Antitumor activity and toxicity of peroxo heteroligand vanadates(V) in relation to biochemistry of vanadium

A selected set of 14 V(V) complexes was tested for toxicity and antitumor activity against L1210 murine leukemia, to examine the biological properties of peroxoheteroligand vanadates(V) of the formula (NH4)4[O(VO(O2)2)2], M3I[VO(O2)2C2O4], and MI[VO(O2)L], L = malate, citrate, iminodiacetate, nitrilotriacetate, and EDTA. The x-ray structure is known for five of these compounds. A relationship has been found between the chemical composition and the biological activity (antitumor activity-toxicity) of these complexes. Activity in the L1210 system is defined as greater than or equal to 25% increase in life span, and this was seen with (NH4)4[O(VO(O2)2)2]; M3[VO(O2)2(C2O4)]2H2O, M = K, NH4; and NH4[VO(O2)Malato]H2O. These observations are important for the biochemistry of vanadium. The special nature of electron transfer within the V(V)-peroxo moiety is proposed to be responsible for this phenomenon. Peroxo heteroligand vanadates(V) therefore represent a model system for studying some biochemical interactions of vanadium in living matter.     

Prostaglandin F2α (PGF2α) and prolactin secretion in rats

Plasma prolactin and F-prostaglandins (PGF) were measured in anesthetized male Sprague-Dawley rats before and at 15, 30, 45 and 60 minutes following i.v. injection of either PGF_2α (4 mg/kg), chlorpromazine, 1 mg/kg or chlorpromazine (1 mg/kg) after pretreatment with i.p. indomethacin (2 mg/kg). Following PGF_2α administration, plasma prolactin levels increased significantly only at 15 and 30 minutes in spite of extremely high PGF levels throughout 60 minutes. Besides the expected rise in plasma prolactin, chlorpromazine caused a transient but statistically significant increase in PGF. Indomethacin blocked the chlorpromazine-induced PGF rise but not prolactin increase. Animals stressed with ether anesthesia showed elevation of plasma prolactin, which was not blocked by indomethacin although PGF concentration fell. These results indicate that PGF_2α can stimulate prolactin release. This effect does not appear to be physiologic since very high PGF levels are required. Furthermore, blockade of prostaglandin synthesis by indomethacin does not prevent the release of prolactin in response to chlorpromazine or stress. Our findings do not support a possible role of PGFs as intermediaries in prolactin release. However, it is possible that PGFs may work through other mechanisms not investigated in our study.     

Properties of the nearest neighbor interchange metric for trees of small size

The crossover or nearest neighbor interchange metric has been proposed for use in numerical taxonomy to obtain a quantitative measure of distance between classifications that are modeled as unrooted binary trees with labeled leaves. This metric seems difficult to compute and its properties are poorly understood. A variant called the closest partition distance measure has also been proposed, but no efficient algorithm for its computation has yet appeared and its relationship to the nearest neighbor interchange metric is incompletely understood. I investigate four conjectures concerning the nearest neighbor interchange and closest partition distance measures and establish their validity for trees with as many as seven labeled vertices. For trees in this size range the two distance measures are identical. If a certain decomposition property holds for the nearest neighbor interchange metric, then the two distance measures are also identical at small distances for trees of any size.     

Diltiazem enhancement of [3H]nitrendipine binding to calcium channel associated drug receptor sites in rat brain synaptosomes

The binding of the dihydropyridine calcium channel antagonist [³H]nitrendipine to whole rat brain synaptosomes was studied. Binding was specific, saturable, and of high affinity (K_d = 170 pM). The calcium channel antagonist diltiazem enhanced [³H]nitrendipine binding in synaptosomes in concentrations of 1 and 10 μM. Equilibrium saturation analysis demonstrated that this effect was mediated by a decrease in the dissociation constant, due to a 3-fold reduction in the rate of ligand-receptor complex dissociation. It is concluded that diltiazem allosterically modulates the calcium channel drug receptor labeled by [³H]nitrendipine in this preparation.     

Studies on the chemical reactivity of copper bleomycin

The copper(II) complex of the clinically used antitumor agent bleomycin (Blm) has cytotoxic as well as antitumor properties. To understand the relationship of the bleomycin ligand, copper bleomycin, and other possible metal complexes of this agent, kinetic studies of the formation of Cu(II)Blm, ligand substitution reactions of CuBlm with ethylenediaminetetraaletic acid, and the redox reaction of CuBlm with thiols have been completed and interpreted along with previous studies of the thermodynamic stability of Cu2+ with bleomycin. Cu(II)Bm is found to be kinetically and thermodynamically stable in ligand substitution processes and is only slowly reduced and dissociated by sulfhydryl reagents. The rate constant of reduction of the complex by 2-mercaptoethanol (2-ME) at pH 7.4 and 25 degrees C is 9.5 X 10(-3) M-1 sec-1, explaining the inhibition of Fe2+-dependent strand scission of DNA by Cu2+ in the presence of 2-ME. CuBlm forms in preference to Fe(II)Blm and cannot be reduced and dissociated rapidly enough by thiols to liberate Blm and form the reactive iron complex. In agreement with the observed chemical stability of CuBlm, it is also shown that the complex is stable in human plasma and in the presence of Ehrlich cells suspended in ascites fluid. Interestingly, little CuBlm enters these cells to carry out cytotoxic reactions. Finally, it is shown that both Cu2+ and Zn2+, at equivalent concentrations to Fe2+, effectively inhibit the strand scission of DNA by Fe(II)Blm plus oxygen. However, at substoichiometric amounts of Cu2+, the ferroxidase activity of Blm enables the drug to remain effective in the strand-scission reaction, despite the lowered Cu-free Blm/Fe2+ ratio. These results are discussed in light of the proposed mechanism of action of bleomycin.     

About Bill Arnold, my father

This is a daughter's perspective on Bill Arnold. It is based on recollections of both my parents and is a brief story of Bill's life and his delight in being a scientist.     

William Bateson from <Emphasis Type="Italic">Balanoglossus</Emphasis> to <Emphasis Type="Italic">Materials for the Study of Variation</Emphasis>: The Transatlantic Roots of Discontinuity and the (un)naturalness of Selection

William Bateson (1861–1926) has long occupied a controversial role in the history of biology at the turn of the twentieth century. For the most part, Bateson has been situated as the British translator of Mendel or as the outspoken antagonist of W.␣F. R. Weldon and Karl Pearson’s biometrics program. Less has been made of Bateson’s transition from embryologist to advocate for discontinuous variation, and the precise role of British and American influences in that transition, in the years leading up to the publication of his massive Materials for the Study of Variation (1894). In this paper, I first attempt to trace Bateson’s development in his early career before turning to search for the development of the moniker “anti-Darwinist” that has been attached to Bateson in well-known histories of the neo-Darwinian Synthesis.     

“Theory” in Theory and Practice

A central obstacle to accepting evolution, both among students and the general public, is the idea that evolution is “just a theory,” where “theory” is understood in a pejorative sense as something conjectural or speculative. Although scientists and textbooks constantly explain that the scientific use of “theory” is quite different, the pejorative use continues to cause confusion, in part because of its deep roots in a popular, Baconian, understanding of science. A constructivist approach, whereby students are helped to examine the adequacy of their preconceptions about “theory” for themselves and to revise or replace them appropriately, is recommended.     

Nitrogen fixation by photosynthetic bacteria

In 1949, Howard Gest and Martin Kamen published two brief papers in Science that changed our perceptions about the metabolic capabilities of photosynthetic bacteria. Their discovery of photoproduction of hydrogen and the ability of Rhodospirillum rubrum to fix nitrogen led to a greater understanding of both processes. This revised version was published online in June 2006 with corrections to the Cover Date.     

The history of photosynthetic thermoluminescence

A fundamental discovery of photosynthetis research in the 1950s was the detection of thermally stimulated light emission from preilluminated photosynthetic material [Arnold W and Sherwood H (1957) Proc Natl Acad Sci USA 43: 105–114]. This phenomenon, called thermoluminescence (TL), is characteristic of a wide range of materials (minerals, semiconductors, inorganic and organic crystals, and complex biological systems), which share the ability of storing radiant energy in thermally stabilized trap states. The original discovery of TL in dried chloroplasts later proved to be a phenomenon common to all photosynthetic organisms: photosynthetic bacteria, cyanobacteria, algae and higher plants, which can be observed in isolated membrane particles, intact chloroplasts and unicellular organisms, and whole leaves. Following the initial observations considerable effort has been devoted to the identification and characterization of photosynthetic TL components. This work has firmly established the participation of various oxidation states of the water-oxidizing complex, the redox-active tyrosines, and the quinone electron acceptors of Photosystem II (PS II) in the generation of photosynthetic glow curves. Since TL characteristics are very sensitive to subtle changes in the redox properties of the involved electron transport components, the TL method has become a powerful tool in probing a wide range of PS II redox reactions and their modifications by environmental stress effects. Here, the main milestones of research in photosynthetic TL are covered until the present day. This revised version was published online in August 2006 with corrections to the Cover Date.