleaved by AMV-reverse transcriptase-associated RNase H, indicating that the RNase H activity is essentially regarded as an endonuclease degrading RNA moiety in RNA-DNA hybrid. The modes of action of reverse transcriptase from murine leukemia virus and Rous-associated virus 2 were the same as that of AMV-reverse transcriptase, except that the size of the remaining hybrid and the specificity for cleavage depended on the reverse transcriptase. We propose a possible model to explain the mode of action of RNase H and RNA-dependent DNA polymerase activities in reverse transcription.

Avian Leukosis Virus↗
PubMedDate not supplied

Interactions between human immunodeficiency virus type 1 reverse transcriptase, tRNA primer, and nucleocapsid protein during reverse transcription.

An early step in the life cycle of human immunodeficiency virus type 1 is the reverse transcription of the viral RNA genome into double-stranded DNA, which is subsequently translocated to the cell nucleus. It is then integrated into host DNA and serves as a template for viral gene expression. Reverse transcription is catalyzed by the viral enzyme reverse transcriptase and is a complex process comprising a series of RNA-dependent DNA polymerization, DNA-dependent DNA polymerization, and RNase H reactions. Strand transfer reactions are required to complete the process. Reverse transcription is initiated when a molecule of host cell tRNA(lys3), which serves as a primer, is bound to the primer binding site of viral genomic RNA. The viral nucleocapsid protein is involved in each of the initiation of reverse transcription and in subsequent strand transfer or template-switching events. We review the interactions among reverse transcriptase, viral genomic RNA, the tRNA primer of reverse transcription, and viral nucleocapsid protein in the various steps of reverse transcription, including primer placement, initiation, and processive synthesis.

Anti-HIV Agents↗
PubMed2006

Clinicoradiological factors influencing the reversibility of posterior reversible encephalopathy syndrome: a multicenter study.

PURPOSE: The aim of this retrospective study was to clarify the relation between the reversibility of posterior reversible encephalopathy syndrome (PRES) with three factors: the anatomical region of the brain involved, the background clinical cause, and the diffusion weighted image (DWI) intensity of PRES lesions. MATERIAL AND METHODS: This multicenter study, conducted by the PRES Study Group of the Neuroradiology Workshop, involved 52 cases from 28 institutions. Initial and follow-up magnetic resonance imaging were compared regarding the reversibility of PRES lesions according to anatomical location and clinical background. Initial DWI and apparent diffusion coefficient (ADC) maps were reviewed in 20 cases. RESULTS: Reversibility was significantly lower (P < 0.01) in the brain stem (44%) and deep white matter (47%) compared to the other cortical and subcortical areas (76%-91%). The reversibility was greater in the eclampsia subgroup followed by the hypertension and chemotherapy subgroups. DWI, even with ADC maps, had limitations in predicting the outcome of PRES lesions. CONCLUSION: The typical cortical and subcortical PRES lesions showed reversibility, whereas the brain stem and deep white matter lesions showed less reversibility. PRES due to eclampsia showed maximum reversibility compared to hypertension- and drug-related PRES. DWI, even with ADC maps, had limitations in predicting the course of PRES.

Adolescent↗
PubMed2004

Replication-dependent 65R-->K reversion in human immunodeficiency virus type 1 reverse transcriptase double mutant K65R + L74V.

Understanding of the mechanisms of interaction among nucleoside reverse transcriptase inhibitor (NRTI)-selected mutations in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) coding sequence is essential for the design of newer drugs and for enhancing our vision of the structure function relationship among amino acids of the polymerase domain of HIV-1. Although several nucleoside reverse transcriptase inhibitors select RT mutations K65R and L74V, the combination of 65R + 74V is rare in clinics. A novel NRTI (-)-beta-d-dioxolane-guanosine (DXG) is known to select in vitro either the 65R or 74V mutant virus. These mutations were not selected together during repeated passaging of the HIV-1 in the presence of this drug. To analyze the impact of these RT mutations on viral replication, a double mutant containing K65R + L74V was created by site-directed mutagenesis in a pNL4-3 background. Replication kinetic assays revealed that the mutant K65R + L74V is unstable, and 65R-->K reversion occurs during replication of virus in phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear (PBM) cells in the absence of selection pressure. Replication kinetic assays in MT-2 cells demonstrated that double mutant 65R + 74V is highly attenuated for replication and the initiation of reversion is related to the increase in RT activity. Additionally, the suppression of viral replication in the presence of DXG or under suboptimal human recombinant interleukin-2 leads to minimal or no 65R-->K reversion. These observations provide evidence that 65R-->K reversion in the double mutant 65R + 74V is dependent on a specific rate of viral replication in a pNL4-3 background. A similar phenomenon may occur in vivo, which may have implications for treatment management strategies.

Arginine↗
PubMed2003

Nonnucleoside inhibitors of HIV-1 reverse transcriptase: from the biology of reverse transcription to molecular design.

Replication of human immunodeficiency virus 1 (HIV-1) uses a viral reverse transcriptase (RT) to convert its positive-strand RNA into double stranded DNA, which is then integrated into host genome. Reverse transcription is a complex event involving p66 and p51 RT subunits but also several viral proteins including Nef, Tat, Vif, IN, NCp7 and p55gag. Viral RNA itself forms a primer/template complex by association with a cellular tRNA(Lys3) which is already present in mature virions. A RT initiation complex (RTIC) is thus formed which may also involve cellular protein upon viral entry. X rays diffraction and NMR studies of free or inhibitor-bound RT have led to the recognition of RT 3D structure, and allowed a thorough understanding of the mode of action of classical competitive nucleoside RT inhibitors (NRTIs) and of the binding of allosteric, non NRTIs (NNRTIs) inhibitors. This also opened an access to computer-aided drug design and modeling. Current NNRTIs represent, in terms of chemical structures, a heterogeneous class of inhibitors currently undergoing extensive development. By contrast with NRTIs, they seem to block initiation steps of reverse transcription. Molecular dynamics, detailed analysis of their interaction with RT as well as the incidence, in the series, of cases of non classical biological behavior, as illustrated here for a new family of compounds, suggest mechanisms of action which are not understandable without considering the involvement of the RTIC as a whole. This opens the exciting perspective of developing new compounds based on this integrated knowledge. Key Words: Nonnucleoside reverse transcriptase inhibitors (NNRTIs); Reverse transcriptase initiation complex (RTIC); Human immunodeficiency virus (HIV); Non classical nonnucleoside reverse transcriptase inhibitors; Molecular modeling; Docking; QSAR; Natural endogenous reverse transcription (NERT).

Drug Delivery Systems↗
PubMed1999

Human immunodeficiency virus type 1 integrase protein promotes reverse transcription through specific interactions with the nucleoprotein reverse transcription complex.

The human immunodeficiency virus type 1 (HIV-1) integrase protein (IN) is essential for integration of the viral DNA into host cell chromosomes. Since IN is expressed and assembled into virions as part of the 160-kDa Gag-Pol precursor polyprotein and catalyzes integration of the provirus in infected cells as a mature 32-kDa protein, mutations in IN are pleiotropic and may affect virus replication at different stages of the virus life cycle in addition to integration. Several different phenotypes have been observed for IN mutant viruses, including defects in virion morphology, protein composition, reverse transcription, nuclear import, and integration. Because the effects of mutations in the IN domain of Gag-Pol can not always be distinguished from those of mutations in the mature IN protein, there remains a significant gap in our understanding of IN function in vivo. To directly analyze the function of the mature IN protein itself, in the context of a replicating virus but independently from that of Gag-Pol, we used an approach developed in our laboratory for incorporating proteins into HIV virions by their expression in trans as fusion partners of either Vpr or Vpx. By providing IN in trans as a Vpr-IN fusion protein, our analysis revealed, for the first time, that the mature IN protein is essential for the efficient initiation of reverse transcription in infected cells and that this function does not require the IN protein to be enzymatically (integration) active. Our findings of a direct physical interaction between IN and reverse transcriptase and the failure of heterologous HIV-2 IN protein to efficiently support reverse transcription indicate that this novel function occurs through specific interactions with other viral components of the reverse transcription initiation complex. Studies involving complementation between integration- and DNA synthesis-defective IN mutants further support this conclusion and reveal that the highly conserved HHCC motif of IN is important for both activities. These findings provide important new insights into IN function and reverse transcription in the context of the nucleoprotein reverse transcription complex within the infected cell. Moreover, they validate a novel approach that obviates the need to mutate Gag-Pol in order to study the role of its individual mature components at the virus replication level.

DNA, Viral↗
PubMed1983

Studies on rapid reversible and non-reversible inactivation of fructose-1,6-bisphosphatase and malate dehydrogenase in wild-type and glycolytic block mutants of Saccharomyces cerevisiae.

Experimental conditions have been elaborated to test for reversibility of the malate dehydrogenase inactivation (E.C.1.1.1.37) after addition of glucose to derepressed yeast cells. Malate dehydrogenase inactivation was shown to be irreversible at all stages of inactivation. In contrast fructose-1,6-bisphosphatase inactivation (E.C.3.1.11) remained reversible for at least 30 min after addition of glucose. Rapid reversible inactivation of fructose-1,6-bisphosphatase and irreversible inactivation of malate dehydrogenase were additionally investigated in glycolytic block mutants. Normal inactivation kinetics were observed in mutants without catalytic activity of phosphoglucose isomerase (E.C.5.3.1.9), phosphofructokinase (E.C.2.7.1.11), triosephosphate isomerase (E.C.5.3.1.1) and phosphoglycerate kinase (E.C.2.7.2.3). Hence, neither type of inactivation depended on the accumulation of any glucose metabolite beyond glucose-6-phosphate. Under anaerobic conditions irreversible inactivation was completely abolished in glycolytic block mutants. In contrast rapid reversible inactivation was independent of energy provided by respiration or fermentation. Reversibility of fructose-1,6-bisphosphatase inactivation was tested under conditions which prevented irreversible malate dehydrogenase inactivation. In these experiments, fructose-1,6-bisphosphatase inactivation remained reversible for at least 120 min, whereas reversibility was normally restricted to about 30 min. This indicated a common mechanism between the irreversible part of fructose-1,6-bisphosphatase inactivation and irreversible malate dehydrogenase inactivation.

Adenosine Triphosphate↗
PubMed1995

Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal anti-inflammatory drug regimen in reversing adenomas exceeding 33 months.

PURPOSE: This nonrandomized, controlled Phase II pilot study aims at the lowest effective dose of rectally applied sulindac to achieve and maintain adenoma reversion in colectomized patients with familial adenomatous polyposis (FAP). METHODS: The study group (n = 15) underwent proctoscopic and laboratory follow-up for polyp reversion every 6 to 12 weeks. Polyp reversion was followed by dose reduction in predefined steps. Proliferating cell nuclear antigen/cyclin (PCNA) and KI-67 proliferation indices (PI) were performed by point counting. Prostaglandin (PG)E2 and PGF2 alpha were quantified by time-resolved competitive fluorescence immunoassay. RESULTS: All patients responded to therapy within 6 to 24 weeks. Sixty and 87 percent of patients achieved complete adenoma reversion after 48 weeks at 53 and 67 mg of sulindac per day per patient on average, respectively. Reversion was evident compared with the control group. Dose reduction by one-sixth to one-eighth of the usual oral dose was significant (Mann's trend test, P < 0.05). PCNA and KI-67 PIs of adenomatous and flat mucosa were significantly reduced (Wilcoxon's test, P < 0.05). Correlation of PCNA and KI-67 PIs indicate similar reaction of different tissue structures (Spearman's rank correlation test, P < 0.01). Nonsteroidal anti-inflammatory drug-induced redifferentiation from high-grade to low-grade dysplasia occurred in all but two patients. Tissue-PGE2 levels were greatly reduced. Unwanted, curable side effects were rare (gastritis, n = 2), and laboratory controls are within detection limits. CONCLUSIONS: Low-dose rectal sulindac maintenance therapy is highly effective in achieving complete adenoma reversion without relapse in 87 percent of patients after 33 months. Rectal FAP phenotype should be crucial for the surgical decision. Colectomy with ileorectal anastomosis and regular chemoprevention might proceed to be a promising alternative to pouch procedures. Chemoprevention with lower incidence of FAP-related tumors via dysplasia reversion may be possible in the future.

Adenomatous Polyposis Coli↗
PubMed2003

Mobility of the Sinorhizobium meliloti group II intron RmInt1 occurs by reverse splicing into DNA, but requires an unknown reverse transcriptase priming mechanism.

The mobile group II introns characterized to date encode ribonucleoprotein complexes that promote mobility by a major retrohoming mechanism in which the intron RNA reverse splices directly into the sense strand of a double-stranded DNA target site, while the intron-encoded reverse transcriptase/maturase cleaves the antisense strand and uses it as primer for reverse transcription of the inserted intron RNA. Here, we show that the Sinorhizobium meliloti group II intron RmInt1, which encodes a protein lacking a DNA endonuclease domain, similarly uses both the intron RNA and an intron-encoded protein with reverse transcriptase and maturase activities for mobility. However, while RmInt1 reverse splices into both single-stranded and double-stranded DNA target sites, it is unable to carry out site-specific antisense-strand cleavage due to the lack of a DNA endonuclease domain. Our results suggest that RmInt1 mobility involves reverse splicing into double-stranded or single-stranded DNA target sites, but due to the lack of DNA endonuclease function, it requires an alternate means of procuring a primer for target DNA-primed reverse transcription.

Base Sequence↗
PubMed2000

Intramolecular charge transfer at reverse micelle-water pool interface: p-N,N-dimethylaminobenzoic acid in AOT/cyclohexane/water reverse micelle.

Photoinduced intramolecular charge transfer (ICT) of p-N,N-dimethylaminobenzoic acid (DMABOA) in AOT/cyclohexane/H2O reverse micelle was investigated and compared with that in CTAB/1-heptanol/H2O reverse micelle. It is proposed that the DMABOA molecule exists at the AOT reverse micelle water pool interface with its carboxylic group heading toward the water pool while the dimethylaminophenyl moiety buried in the micellar phase. Dual fluorescence of DMABOA that is indicative of the ICT reaction in the excited state was observed over the investigated water pool size, W of 3-17, in the AOT reverse micelle. The ICT emission of DMABOA in the AOT reverse micelle-water pool interface was found to be much weaker than that in the CTAB reverse micelle-water pool interface, and was attributed to the parallel direction of the electric field at the AOT reverse micelle-water pool interface to the charge transfer.

4-Aminobenzoic Acid↗
PubMed2001

Characterization of the reversible nature of the reaction catalyzed by sphingolipid ceramide N-deacylase. A novel form of reverse hydrolysis reaction.

Sphingolipid ceramide N-deacylase catalyzes a reversible reaction in which the amide linkages of the ceramides of various sphingolipids are cleaved or synthesized. Hydrolysis of sphingolipids by the enzyme proceeded efficiently at acidic pH in the presence of high concentrations of detergents, whereas the reverse reaction tended to be favored at neutral pH with a decrease in the detergent concentration. Although the catalytic efficiency (V(max)/K(m)) of the hydrolysis and reverse reactions was changed mainly by the concentration of detergents in the reaction mixture, V(max) and K(m) for the reverse reaction were relatively higher than those for the forward reaction, irrespective of the detergent concentration. The reverse reaction proceeded most efficiently when the molar ratio of lyso-sphingolipids and fatty acids was fixed at 1 : 1-2, the yield of the reaction exceeding 70-80%. The reverse and exchange (transacylation) reactions did not require ATP, CoA, metal ions or addition of organic solvents. Studies using inhibitors and chemical modifiers of the enzyme protein suggested that both the hydrolysis and condensation reactions are catalyzed at the same catalytic domain. These results indicate that the reverse hydrolysis reaction of the enzyme is unique, being completely different from those of lipases, proteases and glycosidases reported to date.

Adenosine Triphosphate↗
PubMed1990

Reversibility bull's-eye: a new polar bull's-eye map to quantify reversibility of stress-induced SPECT thallium-201 myocardial perfusion defects.

Myocardial ischemia is currently interpreted from SPECT thallium-201 (201Tl) tomograms by the subjective visual finding of stress-induced perfusion defects which "normalize" or "reverse" by 4 hr. Thus, we have developed a computer method to quantify and display the three-dimensional distribution of reversible segments. Circumferential profiles generated from the short axis slices are normalized to the reference area in the stress study. The stress is subtracted from the normalized delayed data, and then displayed as a polar bull's-eye plot so that positive values show areas that have "reversed" or "improved." Patient profiles are compared to means and standard deviations of reversibility for all pixels determined from the Emory normal male files. Criteria for reversibility were developed from studies of 42 male patients found to have 48 defects, as determined by the consensus of five blinded expert observers. There was computer agreement with the experts on 25 of 31 relatively fixed and 14 of 17 reversible defects. Our preliminary results indicate that this new method promises to aid observers to more consistently identify and quantify the reversibility of SPECT 201Tl myocardial perfusion defects.

Adult↗
PubMed1993

Reverse transcription of the Mauriceville plasmid of Neurospora. Lack of ribonuclease H activity associated with the reverse transcriptase and possible use of mitochondrial ribonuclease H.

The Mauriceville mitochondrial plasmid of Neurospora encodes a reverse transcriptase that synthesizes a full-length cDNA copy of the major plasmid transcript beginning directly opposite the 3' end of the template RNA (Kuiper, M. T. R., and Lambowitz, A. M. (1988) Cell 55, 693-704). Here, we show that the Mauriceville plasmid reverse transcriptase has no detectable RNase H activity and that cDNAs synthesized either by the column-purified reverse transcriptase or by the endogenous reverse transcriptase in purified ribonucleoprotein particles remain in a full-length duplex with the template RNA. The column-purified Mauriceville plasmid reverse transcriptase initiates cDNA synthesis by using short DNA primers, which remain attached to the 5' end of the (-) strand DNA (Wang, H., Kennell, J. C., Kuiper, M. T. R., Sabourin, J. R., Saldanha, R., and Lambowitz, A. M. (1992) Mol. Cell. Biol. 12, 5131-5144). We find that these primer DNAs can be precisely removed by S1 nuclease digestion of the initial cDNA.RNA duplex, suggesting a mechanism whereby this structure may contribute to primer removal in vivo. Finally, we show that Neurospora mitochondria contain an endogenous RNase H activity, which is present in mitochondrial ribonucleoprotein particle preparations prior to their purification. This mitochondrial RNase H can degrade the endogenous plasmid transcript in ribonucleoprotein particles in vitro and could play a similar role in vivo. The finding that the Mauriceville plasmid reverse transcriptase, which is believed to be a primitive enzyme, has no detectable RNase H activity is consistent with the hypothesis that retroviral reverse transcriptases acquired their RNase H domains from a gene encoding a cellular RNase H.

Amino Acid Sequence↗
PubMed1970

The effects of amount of training per reversal on successive reversals of a color discrimination.

Three groups of pigeons were trained on a red-green discrimination in which the stimuli were alternately presented in a multiple schedule of reinforcement. The discrimination was reversed 24 times. Groups were given 1, 2, or 4 hr of training on each discrimination. Increasing the length of training had two principal effects on reversal performance: it increased the rate of extinction of responding to one of the stimuli and increased the rate of reacquisition of responding to the other. The latter effect involved both an increase in reacquisition of responding to a positive stimulus within reversals and an increase in recovery of responding to the previous negative stimulus between reversals. Improvements in performance of each group over the series of reversals were qualitatively similar to the two effects of length of training on each discrimination, and were analogous to effects obtained in other studies involving overtraining and successive reversals of simultaneous discriminations.

Animals↗
PubMed1989

Human laterality reversal auditory evoked potentials: stimulation by reversing the interaural delay of dichotically presented continuous click trains.

Long-latency responses to bidirectional reversals in the laterality of a sound image were recorded from vertex with left and right earlobe references simultaneously. Laterality reversal stimuli with regular ISIs of 3 sec were obtained by alternating between +1 msec and -1 msec the interaural delay (ID) of dichotically presented 70 c/sec continuous click trains. Monaural presentation of this temporal modulation did not evoke any potential or any sensation whereas, when dichotically presented, the same ID modulation was perceived as laterality reversals. Evoked potentials from 9 right-handed volunteers with normal hearing were evaluated. The recorded laterality reversal auditory evoked potentials (LRAEPs) consisted, characteristically, of a negative and a positive wave with average peak latencies of 160 msec and 260 msec, respectively. Statistical analysis indicated significant dependence of the response parameters on the direction of the sound image shifts, but the laterality of the earlobe reference did not prove to be important. The appropriateness of the stimulus parameters employed was discussed from the viewpoint of dynamic systems analysis. By contrasting with the monaural auditory off-responses recorded from the same subjects, it was demonstrated that the laterality reversal responses we obtained did not seem to be non-specific 'rest-to-motion' responses to any change in the acoustic background. Similarities and differences between these laterality reversal responses and various ERP components in the same latency range were also discussed. It is concluded that the LRAEPs introduced in this communication can be used in assessing the functional integrity and studying the dynamics of the neurophysiological system that accomplishes sound lateralization using cues of interaural time disparity (ITD).

Acoustic Stimulation↗
PubMed1979

Reversible depression of electrically-induced contractions of guinea pig longitudinal muscle by a reversible inhibitor of prostaglandin synthetase.

The pesticide chlordimeform (CDM) depressed the electrically-induced twitch responses of the guinea pig longitudinal muscle ED50 = 3 X 10(-5)M). Naloxone reversed twitch depression induced by morphine but not by CDM. Phentolamine reversed twitch depression induced by either norepinephrine or clonidine, but not by CDM. PGE2 completely reversed twitch depression induced by either CDM or indomethacin, but only partially reversed twitch depression induced by lidocaine. The actions of CDM best resemble those of the nonsteroidal anti-inflammatory agents. The reversibility of the CDM depression by washing indicates that the guinea pig ileal preparation is a convenient screen for distinguishing reversible from irreversible inhibitors of prostaglandin biosynthesis.

Amidines↗