Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Daily journals in France recently published a declaration of eight AIDS-assistance associations stating, because of already established resistance of most of types of HIV1 to the so called "tritherapies" 8,000 subjects in France will soon be "in condition of treatment failure". This tritherapeutic "flat note" is a double flat, for relative and absolute reasons: a) relative indeed was the case of well-known results: the tritherapies initially performed better than bitherapies, which had done better than monotherapies; b) absolute is their failure, which induce, as the other types, toxicity, resistance and relapses. Toxicity and resistance are due to the fact that, as the T1/2 of the virus is very short, virostatics must be applied continuously. But in AIDS groups tritherapies are applied not only in a continuous fashion, but in an identical form and for an undefined time, the process which is used in experimental cancer chemotherapy to induce resistant cell lines. Applying them in sequences of 3 weeks (a duration chosen with the knowledge that resistance may occur in about 12 weeks), we have shown in AIDS not only an absence of toxicity, but also an absence of resistance in patients treated with four drugs affecting four different targets. There is indeed another point to underline: AIDS group tritherapies are comprised of three drugs, but whatever the choices of these drugs they affect only two targets: retrotranscriptase and HIV1-protease. We had obtained in the best murine model of HIV1-infection (Friend's virus infection) eradication with a combination of three drugs, AZT, acriflavine (ACF) and the ellipticine analogue methyl-hydroxy-ellipticine (MHE); (the two last were discovered to be rather more efficient that AZT in our virostatic screening). This combination affects three virus targets (AZT, retrotranscriptase; MHE, topoisomerase 2; and ACF, integrated and proviral DNA). The next article will show that sequential drug combinations of three virostatics chosen from ten drugs available, affecting four targets, are more efficient in HIV1-AIDS than three drug combinations affecting three targets because they were chosen from a pool of only five drugs. It will, however, be shown that the same type of sequential combinations with four drug rotations chosen among the ten available ones affecting four targets rapidly reduced, and for years maintained, the viral load at undetectable levels. This level has been < 200 RNA copies/mL during the trial and is, at the end of the study, < 20 RNA copies/mL.
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PMID:Hypothetical reasons of the HIV1-AIDS "tritherapy" failure. A challenging model. 986 99

This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.
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PMID:Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers. 986 98

Between 1992 and 1995, we have had five virostatics available: zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) (as retrotranscriptase nucleosidic antagonists, RTNA), acriflavine (ACF), and hydroxy-methyl-ellipticine (HEL), as respectively a DNA synthesis and structure antagonist, and a topoisomerase II inhibitor. Between 1995 and now, we have had ten virostatics the same, plus lamivudine (3TC), stavudine (d4T) as RTNA, and indinavir (IDV), ritonavir (RTV) and saquinavir (SQV) as protease inhibitors. We first conducted a phase I-like study concerning the ratios of the drug numbers in combinations over the numbers available. The optimal model for the study was that of four virostatics selected out of the ten. The four virostatic combinations were applied in short (3 week) sequences, differing each others by drug rotation. The patients were, before treatment, nine at the phase of AIDS, one at the A3 stage. They presented a very rapid decrease of viral load (VL) which became undetectable at PCR, being first below 200 RNA copies/mL, then below 20. We call this condition 'minimum residual disease' as HIV1 persistence is revealed by virus rebounds, reversible, and probably induced by cofactors. The frequency of the latter selection is due to the very frequent (each 3 weeks) VL evaluations. The last part of the VL exponential curve which the minimum residual disease represents, is almost horizontal and quasi insensitive to the powerful virostatic model described above, though no resistance has appeared at the combination or sequence levels. Thus we propose to add phases of: a) reinforcements by virostatics, adding two more ones to the four of the model; and b) treatment complement by active immunotherapy phases: the most adapted immunomodulator is the combination of the peptidic cytokine, tuftsine, and of its antipeptidase, bestatine If they are not available, another interleukine, able to help restoring the AIDS disturbed immunologic system, interleukin 2, could be tried, as it has induced beneficial effects at very small doses by subcutaneous injections.
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PMID:Combinations of four virostatics applied in rotational sequences induce an exponential VL regression curve, the first part of which is rapidly decreasing to a PCR-undetectable level, while the last part is insensitive to the model. Indications for virostatic and immunotherapeutic reinforcements? 1033 59

Human immunodeficiency virus (HIV) reverse transcription can be notably affected by cellular activation, differentiation, and division. We hypothesized that changes in the cell cycle could also affect HIV susceptibility to nucleoside analogues, which compete with natural nucleotides for incorporation into viral DNA and inhibit viral replication through premature termination of reverse transcription. Proliferating HeLa-derived indicator cells were arrested in the S/G2 phase with etoposide, a topoisomerase II inhibitor, or in the G1/S phase with aphidicolin, a polymerase alpha inhibitor. Cell cycle arrest by both agents induced a remarkable decrease in HIV susceptibility to zidovudine (AZT). This decrease was seen both with a single-cycle infectivity assay and with a viral DNA quantitation assay, indicating that the effect of cell cycle arrest was exerted at the reverse transcription stage. The increase in the 50% inhibitory concentration (IC50) seen with arrested cells was strongest for AZT (23-fold) and stavudine (21-fold) but more modest for other drugs (lamivudine, 11-fold; dideoxyinosine, 7-fold; and nevirapine, 3-fold). In drug-resistant reverse transcriptase mutants, the increase in AZT IC50 (relative to that in dividing cells) was most prominent with a Q151M mutant and was comparable to the wild type in other drug-resistant mutants. Quantitation of intracellular pools of dTTP and AZT 5'-triphosphate (AZTTP) showed that etoposide treatment induced a significant increase in intracellular dTTP and consequently a decrease in AZTTP/dTTP ratios, suggesting that the decrease in viral susceptibility to AZT was caused by reduced incorporation of the analogue into nascent viral DNA. These results emphasize the importance of cellular proliferation and deoxynucleoside triphosphate metabolism in HIV susceptibility to nucleoside analogues and underscore the need to study the activities of drugs of this class with natural target cells under physiological conditions of activation and proliferation.
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PMID:Effect of cell cycle arrest on the activity of nucleoside analogues against human immunodeficiency virus type 1. 1628 81