Potential applicability of nonclonogenic measurements to clinical oncology

A number of assays are currently under evaluation for their potential usefulness in the selection of new chemotherapeutic agents or as predictive indicators for use in the design of optimal cancer treatment. Assays fall under the general categories of tumor cell survival, treatment-induced cellular damage, and determination of inherent tumor factors which includes tumor cell kinetics, tumor oxygenation, and measurement of specific biochemical systems. While technical advances to optimize these assays are continuing, possible inter- and intra-tumor cell variability to anticancer treatment modalities may complicate the interpretation and subsequent use of these assays. Regardless of their ultimate usefulness as clinical predictors, these assays will be extremely valuable in better characterizing and understanding the cell biology and biochemistry of human malignancies.     

Melatonin in clinical oncology

The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology. Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status).     

The controversial role of ABC transporters in clinical oncology

The phenomenon of multidrug resistance in cancer is often associated with the overexpression of the ABC (ATP-binding cassette) transporters Pgp (P-glycoprotein) (ABCB1), MRP1 (multidrug resistance-associated protein 1) (ABCC1) and ABCG2 [BCRP (breast cancer resistance protein)]. Since the discovery of Pgp over 35 years ago, studies have convincingly linked ABC transporter expression to poor outcome in several cancer types, leading to the development of transporter inhibitors. Three generations of inhibitors later, we are still no closer to validating the 'Pgp hypothesis', the idea that increased chemotherapy efficacy can be achieved by inhibition of transporter-mediated efflux. In this chapter, we highlight the difficulties and past failures encountered in the development of clinical inhibitors of ABC transporters. We discuss the challenges that remain in our effort to exploit decades of work on ABC transporters in oncology. In learning from past mistakes, it is hoped that ABC transporters can be developed as targets for clinical intervention.     

The birth of chronobiology: Julien Joseph Virey 1814

Julien-Joseph Virey (1775-1846) held the position of pharmacist-in-chief at the Val-de-Grace, a military hospital. He was an innovative pharmacist, naturalist, anthropologist, and philosopher and a prolific author. His writings encompassed a wide range of topics, although many of his ideas were sometimes harshly questioned. Interest in Virey's work today stems from renewed appreciation of his doctoral thesis in medicine, which was completed in 1814 in Paris and was the first devoted to biological rhythms. Virey envisioned biological rhythms to be innate in origin and controlled by living clocks entrained by periodic environmental changes, such as the day-night alternation in light and darkness. He also reported that the effects of drugs vary according to their administration time. But, above all, he collected and published quantified time series that demonstrated human circadian and annual mortality rhythms. Statistical analysis of Virey's data using modern time series methods confirms his deduction that human mortality exhibits rhythmicity. Comparison of his findings with those derived from analyses of more recent human mortality time series shows the characteristics of these rhythms have changed little since 1807 despite differences in environmental conditions. Virey deserves credit for establishing the field of chronobiology based on his insights and writings.     

Antisense therapy in clinical oncology

Nucleic acid molecules have emerged as versatile tools with promising utility as therapeutics for human diseases. The specificity of hybridization of an antisense oligonucleotide (AS ODN) to the target mRNA makes the AS strategy attractive to selectively modulate the expression of genes involved in the pathogenesis of malignant or non-malignant diseases. One AS drug has been approved for local therapy of cytomegalovirus retinitis, and a number of AS ODN are currently tested in clinical trials including ODN that target bcl-2, survivin, and DNA methyltransferase. The clinical studies indicate that AS ODN are well tolerated and may have therapeutic activity. In this overview, we summarize therapeutic concepts, clinical studies, and new promising molecular targets to treat human cancer with AS ODN.     

Current concepts in clinical radiation oncology

Based on its potent capacity to induce tumor cell death and to abrogate clonogenic survival, radiotherapy is a key part of multimodal cancer treatment approaches. Numerous clinical trials have documented the clear correlation between improved local control and increased overall survival. However, despite all progress, the efficacy of radiation-based treatment approaches is still limited by different technological, biological, and clinical constraints. In principle, the following major issues can be distinguished: (1) The intrinsic radiation resistance of several tumors is higher than that of the surrounding normal tissue, (2) the true patho-anatomical borders of tumors or areas at risk are not perfectly identifiable, (3) the treatment volume cannot be adjusted properly during a given treatment series, and (4) the individual heterogeneity in terms of tumor and normal tissue responses toward irradiation is immense. At present, research efforts in radiation oncology follow three major tracks, in order to address these limitations: (1) implementation of molecularly targeted agents and ‘omics’-based screening and stratification procedures, (2) improvement of treatment planning, imaging, and accuracy of dose application, and (3) clinical implementation of other types of radiation, including protons and heavy ions. Several of these strategies have already revealed promising improvements with regard to clinical outcome. Nevertheless, many open questions remain with individualization of treatment approaches being a key problem. In the present review, the current status of radiation-based cancer treatment with particular focus on novel aspects and developments that will influence the field of radiation oncology in the near future is summarized and discussed.     

Patient-derived micro-organospheres enable clinical precision oncology

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Cell cycle markers in clinical oncology

Analysis of complex and redundant pathways that control proliferation, differentiation, apoptosis and DNA damage response by global genome wide analysis is an intensive area of investigation aimed at identifying unique molecular signatures of prognostic significance in cancer. An alternative approach is to focus on the cell cycle machinery, which acts as an integration point for information transduced through upstream signalling pathways. Analysis of the DNA replication licensing pathway and the mitotic regulatory machinery in tumour biopsy material is now leading to the identification of novel biomarkers that are being exploited in cancer detection and prognostic assessment.     

Perspectives in chronobiology of air pollution

In a series of experiments, male and female Sprague Dawley rats, kept in light (L) from 06(00) to 18(00) alternating with darkness (LD 12:12) inhaled different concentrations of carbon monoxide (50-1,700 ppm) at each of two test times, 12 h apart. A decrease in flow of CO2 (VCO2) resulting from CO inhalation was greater in the active dark (D) than resting light (L) span. Experimental hypoxic mortality of male and female mice also shows circadian variations, being greater in the D than in the L span. Moreover, a difference of mortality was observed betwen hypoxic exposures performed at 12(00) (in LD or DL) and hypoxic exposures performed at 00(00) (in LD or DL). Such results await tests of any extent to which they model responses of human beings to air pollution. In human beings any external environmental circadian, circaseptan and circannual variations in air pollution as such may serve to variable extent as socioeconomic synchronizers of innate rhythms with a corresponding frequency, rather than as solely generators of time patterns in any physiopathologic response to air pollution.     

Application of flow cytometry in chronobiology

A survey is given on flow cytometric techniques and their applications in chronobiology. Rapid automatic single cell measurements with a high rate (1,000-5,000 single cells/sec) enable the accumulation of large numbers of data at short intervals, thus obtaining important knowledge on circadian variations of cell proliferation in epidermis and other types of surface epithelium as well as hemopoiesis. In addition, the method has to some extent been used for monitoring cancer chemotherapy, and is thus available for the application in chronotherapy of malignancy. The introduction of rapid automatic techniques such as flow cytometry is a great advantage for any study on single cells and tissues where rhythmic variations in different functions have to be taken into consideration.     

代谢组学在临床研究中的应用及进展

代谢组学是"后基因组学"时期新兴的一门学科,也是系统生物学的重要组成部分。代谢组学通过全面、定量检测生物样本中多种类型小分子化合物,来了解在内在和外界因素作用下生物体内源性物质的变化及规律,特别适合于临床上研究机体因受到遗传、生长、生理、环境因素和异物、病源等刺激的影响而产生的变化。借助于代谢组学技术不仅能够描述疾病发生、发展以及治疗过程中机体代谢机能的状态和变化,为临床疾病的诊断、病理机制的探索、新治疗靶点的发现等提供新的途径和思路,还可以揭示外界干扰因素(药物/毒物、环境、饮食、生活方式等)对机体的影响,为药效评价和疾病病因的筛查提供基础数据。近年来,代谢组学在临床研究方面得到了广泛的应用,取得了巨大的进展并展现了鼓舞人心的应用前景。该文分别就代谢组学在描述疾病发展状态、研究疾病诊断方法、探索疾病发病原因和发病机理、药效学评价等几个方面的应用及进展进行回顾和综述。     

Contributions made to chronobiology by studies of fiddler crab rhythms.

One of the classic organisms used in chronobiological research is the fiddler crab (genus Uca), an animal unique in that it displays both circadian and tidal (i.e., circalunidian) rhythms. The pioneering work on this animal helped produce the early evidence for many of the standard properties now recognized for all circadian rhythms: near temperature independence of the period, phase lability and setability, the light and temperature sensitivity rhythms expressed by phase response curves, and the persistence of rhythms in organs isolated from a multicellular animal. Importantly, results arising from studies of this crab--and a few other organisms--resulted in the development of the exogenous timing hypothesis. While philosophically sound, the lack of supporting evidence for this hypothesis has resulted in it being discarded by most chronobiologists; but while still in its prime, it drew great interest, and therefore grant support, to the field in general, stimulated a great deal of research that otherwise might not have been performed, and resulted in the discovery of environmental stimuli previously unsuspected to influence organisms. As could be expected, continuing work with this crab, using modern approaches and statistical techniques, has modified earlier findings and interpretations, has revealed new properties, and has resulted in the creation of new hypotheses. The review and update is a synthesis of 45 years of this work.     

WIF1: perspectives of application in oncology

Changes in the intracellular signaling cascades underlay many human pathologies including oncological diseases. Modification of the Wnt-signaling pathway are often associated with development of tumor and may play a significant role in carcinogenesis. This gives rise to a significant interest to studies of regulators and components of the Wnt-signaling pathway and search for approaches to practical implementation of the properties of the regulators. The goal of this work was to review the properties of WIF1 (Wnt inhibitor factor-1), a regulator of Wnt-signaling pathway, as a possible diagnostic and prognostic marker of human tumors, as well as basis for development of novel antitumoral preparations.