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PubMed1993

Trypanosoma evansi: in vivo and in vitro determination of trypanocide resistance profiles.

We have determined the in vivo and in vitro sensitivities to six common trypanocides of two groups of trypanosomes, (1) two Trypanosoma equiperdum clones and three Trypanosoma evansi clones originating from Asia, Latin America, and Africa; and (2) six laboratory-derived drug-resistant subclones from two of the T. evansi and one of the T. equiperdum clones. We found that (1) we could induce trypanocide resistance by successive passage through mice treated with subtherapeutic doses of drugs; (2) clones selected for resistance to berenil and cymelarsan are not cross-resistant to suramin; (3) clones resistant to berenil, cymelarsan, and suramin are more sensitive to quinapyramine in vivo than the parental clones; (4) berenil resistance is stable; (5) some berenil-resistant clones acquire resistance to cymelarsan; (6) in vivo resistance to isometamidium is not detectable in vitro; and (7) the in vitro sensitivities to berenil and cymelarsan of parental clones and their laboratory-derived resistant subclones generally agreed with the in vivo results. We conclude that with further refinement the in vitro assay procedure may be useful for rapid determination of the sensitivity of trypanosome isolates to some current drugs and for screening new trypanocides. Our data also raise the possibility that conventional treatment regimens should be reevaluated and support the presence of at least two drug-resistance mechanisms in T. evansi and T. equiperdum, single drug resistance (berenil), and cross-resistance (berenil and cymelarsan).

Animals↗
PubMed1996

Minor groove binding ligands alter the rotational positioning of DNA fragments on nucleosome core particles.

We have used hydroxyl radical and DNase I footprinting to examine the interaction of four AT-selective minor groove binding ligands (Hoechst 33258, distamycin, netropsin and berenil) with DNA fragments which have been reconstituted with nucleosome core particles. Hydroxyl radical footprints of reconstituted tyrT DNA show that all four ligands induce changes in the phased cleavage pattern, consistent with the suggestion that they cause the DNA to rotate by 180 degrees on the nucleosome surface. This observation was confirmed by a series of hydroxyl radical and DNase I footprinting experiments on a synthetic DNA fragment containing five different (A/T)4 sites spaced ten bases apart, in phase with the nucleosomal repeat. This fragment produces a phased cleavage pattern when bound to the nucleosome cores, with minima in the AT regions, suggesting that these regions are positioned with their narrow minor grooves facing towards the protein surface. In the presence of the minor groove binding ligands the hydroxyl radical cleavage maxima are shifted by about five base-pairs. It appears that the ligands have caused the DNA to rotate by about 180 degrees on the protein surface; those DNA regions which were facing out are turned in and vice versa. Regions to which the ligands are bound are turned away from the protein surface, thereby minimising electrostatic repulsion between the cationic charges on the ligand and protein. The absence of any observable footprints in the AT-regions suggests that these changes are induced at low levels of occupancy.

Base Composition↗
PubMed2002

Inhibition of DNA replication by berenil in plasmids containing Poly(dA)poly(dT) sequences.

The effect of berenil on plasmid DNA replication was studied on pBR322-derived plasmids containing poly(dA)poly(dT) sequences. In comparison to the parental plasmid pBR322, plasmid pKH47 harboring 100 bp of poly(dA)poly(dT) at the PvuII site showed a decrease in plasmid yield in the presence of berenil. This effect was also observed in pVL26, a related plasmid in which the location of the poly(dA)poly(dT) region had been shifted to the EcoRV site in pBR322. [(3)H]Thymidine incorporation experiments indicated that DNA synthesis may be affected in these plasmids in the presence of the drug. Bromodeoxyuridine incorporation experiments coupled to Cs(2)SO(4) equilibrium density gradient centrifugation indicated that the lower plasmid yield was due to an inhibition of DNA replication by berenil. We have also found that berenil induces DNA degradation in plasmids containing the homopolymer. Our studies strongly suggest that the effect of berenil on plasmid replication and DNA stability results from its binding to the poly(dA)poly(dT) region present in these plasmids. Moreover, we have found a correlation between the position of the poly(dA)poly(dT) region and this inhibitory effect. Thus, plasmid pKH47, containing the poly(dA)poly(dT) region most proximal to the origin of pBR322 replication, was most severely affected.

DNA↗
PubMed1988

Studies on DNA topoisomerase activity during in vitro chromatin assembly.

The in vitro assembly of chromatin, promoted by the Xenopus cell-free extract (S-150), can be inhibited by oxolinic acid and to a lesser extent by nalidixic acid. Both of these antibiotics have been shown to block the activity of the specialized type II Topoisomerase, bacterial DNA Gyrase. Oxolinic acid induces a DNA cleavage by Micrococcal Nuclease at specific sequences in the multiple cloning vector pGEM-4. Nalidixic acid does not inhibit DNA supercoiling, but does diminish the extent of chromatin formation achieved by the S-150 on circular DNA templates. The Topoisomerase I inhibitor, berenil, does not inhibit extensive chromatin assembly, although it does diminish the level of supercoiling. Taken together, these results suggest that both topoisomerases play a role in the assembly process. Topoisomerase I may catalyze both the introduction of unconstrained supercoils into relaxed DNA and the formation of monosomes, while Topoisomerase II may promote extended chromatin assembly.

Animals↗
PubMed1979

Studies on the induction of petite mutants in yeast by analogues of berenil. Characterization of three mutants resistant to the compound Hoe 15,030.

Compound Hoe 15,030 is an analogue of berenil which is as effective as berenil in inducing petite mutants in Saccharomyces cerevisiae. Hoe 15,030 has greater stability than berenil in aqueous solution, and is less toxic to yeast at high drug concentrations. Mutants of S. cerevisiae strain J69-1B have been isolated which are resistant to the petite inducing effects of Hoe 15,030. Three mutant strains (HR7, HR8 and HR10) were characterized and each was shown to carry a recessive nuclear mutation determining resistance to Hoe 15,030. The degree of resistance to Hoe 15,030 is different for each mutant, and each was found to be co-ordinately cross-resistant both to berenil and to another analogue of berenil, Hoe 13,548. However, the three mutants show no cross-resistance to other unrelated petite inducing drugs, including ethidium bromide, euflavine and 1-methyl phenyl neutral red. Further studies on the mutants revealed that each strain exhibits characteristic new properties indicative of changes in mitochondrial membrane functions concerned with the replication (and probably also repair) of mitochondrial DNA. Thus, mutant HR7 is hypersensitive to petite induction by the detergent sodium dodecyl sulphate under conditions where the parent J69-1B is unaffected by this agent. Mutant HR8 is even more sensitive to sodium dodecyl sulphate than is HR7, and additionally shows a markedly elevated spontaneous petite frequency. Isolated mitochondria from strains HR8 and HR10 (but not HR7) show resistance to the inhibitory effects of Hoe 15,030 on the replication of mitochondrial DNA in vitro.

DNA Replication↗
PubMed1987

The fragile site (16)(q22). II. Sister chromatid exchanges.

In the lymphocytes of heterozygous carriers of the rare autosomal fragile site (16)(q22) an exceptionally high frequency of sister chromatid exchanges was demonstrated at the induced fragile site by means of simultaneous berenil and BrdU treatment of the cultures. The rate of sister chromatid exchanges at q22 is also increased in the fragile chromosome 16 by treating the cells with BrdU alone. The possible reasons for the preferential occurrence of induced and spontaneous sister chromatid exchanges at fra (16)(q22) are discussed.

Bromodeoxyuridine↗
PubMed1983

The role of the nuclear gene "mitochondrial mutability control" (MMC1) in the process of mutability of the mitochondrial genome by different mutagens in Saccharomyces cerevisiae.

The accumulation of respiratory deficient (RD) mutants in Saccharomyces cerevisiae depended upon the mutagens used and upon the presence of the nuclear gene previously identified as MMC1 (one) which we showed to control the spontaneous and the erythromycin-induced RD mutability. In this paper data are reported about the accumulation of RD mutants in the presence of manganous ions (Mn++) and UV which was higher in the mmc1 (one) than in MMC1 strains. We found that the characters 'low spontaneous' and 'low induced' RD mutability by erythromycin, manganous ions and UV, were controlled by the same genetic determinant. In the presence of manganous ions, also the frequency of antibiotic resistant mutants capR and eryR was higher in the mmc1 strains. Moreover, the accumulation of RD mutants in the presence of berenil, 5-fluorouracil and basic fuchsin was higher in the mmc1 than in MMC1 strains. In contrast, RD mutants accumulation by acriflavine and ethidium bromide treatments did not appear affected by the MMC1 genetic constitution.

Acriflavine↗
PubMed1975

Biogenesis of mitochondria. 43. A comparative study of petite induction and inhibition of mitochondrial DNA replication in yeast by ethidium bromide and berenil.

The action of ethidium bromide and berenil on the mitochondrial genome of Saccharomyces cerevisiae has been compared in three types of study: (i) early kinetics (up to 4 h) of petite induction by the drugs in the presence or absence of sodium dodecyl sulphate; (ii) genetic consequences of long-term (8 cell generations) exposure to the drugs; (iii) inhibition of mitochondrial DNA replication, both in whole cells and in isolated mitochondria. The results have been interpreted as follows. Firstly, the early events in petite induction differ markedly for the two drugs, as indicated by differences in the short-term kinetics. After some stage a common pathway is apparently followed because the composition of the population of petite cells induced after long-term exposure are very similar for both ethidium bromide and berenil. Secondly, both drugs probably act at the same site to inhibit mitochondrial DNA replication, in view of the fact that a petite strain known to be resistant to ethidium bromide inhibition of mitochondrial DNA replication was found to have simultaneously acquired resistance to berenil. From consideration of the drug concentrations needed to inhibit mitochondrial DNA replication in vivo and in vitro it is suggested that in vivo permeability barriers impede the access of ethidium bromide to the site of inhibition of mitochondrial DNA replication, whilst access of berenil to this site is facilitated. The site at which the drugs act to inhibit mitochondrial DNA replication may be different from the site(s) involved in early petite induction. Binding of the drugs at the latter site(s) is considered to initiate a series of events leading to the fragmentation of yeast mitochondrial DNA and petite induction.

Amidines↗
PubMed1977

Mitochondrial DNA replication in petite mutants of yeast: resistance to inhibition by ethidium bromide, berenil and euflavine.

Mitochondrial DNA (mtDNA) replication in petite mutants of Saccharomyces cerevisiae is generally less sensitive to inhibition by ethidium bromide than in grande (respiratory competent) cells. In every petite that we have examined, which retain a range of different grande mtDNA sequences, this general phenomenon has been demonstrated by measurements of the loss of mtDNA from cultures grown in the presence of the drug. The resistance is also demonstrable by direct analysis of drug inhibition of mtDNA replication in isolated mitochondria. Furthermore, the resistance to ethidium bromide is accompanied, in every case tested, by cross-resistance to berenil and euflavine, although variations in the levels of resistance are observed. In one petite the level of in vivo resistance to the three drugs was very similar (4-fold over the grande parent) whilst another petite was mildly resistant to ethidium bromide and berenil (each 1.6-fold over the parent) and strongly resistant (nearly 8-fold) to inhibition of mtDNA replication by euflavine. The level of resistance to ethidium bromide in several other petite clones tested was found to vary markedly. Using genetic techniques it is possible to identify those petites which display an enhanced resistance to ethidium bromide inhibition of mtDNA replication. It is considered that the general resistance of petites arises because a product of mitochondrial protein synthesis is normally involved in facilitating the inhibitory action of these drugs on mtDNA synthesis in grande cells. The various levels of resistance in petites may be modulated by the particular mtDNA sequences retained in each petite.

Acridines↗
PubMed1982

The possible use of Trypanosoma musculi infection in mice as a screening test for potential Trypanosoma cruzi-active drugs.

The ability of a range of trypanocidal drugs, including a number known to be active in Trypanosoma cruzi infections were tested against Trypanosoma musculi infections in the mouse. The ability of these drugs, particularly in their ability to eliminate the "cryptic phase" of T. musculi infections remaining in the kidneys, was investigated and their activity against this phase of T. musculi largely paralleled their known activity against T. cruzi infections. It is suggested that this could be used as a preliminary screening test for potential T. cruzi-active drugs.

Animals↗
PubMed1992

Trypanocidal drugs and their effect on parasitaemia, specific IgG production and protective immunity in rats infected with Trypanosoma lewisi.

In rats infected with Trypanosoma lewisi, parasitaemia normally resolves by day 32; thereafter, the rodents become solidly immune to re-infection. Rats treated on day 5 of infection with a single i.m. dose of 35 mg/kg of the trypanocidal drug ethidium bromide (EB) had recovered from parasitaemia by day 12, whereas berenil (BE) given at 100 mg/kg, more than twice the recommended dose, had no effect on parasitaemia. However, rats treated for 4 consecutive days beginning on day 5 of infection with Lampit (LA) and Radanil (RA) at 350 mg/kg showed no parasitaemia on days 16 and 20, respectively. EB was the most effective drug in lowering the total IgG antibody as compared with the control animals, whose specific IgG titres remained elevated for over 200 days after the parasitaemia had been cleared. LA also significantly reduced the antibody levels through day 240, whereas RA only transitorily depressed the antibody levels on days 20 and 30. BE, which had no effect on parasitaemia, correspondingly failed to depress the total IgG levels. Re-challenge infection of the drug-treated, recovered animals on day 240 (208 days after the normal resolution of the infection) revealed that except for the EB group, which displayed transitory parasitaemia for 4 days, other treated and control rats completely resisted the challenge; pre-challenge antibody titres were lower than 1:160 in EB-treated animals in contrast to the levels of 1:320 or higher measured in the other drug-treated and control animals, which resisted the infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Polyamine content and drug sensitivities of different clonal lines of Leishmania infantum promastigotes.

Two isolates (skin and lymph node) of Leishmania infantum obtained from a naturally infected dog were cloned and the free pools of polyamines for both complete isolates and clones were determined. Putrescine (Put) and spermidine (Spd) levels were highly variable among the lines studied, ranging from 0.89 to 2.1 nmol Spd/10(7) promastigotes. The Put/Spd ratio was also variable (1.54-0.51) and correlated with the cell growth of the lines studied. There were important differences in the clones' sensitivities to difluoromethylornithine (DFMO) and Berenil, with some of the clones being almost refractory to the inhibitory effect of 50 microM DFMO, whereas the growth of others was reduced by 60%; similar findings were obtained with 50 microM Berenil. L. infantum sensitivities to DFMO and Berenil were correlated and apparently related to the values for the Put/Spd index.

Animals↗
PubMed1989

Biochemical and genetic analysis of toxic effect of HOE 15030 in mammalian cells.

HOE 15030 inhibited the growth of BHK cells at concentrations that did not inhibit their nuclear DNA and RNA syntheses. When BHK cells were cultured in the presence of 30 micrograms/ml of HOE 15030, cells were arrested in the G1 phase after one or two cell divisions. After removal of the drug, cells progressed through the G1 to the S phase. HOE 15030 inhibited the activities of both topoisomerases I and II in vitro. To determine the target molecule of HOE 15030 in cells, we isolated a HOE 15030-resistant (HOEr) mutant of BHK cells. The HOEr cells exhibited cross-resistance to ethidium bromide, acriflavine, and rhodamine 123, and slight cross-resistance to 4'-dimethylepipodophyllotoxin-4-(4,6-O-ethylidine-beta-D-glu copyranoside) (VP-16) and adriamycin, but not to chloramphenicol, oligomycin, novobiocin, colchicine, or vinblastine. The uptake and retention of rhodamine 123 by HOEr cells were lower than those by BHK cells. Mitochondrial DNA synthesis of HOEr cells was more resistant to HOE 15030 and ethidium bromide than that of wild-type cells. These results indicate that the resistance of HOEr cells to drugs is due to reduced uptake or accumulation of the drugs by mitochondria and suggest that the mitochondria are the main target of HOE 15030 in cells.

Amidines↗
PubMed1978

The successful use of work oxen in agricultural development of tsetse infested land in Ethiopia.

For the past five years a herd of work oxen, now numbering some 450 individuals, has been maintained under the protection of trypanocidal drugs on a settlement scheme in an area of western Ethiopia infested with tsetse. This paper describes the environmental conditions and the epizootiology of trypanosomiasis in the oxen and in the vector, Glossina morsitans. It is concluded that with the strategic use of drugs, oxen can be kept alive and perform useful agricultural work, in areas of high tsetse challenge, provided reasonable standards of veterinary supervision and management are maintained.

Agriculture↗
PubMed1979

The economic effects of trypanosomiasis in sheep and goats at a range research station in Kenya.

A study on the economic effects of naturally acquired trypanosomiasis in sheep and goats over a period of 35 weeks under range conditions in the Kiboko area of Kenya indicated that the financial loss from reduced weight gain and death amounted to 36.2 and 62.9 Kenya shillings per head for goats and sheep respectively. This was derived from the weight loss through death together with the reduced weight gain of the survivors compared with treated animals. The study also compared the efficacy of 3 drug regimes in goats and suggests that although quinapyramine (prophylactic) B.vet.C. provided the longest protective period, the weight increase of the stock under isometamidium chloride treatment was higher. The benefits of the drugs used are discussed.

Animals↗
PubMed1981

Acute Trypanosoma vivax infection in dairy cattle in Coast Province, Kenya.

In an outbreak of a fatal haemorrhagic disease in exotic dairy cattle (Friesian, Guernsey, Ayrshire and Jersey) on 2 farms in the Coast Province of Kenya, and investigation was conducted to establish the aetiological agent involved. Blood and lymph node smears made from clinically sick cattle indicated infection with Trypanosoma vivax. Five calves were then experimentally inoculated with heparinised blood from cows naturally infected with T. vivax. All calves had a high T. vivax parasitemia, marked depression and fever; 2 developed blood-tinged diarrhoea 6 and 7 days were treated with isometamidium chloride while others were left untreated. Cases of abortions, bloody diarrhoea and deaths dropped markedly in the treated animals whereas they continued to occur in the untreated animal.

Acute Disease↗
PubMed1994

Trypanosoma brucei, T. congolense and T. vivax infections in horses on a farm in Kenya.

Equines are particularly susceptible to infection with Trypanosoma evansi and T. brucei, but rarely is natural T. congolense and T. vivax infection seen in horses. An outbreak of trypanosomosis occurred in a herd of horses used for patrolling the pineapple fields on the Del Monte Farm, Thika, Kenya initially involving 6 horses. On subsequent screening of the entire group, T. brucei, T. congolense and T. vivax infections were detected in 16 of the 35 horses. The tests used for diagnosis included microscopic examination of stained blood smears, buffy coat technique, mouse inoculation and antigen detection enzyme immunoassay (antigen ELISA).

Animals↗