CHEMICAL AGENTS IN NEOPLASTIC DISEASES—An Evaluation of Chemotherapeutic Substances for Clinical Management

The rapid appearance of many new chemical substances which possess some antineoplastic effects has created a complex problem for the practicing physician. These agents which have shown promise in man and lower animals are grouped according to their modes of action. Each substance is discussed thoroughly with regard to its structure, activity, and influence upon the neoplasms of man. Key references are cited, and the practical value of each chemical agent is defined. The proper methods of administration of the compounds recommended for use are carefully described. In addition a section on agents whose therapeutic value has been disproven is also included.     

Papaver bracteatum,potential commercial source of codeine

Papaver bracteatum, native to Iran and southern Russia, has been grown successfully in many countries. Research in the northwest United States has confirmed the potential for its commercial production as a source of the alkaloid thebaine. Potential for the chemical conversion of thebaine into codeine, one of man’s most widely used alkaloidal medicinal agents, is reviewed. Economic and social advantages of growing this species over opium poppy (Papaver somniferum) are discussed. The value of the seed oil for cooking and industrial use is considered.     

The transport of chemicals in semen

Three mechanisms have been proposed for exposure of the conceptus to chemicals in semen: access of chemicals to the maternal circulation after absorption from the vagina, direct chemical exposure of the conceptus following transport from the vagina to the uterine cavity, and delivery to the egg and subsequent conceptus of chemical bound to the sperm cell. We review published data for each of these three mechanisms. Human seminal fluid chemical concentrations are typically similar to or lower than blood concentrations, although some antimicrobial agents achieve higher concentrations in semen than in blood. Vaginal absorption of medications has been shown to occur, although the vehicles in which these medications are delivered to the vagina may maintain contact with the vaginal epithelium to a greater extent than does semen. Assuming total absorption of a seminal dose of a chemical with a high semen:blood concentration ratio, distribution within the recipient woman would result in a blood concentration at least three orders of magnitude lower than that in the man. Direct delivery of seminal chemicals into the uterine cavity of humans has not been shown to occur, although it may occur in species such as the rat in which seminal fluid has access to the uterine cavity. Chemicals in or on human sperm cells have been demonstrated with respect to tetracycline and cocaine in vitro and aluminum, lead, and cadmium in vivo. The in vitro cocaine study offers sufficiently quantitative data with which to predict that oocyte concentrations would be five orders of magnitude lower than blood concentrations associated with cocaine abuse, assuming a maximally cocaine-bound sperm were capable of fertilizing. Thus, even using liberal assumptions about transmission of chemicals in semen or sperm, predicted exposure levels of a pregnant woman or of the conceptus are three or more orders of magnitude lower than blood concentrations in the man whose semen is the putative vehicle for chemical transport.     

Neurons as sensors: individual and cascaded chemical sensing

A single neuron sensor has been developed based on the interaction of gradient electric fields and the cell membrane. Single neurons are rapidly positioned over individual microelectrodes using positive dielectrophoretic traps. This enables the continuous extracellular electrophysiological measurements from individual neurons. The sensor developed using this technique provides the first experimental method for determining single cell sensitivity; the speed of response and the associated physiological changes to a broad spectrum of chemical agents. Binding of specific chemical agents to a specific combination of receptors induces changes to the extracellular membrane potential of a single neuron, which can be translated into unique “signature patterns” (SP), which function as identification tags. Signature patterns are derived using Fast Fourier Transformation (FFT) analysis and Wavelet Transformation (WT) analysis of the modified extracellular action potential. The validity and the sensitivity of the system are demonstrated for a variety of chemical agents ranging from behavior altering chemicals (ethanol), environmentally hazardous agents (hydrogen peroxide, EDTA) to physiologically harmful agents (pyrethroids) at pico- and femto-molar concentrations. The ability of a single neuron to selectively identify specific chemical agents when injected in a serial manner is demonstrated in “cascaded sensing”.     

蔊菜杂草性的研究

本文通过对十字花科常见杂草芹菜[Rorippa in lica(L.)Hiern]在南京地区的自然群体的周期性观察,以了解其在不同生态环境下的生活周期。本文还通过一系列实验来观察其繁育系统、种子传播的动因、结实力、种子发芽率和植物抗人为干扰的耐受性。花蕾套袋试验证明蔊菜主要是自交可亲和的,即使存在异型杂交也是微不足道的。种子传播效应试验揭示水和风都是种子传播的自然力。该种具有范围很广的耐受性,踏践和刈割试验证明在严重的人为于扰下仍能完成其生活周期。蔊菜尽管本质上属于多年生草本,能产生大量的种子,在很大程度上靠种子繁殖。种子萌芽试验证明它的种子萌发参差不齐。总之,蔊菜具有典型杂草的许多特性,而这些特性给它以适合在多种自然的和人为干扰的环境中正常地生长的能力。     

Critical components of testicular function and sensitivity to disruption

Toxic agents can interfere with the male reproductive system at many targets. Radiation and cancer chemotherapeutic drugs represent one class of toxins the sterilizing effects of which can be analyzed qualitatively and quantitatively in terms of testicular cell kinetics. The cells most sensitive to killing by these agents are the rapidly dividing, differentiating spermatogonia. Cells past the DNA-synthetic stages, including spermatocytes, spermatids, and nongerminal cells, are generally resistant. The slow cycling stem spermatogonia show an intermediate sensitivity, but appear to be the critical targets for the resulting long-term oligo- or azoospermia and infertility. The extent of recovery of spermatogenesis and the duration of infertility can be predicted on the basis of stem cell survival alone, independent of the antineoplastic agent used. When murine stem cells are killed, regeneration of their number and repopulation of the seminiferous epithelium begin almost immediately. In man, recovery can be delayed for years after exposure to agents that kill stem cells. This is a result of the regulation of stem cell regeneration and differentiation in man, the mechanisms of which are unknown. This regulation can explain quantitative differences in interspecies sensitivities to toxic agents. For example, man is much more sensitive than the mouse to reduction in sperm count by radiation at short times after exposure, but not when sufficient recovery times are allowed.     

Cardiotonic steroids on the road to anti-cancer therapy

The sodium pump, Na(+)/K(+)-ATPase, could be an important target for the development of anti-cancer drugs as it serves as a versatile signal transducer, it is a key player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids, known ligands of the sodium pump have been widely used for the treatment of heart failure. However, early epidemiological evaluations and subsequent demonstration of anti-cancer activity in vitro and in vivo have indicated the possibility of developing this class of compound as chemotherapeutic agents in oncology. Their development to date as anti-cancer agents has however been impaired by a narrow therapeutic margin resulting from their potential to induce cardiovascular side-effects. The review will thus discuss (i) sodium pump structure, function, expression in diverse cancers and its chemical targeting and that of its sub-units, (ii) reported in vitro and in vivo anti-cancer activity of cardiotonic steroids, (iii) managing the toxicity of these compounds and the limitations of existing preclinical models to adequately predict the cardiotoxic potential of new molecules in man and (iv) the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules.     

Thoughts on the cultural evolution of man. Developmental imprinting and transgenerational effect

The biological evolution of man stopped since it has been conveyed to the objects, created by man. This paper introduces the concept of "conveyed evolution". Being part of the cultural evolution, the conveyed evolution is a continuation of the biological one. There are several similarities between the laws of biological and conveyed evolution, albeit the differences are important as well. Some laws of the conveyed evolution are described here. The conveyed evolution has man-made repair mechanisms (medicine, protection of environment) which defend man from harm. Man's fragility limits the progress of conveyed evolution. However, artificial compounds or environmental pollutants which are provoked by the conveyed evolution induce chemical (hormonal) imprinting in the developmental critical periods, which is transmitted to the progeny generations (transgenerational effect). This could cause evolutionary alterations without mutation.     

Environmental history as an anthropologic topic. Contribution to "chemical anthropology"

Human population history is firmly connected with temporal and regional changes of the environment. Whether natural or anthropogene, alteration of environmental features lead to changes of human life-style and to the development of adaptive strategies. The demand of resources for his subsistence has led man to diverse impacts on his environment since ever. Thus, environmental history is a scientific topic for anthropologists. The research potential of trace element studies of excavated human skeletons for the reconstruction of natural and socio-cultural environments as well as for distribution patterns of hazardous substances is outlined for the European Middle Ages. The scientific value of unravelling past man/environment-interrelationships for both the historical and applied sciences and the place of any "chemical anthropology" within this context is discussed.     

Positional Information and Positional Signalling in Hydra

A model is proposed for regulation and regeneration of the headend of hydra in terms of positional information, which involvestwo gradients. One is a diffusible substance made at the headend, which may be regarded as a positional signal. The otheris a more stable cellular parameter which is the positionalvalue. The rule for head end formation is that the concentrationof the diffusible substance falls a threshold amount below thepositional value. This model, for which some computer simulationis provided, can account for head end formation in a wide varietyof grafts. Evidence for a diffusable signal is provided by experimentsin which the time/distance relationships for head inhibitionby a grafted head are determined. Changes in positional valueduring regulation have been assayed and are much slower awayfrom the boundary. Polarity is interpreted in terms of the interactionbetween the two gradients. The biochemical basis of the gradientsis not known, but an approach to the problem has been made bytreating hydra with a variety of chemical agents.     

The enzymatic synthesis of antiviral agents.

The majority of potential antiviral agents which are currently undergoing clinical trials are inhibitors of the replication of nucleic acids. The most common class of these inhibitors are nucleoside analogues and the elucidation of synthetic routes to these compounds has been of interest for many years as many are anticancer agents. One synthetic development has been the application of bio-transformations to nucleoside syntheses. This topic has been reviewed recently (Shirae et al., 1991) but this review is not widely available. In the present review, the application of biotechnology to the synthesis of antiviral agents including those which are not nucleoside analogues will be discussed. Enzymatic syntheses of nucleosides can be simpler and quicker than syntheses carried out by chemical methods. The most useful enzymes are those found in catabolic pathways. Nucleoside phosphorylases and N-deoxyribosyltransferases have both been widely used for nucleoside synthesis catalysing the transfer of sugar residues from a donor nucleoside to a heterocyclic base. Enzymatic methods have also been applied to the resolution of racemic mixtures and adenosine deaminase is a convenient catalyst for the hydrolysis of amino groups on purines and purine analogues. Regioselective deprotection of nucleoside esters has been achieved with lipases and these enzymes have also been applied to the synthesis of esters of sugar-like alkaloids. The latter have potential as inhibitors of the replication of HIV. Esterases have also been used in combined chemical and enzymatic syntheses of organophosphorus antiviral agents.     

Impacts and concerns for vCJD in blood transfusion: current status

The impact of vCJD upon blood transfusion practice hinges on its lymphoreticular involvement. B lymphocytes play a key supporting role for the capture and replication of infectivity by follicular dendritic cells of the lymphoid tissue in animal models of transmissible spongiform encephalopathies (TSE) and tonsils, spleen and appendix in man can harbour vCJD infectivity, a situation not seen with the other human TSEs. Leucodepletion of blood donations in the UK was implemented to reduce possible vCJD transmission and preliminary data suggests that white cell associated infectivity will be effectively removed although plasma infectivity will not. Blood screening assays are under development but none yet are ready for application. The conformation dependant immunoassay, based on differences in secondary and tertiary structure between normal and TSE-associated abnormal prion protein, has a sensitivity now approaching the best bioassay. Even so further development is needed to detect the fg/ml levels likely in the event that vCJD blood does contain abnormal prion, which is as yet unproven. Surrogate assays, such as for erythroid associated factor, may provide additional means of identifying donors harbouring vCJD. Validation of clearance of TSEs from pooled plasma products consistently demonstrates effective removal of the agents in downscaled systems and studies comparing vCJD, BSE and scrapie agents yield similar results. Many approaches to therapy are under investigation, in cell culture and animal models, targeted to normal or abnormal prion metabolism, including chemical and immunological interventions. Efficacy of quinacrine/chlorpromazine and pentosan polysulphate in a clinical setting, and agents yet to be used, will be more accurately known following recent agreement of clinical drug evaluation protocols.     

Immunology and molecular biology of Echinococcus infections

Echinococcus spp. are the etiological agents of hydatid disease in man and other intermediate hosts. Many questions regarding the factors which determine susceptibility/resistance to hydatid disease, and the factors which influence the viability and fertility of hydatid cysts, remain to be answered. Recent research into the effects of hydatid infection on the immune system of the host has provided some insights into the host-parasite relationships. Immunochemical and recombinant DNA techniques are being applied to improve diagnosis of hydatidosis in man and E. granulosus infection in dogs, and also in the development of vaccines against infection with taeniid cestode larvae. The successes which have been achieved in these areas are likely to provide valuable tools for the control of cystic hydatidosis in man. These recent studies in the areas of immunobiology, serological diagnosis and vaccination are reviewed.     

稻飞虱天敌螯蜂研究进展

稻飞虱（褐飞虱Nilaparvata lugens、白背飞虱Sogatella furcifera、灰飞虱Laodelphax striatellus）是世界性重要的水稻Oryza sativa L.害虫之一,给水稻生产造成了重大经济损失。化学防治一直是控制稻飞虱的主要途径,但长期使用化学药剂使稻飞虱产生抗药性,并引起害虫增殖等诸多弊端,迫切需要有效的生物防控手段进行控害。螯蜂是稻飞虱若虫和成虫期重要天敌,兼具捕食与寄生的双重习性,在控制稻飞虱种群数量方面发挥着重要的作用,然而,国内外有关螯蜂的研究报道仍然偏少。本文综述了我国稻飞虱天敌螯蜂常见种类、生物学特性、控害效果及其影响因子,分析了存在的问题,旨在为进一步开发利用螯蜂资源提供参考。     

Environmental pollutants and skin cancer

We are increasingly exposed to environmental pollution. Pollutants can be inhaled, ingested or come into contact with the skin depending on the form in which they occur. On metabolization, activation, or accumulation, pollutants can become extremely toxic for the vital organs and this is often related to a strong genotoxic effect. Since the skin acts as a barrier between the organism and the environment, it is frequently directly exposed to pollution. It is very often degraded by polluting agents and acts as an inlet toward other tissues. Numerous studies in man recognize and demonstrate the carcinogenic power of certain pollutants in the digestive and respiratory tracts. The "pollutants" that react most specifically with the skin are: ultraviolet radiation, polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene), volatile organic compounds (e.g., benzene), heavy metals, and ozone. Ultraviolet radiation, a "physical" pollutant, has been described as being the factor responsible for most skin cancers in man. The genotoxicity of UV light is well documented (type of lesion or mutation, etc.) and its carcinogenic effect is clearly demonstratedin vivo in man. A few epidemiological studies describe the carcinogenicity of certain pollutants such as arsenic or lead on the skin. However, most of the evidence for the role of pollutants in skin cancers comes fromin vivo animal studies or fromin vitro studies (e.g., PAHs). In this report, different studies are presented to illustrate the research strategies developed to investigate the mechanism of action of "chemical" pollutants and their potential role in human skin pathology. All the study models and the associated techniques of investigation are tools for a better understanding and thus more efficient prevention of the deleterious effects caused by the environment. This revised version was published online in August 2006 with corrections to the Cover Date.     

Pyrazolopyrimidine metabolism in Leishmania and trypanosomes: significant differences between host and parasite

The pathogenic hemoflagellates of the genera Leishmania and Trypanosoma are major causes of human disease in the tropical and subtropical areas of the world. In general, the agents used to treat diseases caused by these organisms are toxic and not suitable for administration to the millions of people infected. Investigations over the past several years have shown that there are several major differences between man and these protozoans with respect to purine metabolism. The differences appear to offer promise for the development of effective chemotherapeutic compounds. These organisms do not synthesize purines de novo, as does man. They are able to concentrate pyrazolopyrimidines with the cell and metabolize them as purines through the salvage pathways, ultimately incorporating them into nucleic acids. This does not occur in mammals. The pyrazolopyrimidine base allopurinol, which has served as a prototype, is activated by a phosphoribosyltransferase to the ribonucleotide. The ribonucleotide is aminated to the 4-amino-pyrazolopyrimidine ribonucleotide and subsequently phosphorylated to the triphosphate form and incorporated into RNA. The pyrazolopyrimidine ribonucleosides formycin B and allopurinol ribonucleoside are activated through a nucleoside phosphotransferase. The resulting ribonucleotide is aminated and incorporated into RNA as described above. These metabolic peculiarities occur not only in the forms of these parasites which are found in the insect vectors but also in the intracellular forms which are pathogenic in man. The differences in the enzymology and metabolism of purines which exist in the genera Leishmania and Trypanosoma offer excellent opportunities for chemotherapeutic exploitation.     

A genotoxicity study on N-acryloyl-N′-phenylpiperazine: implications of aneugenic effects in risk evaluations

Further to a previous genotoxicity study, we analyzed sister-chromatid exchange (SCE) and DNA-repair induction (V79 and EUE cells in vitro) and DNA damage (rat liver in vivo) with regard to N-acryloyl-N-phenylpiperazine (AcrNPP), a chemical proposed for biomaterial polymerization which contains an aromatic tertiary amino function in a piperazine cycle. This chemical induced SCEs in a dose-dependent fashion (up to ≈ 3.7 times the control value), while it was negative for DNA-repair induction and weakly yeat significantly positive for in vivo DNA damage (maximum increase ≈ 1.4 times the control value). Taken together with our previous genotoxicity data on AcrNPP and structurally related compounds, the present results confirm that aneuploidy is a possible major effect of aromatic tertiary amines. As regards exposure to aneugenic agents, considerations on cancer risk evaluation are presented.     

Conditional drug screening shows that mitotic inhibitors induce AKT/PKB-insensitive apoptosis

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently upregulated in human cancer. Activation of this pathway has been reported to be associated with resistance to various chemotherapeutical agents. We here used a chemical biology/chemical informatic approach to identify apoptotic mechanisms that are insensitive to activation of the PI3K/AKT pathway. The National Cancer Institute (NCI) Mechanistic Set drug library was screened for agents that induce apoptosis in colon carcinoma cells expressing a constitutively active form of AKT1. The cytotoxicity screening data available as self-organized maps at the Developmental Therapeutics Program (DTP) of the NCI was then used to classify the identified compounds according to mechanism of action. The results showed that drugs that interfere with the mitotic process induce apoptosis which is comparatively insensitive to constitutive AKT1 activity. The conditional screening approach described here is expected to be useful for identifying relationships between the state of activation of signaling pathways and sensitivity to anticancer agents.     

Affinity Distance Values among Somatic Metaphase Chromosomes in Maize

In maize root-tip metaphase preparations, all distances between two chromosomes were measured in 50 cells from each of seven stocks and in 30 from one stock; four were arrested with cold, two with 8-hydroxyquinoline, one with colchicine and one with monobromonaphthalene. Standardized, affinity-distance values were calculated for all pairs of homologues and pairs of nonhomologues from each preparation. The homologues of pair X were the least separated, those of pair I the most separated in the cold-arrested stocks. All but pairs I and VIII were shown to be significantly different from the observed mean. The observed mean was less than but not significantly different from the theoretical value for a random distribution. The use of chemical agents for metaphase arrest increased the separation of homologues, except for pair I.—Eleven percent of the comparisons of nonhomologues from cold-arrested, as contrasted to none of the comparisons from the c-metaphase treatments, were significantly different from the theoretical value for a random distribution. This was considered evidence for limited primary nonhomologue association in maize. Although there were specific, differential responses to the two arrest agents, the population of homologous pairs approached a random distribution only in chemically arrested stocks.—Primary homologue association was considered to be maintained by two mechanisms, the more common involving the microtubules and the second involving the nucleolus.—Interpretations are offered regarding the claims of somatic association in other species, especially man. The opportunity in maize for experimentally modifying distance values by cytogenetic techniques is discussed.     

Reinforcement schedules and extrapolations to humans from animals in behavioral pharmacology.

Behavior controlled by various schedules of reinforcement is useful for characterizing drugs as well as for analyzing the mechanisms of action of their effects on behavior. Conditioned avoidance techniques have been useful for studying neuroleptics and for predicting their clinical antipsychotic acitivity; the possible involvement of dopaminergic mechanisms in the effect of neurolpetics on avoidance behavior is discussed. Tricyclic antidepressant agents have been studied in assays involving interactions with other agents, such as cocaine, amphetamine and tetrabenazine. One type of operant behavior, Sidman avoidance, has been used as particularly sensitive assay for such drug interactions. Another schedule, in which "observing" responses in pigeons are measured. seems to provide a method for studying antidepressants without involving drug interaction phenomena. For tricyclic compounds, facilitation of observing responses and weak potency of conditioned avoidance inhibition constitute a pharmacological profile that seems to have some predictive value for clinical imipramine-like antidepressant activity. "Conflict (punishment) schedules have been useful for predicting antianxiety activity in man. Although the degree of anticonflict effect observed is consistent with Dew's rate dependency hypothesis, this principle does not fully account for the observed drug effects. In the conflict model, the actions of benzodiazepines differ in drug-naive versus drug-experienced animals. Experiments with parachlorophenylalnine have not yet provided clear support for the postulated role of serotonin in related phenomena.