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In the present review we summarize different strategies to induce DNA compaction and decompaction. DNA compaction is achieved using different cationic co-solutes, such as trivalent ions, surfactant, and polycations. In addition, single-chained DNA compaction can also be achieved in solvents with low dielectric constants and by confinement. The decompaction strategies depend, naturally, on the method used for the compaction and can be accomplished by, for example, heparins, cyclodextrins, non-ionic or anionic surfactants. Show less

Cisplatin, carboplatin, and oxaliplatin are three FDA-approved members of the platinum anticancer drug family. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of structural adducts and triggering cellular responses, one of which is the inhibition of transcription. In this report we present (i) a detailed review of the structural investigations of various Pt-DNA adducts and the effects of these lesions on global DNA geometry; (ii) research detailing inhibition of cellular transcription by Pt-DNA adducts; and (iii) a mechanistic analysis of how DNA structural distortions induced by platinum damage may inhibit RNA synthesis in vivo. A thorough understanding of the molecular mechanism of action of platinum antitumor agents will aid in the development of new compounds in the family. Show less

AbstractA brief overview is given of platinum anticancer drugs in routine clinical use and under clinical development worldwide. Details of the binding of these drugs with nucleic acids, the preferred binding site, etc. are discussed as well. Using the mechanistic knowledge at the molecular level, in particular DNA binding, possibilities for new drugs are explored. A major part of the review deals with design, synthesis and biochemical/biophysical studies of such new compounds and their possible applications as cytostatic drugs. Special attention is given to the application of bifunctionality in such new compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) Show less

In this review article, we summarize the current state of biophysical knowledge concerning the phase behavior and organization of cardiolipin (CL) and CL-containing phospholipid bilayer model membranes. We first briefly consider the occurrence and distribution of CL in biological membranes and its probable biological functions therein. We next consider the unique chemical structure of the CL molecule and how this structure may determine its distinctive physical properties. We then consider in some detail the thermotropic phase behavior and organization of CL and CL-containing lipid model membranes as revealed by a variety of biophysical techniques. We also attempt to relate the chemical properties of CL to its function in the biological membranes in which it occurs. Finally, we point out the requirement for additional biophysical studies of both lipid model and biological membranes in order to increase our currently limited understanding of the relationship between CL structure and physical properties and CL function in biological membranes. Show less

Z-DNA is a left-handed helical form of DNA in which the double helix winds to the left in a zigzag pattern. DNA containing alternating purine and pyrimidine repeat tracts have the potential to adopt this non-B structure in vivo under physiological conditions, particularly in actively transcribed regions of the genome. Z-DNA is thought to play a role in the regulation of gene expression; Z-DNA is also thought to be involved in DNA processing events and/or genetic instability. For example, Z-DNA-forming sequences have the potential to enhance the frequencies of recombination, deletion, and translocation events in cellular systems. Although the biological function(s) of Z-DNA and related Z-DNA-binding proteins are not fully understood, accumulating experimental and clinical evidence support the idea that this non-B DNA conformation is involved in several important biological processes and may provide a target for the prevention and treatment of some human diseases. In this review, we discuss the properties of Z-DNA, proteins that are known to bind specifically to Z-DNA, and potential biological functions of this non-canonical DNA structure. Show less

The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy. Show less

AbstractThe early phases of commercial drug discovery programs are increasingly guided by information extracted from three‐dimensional structures of the target proteins and in silico design techniques. This review addresses key issues of docking and scoring, a popular technique in structure‐based drug design. The pros and cons of computational tools currently used will be outlined as well as the integration of these methods in the lead finding and lead optimization process. Show less

Oxaliplatin is a relatively new platinum analogue that is currently used in pharmacotherapy of metastatic colorectal cancer. Its dose-limiting toxicity is sensory neuropathy, which can be modulated by infusion of calcium and magnesium. Oxaliplatin exerts its anti-tumour effects by platinum-adduct formation, binding to cellular proteins and possibly interfering with RNA synthesis as well. If they are not removed from DNA, oxaliplatin adducts are lethal. Cellular defense mechanisms prevent adduct formation (e.g., glutathione-S-transferase) or remove DNA adducts (e.g., nucleotide excision repair). Depending on the activity of necessary enzymes in these cellular defense pathways, oxaliplatin induced damage varies from one individual to another. There is growing evidence that polymorphisms in genes coding for DNA repair enzymes and metabolic inactivation routes contribute to the interindividual differences in anti-tumour efficacy and toxicity of oxaliplatin. Single nucleotide polymorphisms (SNPs) may yield inactive enzymes, or increased gene transcription and hence increased enzyme production. This review covers findings of recent investigations on the associations of SNPs and clinical outcome after oxaliplatin chemotherapy in metastatic colorectal cancer. Show less

Cisplatin, carboplatin and oxaliplatin are platinum-based drugs that are widely used in cancer chemotherapy. Platinum-DNA adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. This review focuses on recently discovered cellular pathways that are activated in response to cisplatin, including those involved in regulating drug uptake, the signalling of DNA damage, cell-cycle checkpoints and arrest, DNA repair and cell death. Such knowledge of the cellular processing of cisplatin adducts with DNA provides valuable clues for the rational design of more efficient platinum-based drugs as well as the development of new therapeutic strategies. Show less

Intracellular pH (pHi) has an important role in the maintenance of normal cell function, and hence this parameter has to be tightly controlled within a narrow range, largely through the activity of transporters located at the plasma membrane. These transporters can be modulated by endogenous or exogenous molecules as well as, in some pathological situations, leading to pHi changes that have been implicated in both cell proliferation and cell death. Whereas intracellular alkalinization seems to be a common feature of proliferative processes, the precise role of pHi in apoptosis is still unclear. The present review gathers the most recent advances along with previous data on both the origin and the role of pHi alterations in apoptosis and highlights the major concerns that merit further research in the future. Special attention is given to the possible role played by pHi-regulating transporters. Show less

Of the new generation platinum compounds that have been evaluated, those with the 1,2-diaminocyclohexane carrier ligand-including oxaliplatin--have been focused upon in recent years. Molecular biology studies and the National Cancer Institute in vitro cytotoxic screening showed that diaminocyclohexane platinums such as oxaliplatin belong to a distinct cytotoxic family, differing from cisplatin and carboplatin, with specific intracellular target(s), mechanism(s) of action and/or mechanism(s) of resistance. In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and cumulative distal neurotoxicity, which was reversible within a few months after treatment discontinuation. Moreover, oxaliplatin did not display any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m2 q three weeks or 85 mg/m2 q two weeks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundreds of patients with advanced colorectal cancers (ACRC). Single agent activity reported as objective response rate in ACRC patients is 10% and 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/refractory and previously untreated ACRC, respectively. Synergistic cytotoxic effects in preclinical studies with thymidylate synthase inhibitors, cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations. Phase II trials combining oxaliplatin with 5-FU and folinic acid ACRC patients previously treated/refractory to 5-FU showed overall response rates ranging from 21% to 58%, and survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic acid showed response rates ranging from 34% to 67% and median survivals ranging from 15 to 19 months. Two randomized trials totaling 620 previously untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response rate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These statistically significant differences were confirmed in time to progression advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histological complete responses have been reported in patients with advanced colorectal cancer treated with the combination of oxaliplatin with 5-FU/folinic acid, and secondary metastasectomy is increasingly done by oncologists familiar with the combination. Based on preclinical and clinical reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotecan, and paclitaxel, clinical trials of combinations with other compounds have been performed or are still ongoing in tumor types in which oxaliplatin alone showed antitumoral activity such as ovarian, non-small-cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent. Show less

The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from ónkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage. Show less