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.     

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 2: Ring-Substituted Derivatives

A range of 18 derivatives of flavone-8-acetic acid (FAA) with substituents on the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. There was no clear-cut relationship between in vitro and in vivo activity but the activity in each situation was found to be very sensitive to the precise substitution pattern with closely related isomers giving widely different activities. Some of the compounds, notably 10b,cj , and r , were active in vivo and these require further studies in order to evaluate their potential for development.     

Investigations of a novel ferrocene-containing lipid by cyclic voltammetry and cryogenic transmission electron microscopy

A novel chiral redox-active ferrocene compound (FcVI) with amphiphilic properties has been synthesized. Cryogenic Transmission Electron Microscopy (cryo-TEM) has been used to estimate the shape and size of the FcVI aggregates in solution. Uni- and multi-lamellar vesicles (between 40 and 300 nm in diameter) were observed in water. Large particles (of more than 1 μm in diameter) with a hexagonal fine structure were found in 50 mM aqueous Na₂SO₄ solution. Sonication transformed the latter into ‘rosette’-like structures. Cyclic voltammetry has been employed to investigate the electrochemical properties of FcVI. The amphiphile adsorbed on graphite electrodes and a reversible electrochemical behaviour, characteristic of ferrocene, was observed with redox potentials between 330 and 350 mV.     

Scintigraphic assessment of an ophthalmic gelling vehicle in man and rabbit

Studies of the rate of clearance of a gellan gum formulation (Gelrite) radiolabelled by the inclusion of technetium-99m labelled diethylenetriaminepentaacetic acid were carried out in volunteer subjects and in rabbits. Disposition was followed by gamma scintigraphy and compared with 0.5% w/v hydroxyethylcellulose (HEC) solution and isotonic saline administered to the same subjects. Clearance of all solutions was found to follow bi-exponential kinetics with differences in clearance rates between the two species studied. A significant retention of the gellan gum formulation compared to HEC (p = 0.006) or saline (p = 0.009) was noted in man, but not in the rabbit. In this latter species the HEC showed greater retention compared to Gelrite. The species-specific differences in the precorneal residence of the formulations are attributed to the different physiological responses following instillation of solutions into the eye.     

Successful treatment of superior vena cava syndrome with urokinase in an infant

An 11-month-old infant with a central venous catheter for total parenteral nutrition for short gut syndrome developed head and neck swelling. A thrombus at the catheter tip occluding the superior vena cava was demonstrated roentgenographically. A 48-hr infusion of urokinase (4400 units/kg/hr) was administered for thrombolysis. The thrombus cleared clinically and roentgenographically without adverse effects. There has been no recurrence of the superior vena cava syndrome. Urokinase infusion is an alternative to immediate catheter removal in selected patients.     

DNA probe technology: implications for service planning in Britain

For certain genetic conditions DNA testing identifies carriers and determines the risk status of foetuses, thus helping parents to make more informed prenatal decisions. Data, collected from three genetic centres in England and Wales from August 1986 to July 1990, are used to describe trends in demand for DNA testing, the impact of DNA tests on carrier risk assessment, and the use of DNA tests in relation to pregnancy outcome. Altogether the data include 23,388 subjects and 681 pregnancies in 8738 families divided into five cohorts by year of entry and referral. The most frequent gene disorders referred to the genetic centres are currently being tested or will soon be tested. For these disorders the initial high level of activity has declined and may have reached steady state. Demand for DNA services is high for cystic fibrosis and Duchenne muscular dystrophy, intermediate for Huntington's disease, and low for adult polycystic kidney disease, phenylketonuria and tuberous sclerosis. Based on these findings we suggest that demand for DNA tests will be high in serious, untreatable and slow progressing conditions with early onset; intermediate for conditions affecting intellect and neurological integrity with later onset; and low for treatable, late-onset conditions, or those for which there is evidence of heterogeneity, and variable penetrance. It would be helpful to assess the extent to which this view of demand is confirmed when the new disorders being DNA tested are considered and for the pattern of activity of DNA testing for some types of cancer. Since no DNA centre could offer a fully comprehensive testing service, it is recommended that a structure is created to audit overall activity, assist in policy formulation, and influence supraregional service organisation, in order that the spread of DNA services be planned as effectively as possible. This structure would facilitate monitoring of the evolution of contract specifications agreed by commissioners and providers on a regional basis.     

Rigid contact lens decentration: a risk factor for corneal warpage

Clinically significant contact lens induced corneal warpage is seen in a small proportion of soft and rigid contact lens wearers. Previous studies using the keratometer have found no correlation between the fit of the lens and the induced topographic changes. In this study, using computer-assisted topographic analysis, seven eyes (four patients) with rigid contact lens-induced corneal warpage were noted to have topographic abnormalities that correlated with the decentered resting position of the contact lens on the cornea. The warpage topography for each of these corneas was characterized by a relative flattening of the cornea underlying the resting position of the contact lens. Lenses that rode high, for example, produced flattening superiorly and resulted in a relatively steeper contour inferiorly that simulated the topography of early keratoconus patients who had not worn contact lenses. After discontinuing contact lenses the corneal topography returned to a normal pattern in five eyes. Two eyes retained asymmetry that is not characteristic of normal corneas. Up to 6 months was required for the corneas to return to a stable topography after contact lens wear was discontinued.     

The relationship between neuropsychological function and brain damage detected by neuroimaging after closed head injury

Studies relating neuropsychology and structural neuroimaging after closed head injury are reviewed. Particular attention is given to the question of the relative contribution of focal and diffuse damage to neuropsychological impairment. The evidence currently available emphasizes the importance of diffuse damage in closed head injury. Diffuse damage is not equally distributed in the brain, and the review suggests three axes that are relevant for neuropsychological function: (1) damage may be unilateral or bilateral, (2) damage is characteristically greater in anterior regions than posterior regions, and (3) damage shows a centripetal gradient. A large gap remains between the emergent generalizations concerning head injury and reliable neuropsychological interpretation of scans from individual patients.