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W R Wilson

Publications and source records attributed to W R Wilson.

At least 181 records · Page 10Linked to original sources
PubMed1990

DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard.

A series of DNA-targeted aniline mustards have been prepared, and their chemical reactivity and in vitro and in vivo cytotoxicity have been evaluated and compared with that of the corresponding simple aniline mustards. The alkylating groups were anchored to the DNA-intercalating 9-aminoacridine chromophore by an alkyl chain of fixed length attached at the mustard 4-position through a link group X, while the corresponding simple mustards possessed an electronically identical small group at this position. The link group was varied to provide a series of compounds of similar geometry but widely differing mustard reactivity. Variation in biological activity should then largely be a consequence of this varying reactivity. Rates of mustard hydrolysis in the two series related only to the electronic properties of the link group, with attachment of the intercalating chromophore having no effect. The cytotoxicities of the simple mustards correlated well with group electronic properties (with a 200-300-fold range in IC50S). The corresponding DNA-targeted mustards were much more potent (up to 100-fold), but their IC50 values varied much less with linker group electronic properties. Most of the DNA-targeted mustards showed in vivo antitumor activity, being both more active and more dose-potent than either the corresponding untargeted mustards and chlorambucil. These results show that targeting alkylating agents to DNA by attachment to DNA-affinic units may be a useful strategy.

Alkylating Agents↗
PubMed1990

Hypoxia-selective antitumor agents. 4. Relationships between structure, physicochemical properties, and hypoxia-selective cytotoxicity for nitracrine analogues with varying side chains: the "iminoacridan hypothesis".

The nitroacridine derivative nitracrine is a potent hypoxia-selective cytotoxin for mammalian cells in culture. In an attempt to modulate the degree of hypoxia selectivity among this class of compounds, we have studied a series of side-chain analogues of nitracrine. Both the electronic and steric properties of the side chain are shown to be important in determining the hypoxia selectivity of the compounds, by controlling the degree of aminoacridine/iminoacridan tautomerism. Studies with the repair-defective Chinese hamster cell line UV4 indicate that the cytotoxicity of all the compounds is due to nitro group reduction and subsequent macromolecular adduct formation. However, compounds such as the 9-amino derivative, which exist totally as the aminoacridine tautomer, form much less lethal lesions than the 9-alkylamino derivatives, which exist to varying degrees in the iminoacridan conformation. For the whole set of compounds, the degree of hypoxia-selective cytotoxicity correlates well with the proportion of iminoacridan tautomer present.

Aminoacridines↗
PubMed1990

DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain.

Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.

Acridines↗
PubMed1990

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels.

EMT6 multicellular spheroids were introduced into the peritoneal cavities of mice and allowed to become vascularised, resulting in solid spherical tumours. The necrotic cores of the initially avascular spheroids were replaced by vascularised tumour tissue but the outer zones of the spheroids failed to become vascularised. The presence of both vascular and avascular components in each spheroid allowed the role of the vasculature in the antitumour action of flavone acetic acid (FAA) to be determined. Eighteen hours after treatment with FAA 0.8 mmol kg-1, the vascularised core became necrotic and haemorrhagic, while the outer avascular zone remained viable. Tumour cells which were infiltrating superficial sub-mesothelial fat did not become necrotic despite the presence of numerous thrombi in associated vessels. Injection of two fluorescent vascular markers, the first (Hoechst 33342) together with FAA, and the second (10-nonyl acridine orange) 4 h later, demonstrated that there is a marked loss of blood flow in the spheroids. These results provide further evidence that FAA kills blood vessel-dependent tumour cells by interrupting the tumour blood supply.

Acridine Orange↗
PubMed1990

Ciprofloxacin therapy of experimental endocarditis caused by methicillin-resistant Staphylococcus epidermidis.

Ciprofloxacin or rifampin was significantly (P less than 0.05) more effective than vancomycin or the combination of vancomycin plus gentamicin for the treatment of Staphylococcus epidermidis experimental endocarditis. There were no significant differences in efficacy among any of the combinations of antimicrobial agents that included ciprofloxacin or rifampin. One animal treated with rifampin alone and one treated with the combination of vancomycin, rifampin, and gentamicin were found to be infected with rifampin-resistant strains of S. epidermidis during therapy. Resistant subpopulations of S. epidermidis were not detected during therapy with any other antimicrobial agent used alone or in combination. Ciprofloxacin alone or in combination with rifampin was effective therapy against S. epidermidis experimental endocarditis.

Animals↗
PubMed1990

Transseptal approaches for pituitary surgery.

Our experience with over 147 operations for pituitary disease has given us an opportunity to use and evaluate four separate transseptal approaches. Three approaches have been described previously in the literature: the sublabial transseptal, the open rhinoplasty, and the alotomy with anterior septal dissection. The fourth approach, alotomy with posterior septal dissection, is described here. The advantages and disadvantages of each are discussed, as are the complications of transseptal surgery. A working knowledge of the various transseptal approaches to the pituitary is imperative for the otolaryngologist who participates in pituitary surgery.

Humans↗
PubMed1990

Nitro analogues of chlorambucil as potential hypoxia-selective anti-tumour drugs.

The chlorambucil isomer 4-[3-[N,N-bis(2-chloroethyl)amino]phenyl] butanoic acid (m-chlorambucil) has been synthesized for the first time, and the two isometric nitro derivatives of both m-chlorambucil and chlorambucil itself have been prepared as potential hypoxia-selective cytotoxins. Reduction potentials (E1/2) of the two nitro compounds were determined by cyclic voltammetry, and one-electron reduction potentials (E(1] were estimated. Both the chlorambucil isomers and the derived nitro compounds crosslink DNA, as determined by their cytotoxicity ratios in DNA repair-proficient and -deficient cell lines, but neither of the nitro derivatives showed selective toxicity under hypoxic conditions, probably due to their rather low reduction potentials.

Animals↗
PubMed1990

Radiosensitization of mammalian cells in vitro by nitroacridines.

The nitroacridine nitracrine (1-NC) is a DNA intercalator and a hypoxia-selective, electron-affinic radiosensitizer. Sensitization of Chinese hamster fibroblast cultures at 0 degrees C by the nitro positional isomers of 1-NC has now been compared to help establish structure-activity relationships. The des-nitro analog (E(1) at pH 7 = -899 mV) did not sensitize, suggesting that an electron-affinic chromophore is required. All the nitroacridines (E(1) range -376 to -257 mV) sensitized hypoxic cells with a maximum sensitizer enhancement ratio of about 1.7, but with a 200-fold range in potency. When mean intracellular drug concentrations were compared, 2-, 3-, and 4-NC had potencies which were similar, independent of E(1), and no greater than predicted for non-DNA binding nitroheterocycles. Sensitization by these three isomers occurred at intracellular concentrations likely to saturate the potential intercalation sites on DNA. A large fraction of the radical sites sensitized by O2 are apparently inaccessible to these drugs. It is suggested that sensitization results from electron transfer from migrating transient charge carriers of low reduction potential to immobile bound intercalators. An additional sensitizing mechanism may be available to 1-NC, which was 20 times more potent, a potency not accounted for by E(1), cell uptake, or DNA binding affinity. The dissociation kinetics of the DNA-drug complex was faster for 1-NC than for the other isomers. The higher potency of 1-NC may reflect a short mean residence time (less than 1 ms) in its intercalation site, allowing significant mobility on the DNA within the lifetime of relatively stable radiation-induced target radicals.

Acridines↗
PubMed1989

Blood flow failure as a major determinant in the antitumor action of flavone acetic acid.

Some investigators have suggested that the marked activity of flavone acetic acid (FAA) against advanced solid tumors in mice results from an indirect effect. This study indicates that the critical effect of FAA is irreversible inhibition of tumor blood flow. Perfusion of sc Colon 38 tumors, assessed with H33342 as a fluorescent stain for functional blood vessels, was reduced to 50% of controls within 3 hours of an ip injection of 1.2 mmol of FAA/kg and was completely inhibited by 24 hours. A double-label fluorescence technique demonstrated a significant decrease in blood flow in both sc Colon 38 and im EMT-6/Ak tumors as early as 15 minutes after iv treatment with 1.2 mmol of FAA/kg, with progressively enlarging zones of perfusion failure. The rate of cell death in totally ischemic EMT-6 tumors was shown to be sufficiently rapid to represent a major component of the observed antitumor effect of FAA if the flavonoid acts via inhibition of blood flow. Further, avascular EMT-6/Ak multicellular spheroids growing in the mouse peritoneum are relatively resistant to killing by FAA administered iv or ip, despite extensive infiltration with host immune cells. These results indicate that inhibition of tumor blood flow by FAA is a necessary component of its antitumor activity against solid tumors.

Animals↗
PubMed1989

Side-effects of ivermectin in treatment of onchocerciasis.

In a prospective study to determine the tolerance for and safety of ivermectin therapy for onchocerciasis in a hyperendemic area in Sierra Leone, 28 (32%) of 87 patients had adverse reactions that required treatment with acetylsalicylic acid and antihistamines, but none of the observed adverse reactions were considered life-threatening. A significant relation was found between the frequency and severity of side-effects and the degree of parasite infestation, as quantified by the skin-snip counts. Free administration of ivermectin to severely infected onchocerciasis patients is not recommended without some form of medical supervision.

Adult↗
PubMed1989

Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs.

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4'-(9-acridinylamino)-methanesulphon-O-anisidide (O-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [14C] CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by O-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC cytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a 'cleavable complex' in which the DNA is covalently linked to the enzyme.

Aminacrine↗
PubMed1989

The reaction between nitracrine and glutathione: implications for hypoxic cell radiosensitization and cytotoxicity.

Nitracrine (NC) is an electron affinic DNA intercalating agent and a potent hypoxia-selective cytotoxin and radiosensitizer in cell culture. Although NC is too cytotoxic and too rapidly metabolized to provide hypoxic cell radiosensitization in tumors, it is of mechanistic interest as an example of a DNA affinic radiosensitizer. We have observed a rapid chemical reaction between NC and reduced glutathione (GSH), which suggests that the observed potent in vitro cytotoxicity and radiosensitization might be dependent on thiol depletion by the large extracellular reservoir of drug. However, no GSH depletion was observed under conditions providing radiosensitization or rapid cell killing, and prior depletion of GSH by buthionine sulphoximine had no effect on cytotoxicity or formation of macromolecular adducts. Further, the intracellular reaction of NC with GSH is slower than predicted on the basis of the measured second order rate constant and the total intracellular concentrations of both species. The results are consistent with a role for DNA binding in protecting NC from reaction with GSH, and in improving the efficiency with which reduced electrophilic metabolites react with DNA in preference to GSH.

Aminoacridines↗
PubMed1989

Hypoxia-selective antitumor agents. 1. Relationships between structure, redox properties and hypoxia-selective cytotoxicity for 4-substituted derivatives of nitracrine.

The nitroacridine derivative 9-[[3-(dimethylamino)propyl]amino]-1-nitroacridine (nitracrine) is selectively cytotoxic to hypoxic tumor cells in culture. However, the compound undergoes reductive metabolism too rapidly, with the reduction not being sufficiently inhibited by molecular oxygen in aerobic tissues, for it to demonstrate the same activity in vivo. In a search for derivatives with lower reduction potentials, we have synthesized and evaluated a series of derivatives bearing 4-substituents with a wide range of electronic properties. The one-electron reduction potentials (E(1] of these compounds, when compared under conditions of equivalent ionization, were highly correlated with sigma p values. However, at pH 7 the influence of substituent electronic properties was modified by prototrophic equilibria, with the basic nature of the acridine limiting the extent to which ring substituent electronic effects can be used to modulate reduction potential of the 1-nitro group. Nevertheless, comparison of the kinetics of the killing of AA8 cells under hypoxia suggests that some metabolic stabilization of the compounds can be achieved by the use of electron-donating substituents, with such compounds retaining the hypoxia-selective toxicity of nitracrine in cell culture. However, the 4-substituted nitracrines show no clear relationship between E(1) and cytotoxic potency, in distinct contrast to simpler nitroheterocycles such as nitroimidazoles.

Aminoacridines↗
PubMed1989

Hypoxia-selective antitumor agents. 2. Electronic effects of 4-substituents on the mechanisms of cytotoxicity and metabolic stability of nitracrine derivatives.

The mechanism of cytotoxicity of a series of 4-substituted derivatives of 9-[[3-(dimethylamino)propyl]amino]-1-nitroacridine (nitracrine) has been studied, using a panel of DNA repair-defective mutants of the Chinese hamster ovary cell line AA8. Cell lines UV-4 and UV-5 were hypersensitive to nitracrine, with sensitivities approximately 10-fold greater than that of AA8, while EM-9 showed a hypersensitivity factor (HF) of about 2-fold. This pattern suggests the major cytotoxic lesions induced by nitracrine are bulky DNA monoadducts, rather than DNA interstrand cross-links as previously suggested. The desnitro analogue of nitracrine, which retains the intercalative potential of the latter but cannot be metabolically activated by nitro reduction, showed no hypersensitivity, indicating the specificity with which this panel of cell lines can discriminate different types of DNA damage. Several of the highly cytotoxic 4-substituted nitracrine derivatives showed HFs similar to that of the parent, but the less potent 4-dialkylamino and 4-COOMe derivatives showed much lower HFs for UV-4, suggesting that different mechanisms of cytotoxicity contribute. All compounds showed similar HFs under both aerobic and hypoxic conditions, indicating that hypoxia-selective toxicity in this series is due to a quantitative rather than qualitative change in the presence of oxygen. Rates of metabolic consumption of the compounds were measured under both aerobic and hypoxic conditions by bioassay against the sensitive UV-4 cell line. The results agreed well with previous inferences on metabolic stability derived from cell-killing kinetics and showed that electron-donating 4-substituents can be used to increase metabolic stability in vitro. Such stabilization may enhance the therapeutic utility of the nitroacridines in cancer therapy since rapid metabolism of nitracrine appears to prevent its activity against hypoxic cells in solid tumors.

Aminoacridines↗
PubMed1989

Lack of extracellular slime effect on treatment outcome of Staphylococcus epidermidis experimental endocarditis.

We studied the response of two slime negative Staphylococcus epidermidis strains (NS1 and NS2) and one slime producing strain (S1) to treatment with vancomycin in the rabbit catheter-induced endocarditis model. All micro-organisms had vancomycin minimal inhibitory concentration and minimal bactericidal concentration of 4 mg/l. Three days after infection, treatment with vancomycin 25 mg/kg every 12 h was begun and continued for 4 days. Cardiac valve vegetations were harvested 12 h after the last dose of vancomycin and cultured quantitatively. In treated animals the mean +/- S.D. log10 colony forming units per g of cardiac valve vegetation were 1.6 +/- 0.1 for NS1, 4.4 +/- 1.9 for NS2, and 2.3 +/- 1.2 for S1. Slime production did not influence the results of vancomycin therapy of S. epidermidis experimental endocarditis. Other factors may cause strain-dependent variability in response to antimicrobial treatment in this model.

Animals↗