Mark Grant

The role of reductive and oxidative metabolism in the toxicity of mitoxantrone, adriamycin and menadione in human liver derived Hep G2 hepatoma cells.

The cytotoxic properties of quinones, such as menadione, are mediated through one electron reduction to yield semi-quinone radicals which can subsequently enter redox cycles with molecular oxygen leading to the formation of reactive oxygen radicals. In this study the role of reduction and oxidation in the toxicity of mitoxantrone was studied and its toxicity compared with that of adriamycin and menadione. The acute toxicity of mitoxantrone was not mediated through one-electron reduction, since inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells against oxidative damage, did not affect its toxicity. Adriamycin was the most potent inhibitor of protein and RNA synthesis of the three quinones. Menadione, at concentrations up to 25 microM, did not inhibit either protein or RNA synthesis unless dicoumarol, an inhibitor of DT-diaphorase, was also present. The two-electron reduction of menadione by DT-diaphorase is therefore a protective mechanism in the cell. This enzyme also protected against the toxicity of high concentrations (100 microM) of mitoxantrone. The inhibitory effect of mitoxantrone, but not of menadione or adriamycin, on cell growth was prevented by inhibiting the activity of cytochrome P450-dependent mixed function oxidase (MFO) system using metyrapone. This suggests that mitoxantrone is oxidised to a toxic intermediate by the MFO system.

The toxicity of menadione and mitozantrone in human liver-derived Hep G2 hepatoma cells

The cytotoxic properties of quinone drugs such as menadione and adriamycin are thought to be mediated through one-electron reduction to semiquinone free radicals. Redox cycling of the semiquinones results in the generation of reactive oxygen species and in oxidative damage. In this study the toxicity of mitozantrone, a novel quinone anticancer drug, was compared with that of menadione in human Hep G2 hepatoma cells. Mitozantrone toxicity in these cells was not mediated by the one-electron reduction pathway. In support of this, inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells from oxidative damage, did not affect the response of the Hep G2 cells to mitozantrone, whereas it exacerbated menadione toxicity. In addition, the toxicity of menadione was preceded by depletion of reduced glutathione which was probably due to oxidation of the glutathione. Mitozantrone did not cause glutathione depletion prior to cell death. DT-diaphorase activity and intracellular glutathione were found to protect the cells from the toxicity of both quinones. Inhibition of epoxide hydrolase potentiated mitozantrone toxicity but did not affect that of menadione. Our experiments indicate that mitozantrone toxicity may involve activation to an epoxide intermediate. Both quinone drugs inhibited cytochrome P-450-dependent mixed-function oxidase activity, although menadione was more potent in this respect.

Spermine toxicity and glutathione depletion in BHK-21/C13 cells.

Spermine, a polycationic amine, produced a dose-dependent inhibition of BHK-21/C13 cell growth. This response was not due to the extracellular metabolism of spermine by an amine oxidase found in bovine serum, as the toxicity was observed when the cells were grown in medium supplemented with horse serum. Three indices were used to monitor cell growth, cell number, protein content and [3H]thymidine incorporation into DNA. Spermine (2mM) caused significant reductions in all three measurements after a 6-8 hr exposure. The amine was rapidly taken up into the cells reaching levels 15-16-fold greater than in control cells within 2 hr. There was a rapid loss of intracellular reduced glutathione following exposure to toxic concentrations of spermine, which occurred before any effect on cell growth. Three methods for the determination of intracellular glutathione content were compared in this system. The effect on both cell growth and glutathione was reversible following removal of spermine from the extracellular medium. The possible mechanisms involved in this toxic response are discussed with particular reference to the depletion in intracellular reduced glutathione.

Robot motion planning, weights of cohomology classes, and cohomology operations

The complexity of algorithms solving the motion planning problem is measured by a homotopy invariant TC(X) of the configuration space X of the system. Previously known lower bounds for TC(X) use the structure of the cohomology algebra of X. In this paper we show how cohomology operations can be used to sharpen these lower bounds for TC(X). As an application of this technique we calculate explicitly the topological complexity of various lens spaces. The results of the paper were inspired by the work of E. Fadell and S. Husseini on weights of cohomology classes appearing in the classical lower bounds for the Lusternik - Schnirelmann category. In the appendix to this paper we give a very short proof of a generalized version of their result.

Equivariant topological complexity

We define and study an equivariant version of Farber’s topological complexity for spaces with a given compact group action. This is a special case of the equivariant sectional category of an equivariant map, also defined in this paper. The relationship of these invariants with the equivariant Lusternik‐Schnirelmann category is given. Several examples and computations serve to highlight the similarities and differences with the nonequivariant case. We also indicate how the equivariant topological complexity can be used to give estimates of the nonequivariant topological complexity. 55M99, 57S10; 55M30, 55R91

Spermine toxicity in BHK-21/C13 cells in the presence of bovine serum: The effect of aminoguanidine

Spermine was toxic to BHK-21/C13 cells in the presence of newborn calf serum and the toxicity, but not the metabolism of spermine, was prevented by aminoguanidine. Aminoguanidine treatment resulted in significant alterations in the polyamine profile of these cells with loss of intracellular putrescine after 4 hr of exposure. In the presence of aminoguanidine, intracellular polyamine content returned to control values at 24 hr, possibly as a result of increased uptake of exogenous spermine.

Topological complexity of configuration spaces

The topological complexity is a homotopy invariant which reflects the complexity of the problem of constructing a motion planning algorithm in the space , viewed as configuration space of a mechanical system. In this paper we complete the computation of the topological complexity of the configuration space of distinct points in Euclidean -space for all and ; the answer was previously known in the cases and odd. We also give several useful general results concerning sharpness of upper bounds for the topological complexity.

Bordism groups of immersions and classes represented by self-intersections

A well-known formula of R J Herbert’s relates the various homology classes represented by the self-intersection immersions of a self-transverse immersion. We prove a geometrical version of Herbert’s formula by considering the self-intersection immersions of a self-transverse immersion up to bordism. This clarifies the geometry lying behind Herbert’s formula and leads to a homotopy commutative diagram of Thom complexes. It enables us to generalise the formula to other homology theories. The proof is based on Herbert’s but uses the relationship between self-intersections and stable Hopf invariants and the fact that bordism of immersions gives a functor on the category of smooth manifolds and proper immersions. 57R42; 57R90, 55N22

A mapping theorem for topological complexity

We give new lower bounds for the (higher) topological complexity of a space in terms of the Lusternik‐Schnirelmann category of a certain auxiliary space. We also give new lower bounds for the rational topological complexity of a space, and more generally for the rational sectional category of a map, in terms of the rational category of a certain auxiliary space. We use our results to deduce consequences for the global (rational) homotopy structure of simply connected hyperbolic finite complexes. 55M30, 55P62; 55S40, 55Q15

Topological complexity of motion planning in projective product spaces

We study Farber’s topological complexity (TC) of Davis’ projective product spaces (PPS’s). We show that, in many nontrivial instances, the TC of PPS’s coming from at least two sphere factors is (much) lower than the dimension of the manifold. This is in marked contrast with the known situation for (usual) real projective spaces for which, in fact, the Euclidean immersion dimension and TC are two facets of the same problem. Low TC-values have been observed for infinite families of nonsimply connected spaces only for H-spaces, for finite complexes whose fundamental group has cohomological dimension at most 2, and now in this work for infinite families of PPS’s. We discuss general bounds for the TC (and the Lusternik‐Schnirelmann category) of PPS’s, and compute these invariants for specific families of such manifolds. Some of our methods involve the use of an equivariant version of TC. We also give a characterization of the Euclidean immersion dimension of PPS’s through a generalized concept of axial maps or, alternatively (in an appendix), nonsingular maps. This gives an explicit explanation of the known relationship between the generalized vector field problem and the Euclidean immersion problem for PPS’s. 55M30, 57R42; 68T40