23.08.2014

Anticancer drugs journal impact factor

Sources of tumour-initiating cells (TICs) for enrichment and characterization include samples from cancer patients, primary tumour xenografts and certain cancer cell lines that maintain tumour hierarchy. 9-Aminoacridine (9AA) treatment suppresses the activity of AKT and mammalian target of rapamycin (mTOR) in tumor cells.
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We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Hypoxia, a partial pressure of oxygen (pO2) below physiological needs, is a limiting factor affecting the efficiency of radiotherapy.
Tumor hypoxia results from the imbalance between oxygen delivery by poorly efficient blood vessels and oxygen consumption by tumor cells with high metabolic activities.
The effect of tumor hypoxia on the response to treatment by ionizing radiation has been demonstrated in a multitude of experimental studies.
Currently, the most advanced therapeutic interventions used in the clinic to target tumor hypoxia are either the DAHANCA (Danish head and neck cancer) trial, the application of the ARCON (Accelerated radiotherapy, carbogen, and nicotinamide) protocol, and phase III studies with Tirapazamine. From the clinical analyses cited above, it also appeared that the variation in the results among the trials reflects a considerable heterogeneity among tumors and that patient individualization would be mandatory for the success of such therapeutic approach. Tumors are highly heterogeneous and this heterogeneity extends to the tumor vasculature (see Introduction). Physiologically, the vascular tone is determined by the balance between nitric oxide (NO, a potent vasodilator) and endothelin-1 (ET-1, a potent vasoconstrictor; Sonveaux and Feron, 2005). NO was initially investigated for its vasodilatory activity and NO donors were anticipated to improve the therapeutic efficacy of chemo- and radiotherapy upon combinational delivery (Sonveaux et al., 2009). A smart delivery of exogenous NO would help to resolve the Steal Effect, a process through which systemic vasodilation may in fact reduce tumor perfusion and oxygenation by redirecting blood to normal blood vessels that are generally more sensitive to vasoactive treatments and constitute a denser network (Zlotecki et al., 1995).
While the use of SNO-Hb exploits hypoxia as a mean to selectively deliver NO to tumors, one can also take advantage of the low pH coupled to the high metabolic activities of many solid tumors.
Given that anti-angiogenic agents will likely be combined with radiation therapy, it is critical to understand alterations in tumor oxygenation and perfusion, as well as to define optimal time points for the delivery of radiation. A group of South Korean scientists have developed a microscopic robot that can both detect and treat cancer.
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QTc prolongation assessment in anticancer drug development: clinical and methodological issues.
Alisa Hideg receives a vaccine at UW Medical Center from Erika O'Brietan, a registered nurse with the UW Tumor Vaccine Group. Qingcheng Mao and Jashvant Unadkat, faculty members of the School of Pharmacy, recently learned that a 2005 article they published in the American Association of Pharmaceutical Scientists (AAPS) Journal is one of the 10 most-cited articles in the journal's nine-year history.
Mao and Unadkat’s research helped lay a foundation to improve understanding of how breast cancer patients with high levels of the ABCG2 transporter in their system might respond to chemotherapy. This article summarized knowledge of the transporter ABCG2 and its relevance to multidrug resistance and drug disposition. This was one of the early articles that emphasized the importance of ABCG2 in drug disposition before its role was fully appreciated by the scientific community. Scientists today are building on our study, as well as others like it, by trying to find ABCG2 inhibitors that can overcome drug resistance in the human body and improve the fate of the drugs conveyed by this transporter.
We thought that the scientific community would see that this transporter plays an important role in drug disposition. Based on the hypothesis proposed in our article, we have been conducting research on basic mechanism of ABCG2 as well as the function of this transporter in cells and animal models. We have attracted National Institutes of Health funding for three ABCG2-related grants that total almost $2.6 million.
We want to further investigate the basic mechanism by which ABCG2 acts to transport drugs and interact with inhibitors. Nucleation is followed by elongation of the microtubule at both ends to form a cylinder that is composed of tubulin heterodimers arranged head-to-tail in 13 protofilaments. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button.
This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Among other biological influences, hypoxia is a main factor limiting the efficacy of radiotherapy, primarily because oxygen is involved in the stabilization of the DNA damage caused by ionizing radiations. Indeed, the reaction of reactive oxygen species (ROS, produced by water radiolysis) with DNA is readily reversible unless oxygen stabilizes the DNA lesion. On the one hand, oxygen delivery is impaired by structural abnormalities present in the tumor vasculature (Munn, 2003).
In the DAHANCA phase III study, nimorazole has been used as hypoxic radiosensitizer on 422 patients, and it was shown that this compound improves the effect of radiotherapeutic management in head and neck cancer (Overgaard et al., 1998). The goal of the provascular approach is to temporarily increase tumor perfusion and oxygenation through pharmacological interventions. There is therefore an essential need to predict individually the presence of hypoxic regions in tumors. A number of studies have explored the functionality and the provascular exploitability of these two systems, as described below. We first considered the effect of the application of exogenous NO on tumor hemodynamic parameters and radiation response.
Using hemoglobin (Hb) is an interesting approach because Hb is a physiological NO carrier (in the form of S-nitrosothiol) poised to deliver NO selectively in hypoxic tissues such as tumors (Sonveaux et al., 2005). It has a key role in the accommodation of vasoactive blood vessels to variations in intraluminal pressure: ET-1 mediates the myogenic tone, a vasoconstriction that buffers perfusion changes when the blood pressure increases (Huang and Koller, 1997).
The nanorobot is powered by a special, genetically-modified bacteria that can detect substances and proteins associated with cancer growth.
The group administers clinical drug trials for patients with breast, ovarian or colon cancer.
Their article, “Role of the breast cancer resistance protein (ABCG2) in drug transport,” examined how the transporter ABCG2 relates to a broad range of anticancer drugs and antiviral agents.
It also established the importance of this transporter in drug disposition (getting a drug to its appropriate position in the body and in an appropriate concentration) in human populations including pregnant women. It also helped show that the protein is widely expressed in organs such as the liver, kidney, small intestine, placenta and brain. For example, we emphasized that overexpression of this transporter in an individual is associated with higher levels of resistance to certain chemotherapy drugs. What did this study establish at the time, and how have other scientists used it as a building block? We are also looking at how the ABCG2 transporter impacts drugs taken during pregnancy because ABCG2 is a major transporter of toxic substances out of a cell in the placental barrier in pregnant women.
Such studies could help scientists better understand novel therapeutic agents that can be more effective therapies for human diseases including cancers. TICs can be studied in heterogeneous systems provided their activities can be monitored by cell surface markers or signalling reporter activities.


Radiobiological hypoxia is found in regions of rodent and human tumors with a tissue oxygenation level below 10 mmHg at which tumor cells become increasingly resistant to radiation damage. In biological tissues, irradiation primarily induces water ionization and destabilization, leading to the formation of reactive radical species (A). They include caliber variations with dilated and narrowed single branches of tumor vessels, non-hierarchical vascular networks, disturbed precapillary architecture, and incomplete vascular walls.
Hypoxia in tumors results from a mismatch between the oxygen supply by poorly efficient blood vessels and oxygen consumption by metabolically overactive tumor cells.
These results stimulated considerable efforts in defining and evaluating therapeutic approaches designed to overcome tumor hypoxia as source of resistance (Horsman and van der Kogel, 2009).
Since these results, nimorazole administration became part of the standard irradiation protocol for Head and Neck cancer in Denmark. Accordingly, radiotherapy could benefit from tumor reoxygenation whereas a decrease in interstitial pressure could facilitate tumor accessibility to circulating drugs. These vessels possess the minimal contractile features (such as pericytes or vascular smooth muscle cells) endowing them with vasocontractile properties.
This mode of activation allows the transient production of micromolar amounts of NO responsible for vasodilatation.
They have been used clinically as an antidote for cyanide poisoning (Holland and Kozlowski, 1986) which also indicates that they can be safely administrated to humans. In tumors, the constant exposure arterioles to ET-1 results in an increased myogenic tone that can be detected ex vivo (Sonveaux et al., 2004). Once it reaches a cancer cell, the 3-micrometer robotic device automatically sprays anticancer drugs. The developers are hoping to advance the technology further so that it can detect more types of cancer in earlier stages.
Transporters are membrane proteins in tissues that help the body absorb, distribute and excrete drugs. ABCG2 expression has been detected in a large number of hematological malignancies and solid tumors, and the article improved understanding of that fact. We also hope this larger body of research into ABCG2 helps improve understanding and prediction of fetal drug safety. Even highly purified TICs are expected to gradually become more differentiated under tissue culture conditions.
Since hypoxic tumor cells remain clonogenic, their resistance to the treatment strongly influences the therapeutic outcome of radiotherapy.
These species then react with neighboring molecules to yield reactive oxygen species (ROS) (B), among which the hydroxyl radical is believed to be the most cytotoxic.
A particular area under focus is thus to combine radiotherapy with treatments that increase tumor pO2.
However, these findings have had no impact on general clinical practice except for Denmark because earlier generations of these agents induced rather severe peripheral neuropathy and because nearly all of the individual phase III trials yielded negative or inconclusive results (Ang, 2010). Alternatively, a second approach is to decrease the oxygen consumption by tumor cells since theoretical modeling studies demonstrated that reducing O2 consumption was far more efficient at reducing tumor hypoxia than increasing blood pO2 or flow (Secomb et al., 1995). In the early nineties, invasive techniques such as polarographic electrodes have been used in clinical studies to definitely establish the value of hypoxia as a predictive marker of the response of tumors to irradiation. The intrinsic reactivity of tumor-feeding vessels modulates oxygen delivery and the accessibility of circulating drugs to the tumor. The stimulation of the production of endogenous NO was also achieved by administration of insulin (Jordan et al., 2002).
Using myography, we showed that this system is insensitive to classical eNOS stimulators (such as acetylcholine) selectively in tumor arterioles, thus suggesting that strategies able to restore eNOS activity would selectively target tumor vessels (Sonveaux et al., 2002). We therefore tested whether the low pH of tumors (on average pH 6.7) could be exploited to generate NO from nitrites selectively in tumors. We reasoned that it constituted a reserve for vasorelaxation that could be exploited to sensitize tumors to radio- and chemotherapy. The robot opens the doors for a more targeted approach to fighting cancer, which is likely to have fewer side effects than conventional treatments like chemo or radiation, which attack the entire body. Food and Drug Administration recently recognized it as one of the most important transporters related to drug disposition and drug-drug interactions.
TICs that are dependent on a niche and paracrine or juxtacrine signalling might be better maintained in three-dimensional organotypic culture than two-dimensional culture. There is therefore an urgent need to identify adjuvant treatment modalities aimed to increase tumor pO2 at the time of radiotherapy. Hypoxic tumor cells, which are therefore more resistant to radiotherapy than well oxygenated ones, remain clonogenic, and contribute to the therapeutic outcome of fractionated radiotherapy (Rojas et al., 1992). When generated in the proximity of DNA, hydroxyl radicals and, to a lesser extent, other less energetic species attack DNA (C).
Diffusion-limited hypoxia refers to a gradient of oxygen deprivation from the nearest perfused blood vessels toward tumor cells at increasing distances from this vessel.
Other approaches consist to chemically radiosensitize hypoxic cells or alternatively to exploit hypoxia as a mean to selectively kill the resistant population of hypoxic cells. The ARCON protocol consists in the combination of accelerated radiotherapy to overcome tumor cell proliferation, carbogen breathing to overcome diffusion-limited hypoxia, and nicotinamide to minimize capillary bed shutdown and thereby reduce perfusion-related acute hypoxia.
We will also describe attempts to combine both approaches that can be considered as complementary strategies.
Although this method was successful in demonstrating the central role played by tumor hypoxia in the clinical response to radiation therapy, it has never been used in standard clinical practice because of its invasiveness and the difficulty to systematically carry out longitudinal studies in individual patients.
A selective and transient dilation of these vessels should thus improve the tumor response to radiotherapy (which depends on tumor oxygenation) and chemotherapy (which depends on perfusion and on the vascular exchange area). All treatments resulted in a transient acute improvement of experimental tumor oxygenation with a consecutive increase in tumor radiosensitivity upon sequential administration of X-rays during the reoxygenation window identified for each tumor model (Jordan et al., 2010). Among different treatments, we have found that ionizing radiations themselves were able to restore the normal vasodilatory properties of tumor vessels. In deoxygenated blood, SNO-Hb would otherwise readily deoxygenate and release NO at the site of delivery.
ET-1 induces vasoconstriction when binding to ETA receptors expressed by contractile vascular cells (Maguire and Davenport, 1995). They’ve published their findings in the latest edition of the online journal Scientific Reports. Today, it is considered one of three major transporters causing drug resistance in mammalian cells. Drug effects on TICs can be studied according to standard end points (such as proliferation, survival and colony size) and TIC-focused end points such as aberrant differentiation (for example, disproportionate presence of markers of TICs, lineage or epithelial–mesenchymal transition (EMT)) and self renewal. Since tumor hypoxia fundamentally results from an imbalance between oxygen delivery by poorly efficient blood vessels and oxygen consumption by tumor cells with high metabolic activities, two promising approaches are those targeting vascular reactivity and tumor cell respiration. On the other hand, the altered tumor cell metabolism with elevated metabolic rates also contributes to the occurrence of hypoxic regions in tumors and further causes extracellular acidification. It originates from high-rate of oxygen extraction though layers of cells within a loosened vascular network. Before the advent of imaging methods able to provide non-invasively oxygen estimation, animal, and clinical studies were generally designed to evaluate the effect of a given treatment on tumor pO2 as measured by Eppendorf or histological markers of tumor hypoxia.


Phase I and II clinical trials have shown the feasibility and tolerability of the treatment and have produced promising results in term of tumor control, in particular in cancer of the head and neck and bladder (Kaanders et al., 2002).
The evaluation and validation of these adjuvant therapies (Table 1) require imaging techniques capable of monitoring tumor perfusion and oxygenation. Fortunately, it is now possible to estimate tumor oxygenation by using minimally or non-invasive techniques. X-rays, through the production of ROS, indeed induce an increase in eNOS expression concomitantly with a decrease in Cav-1 expression, which removes a functional brake promoting eNOS activation (Sonveaux et al., 2002, 2009). We also found that the bioactivity of nitrites at low pH encompassed NO-mediated inhibition of tumor cell respiration, which indicates that the robust and transient increase in tumor pO2 after nitrite delivery to mice is the result of the combination of vasoactive and metabolic responses. Using the ETA antagonist BQ123, we observed ex vivo a vasodilation selectively in tumor vessels (compared to size-matched vessels from non-malignant tissues) that translated in vivo into increased tumor perfusion and oxygenation (Sonveaux et al., 2004).
One way to measure self renewal in vitro is to track long-term colony-initiating cells in colony-forming unit assays by replating in semi-solid media. Phosphorylation of 4EBP1 was examined by western blotting using phosphor-specific antibody. This review summarizes the current knowledge about the development and use of tumor-selective vasodilators, inhibitors of tumor cell respiration, and drugs and treatments combining both activities in the context of tumor sensitization to X-ray radiotherapy.
However, in the presence of oxygen, DNA damage can be stabilized through oxidation of DNA radicals, eventually leading to the formation of DNA peroxides (D). Perfusion-limited hypoxia refers to oxygen deprivation along the vascular tree from the tumor margin toward the tumor core. A large improvement in survival was demonstrated using this approach during radiotherapy for bladder cancer. The net effect of systemic vasodilation on tumor pO2 is unpredictable because it primarily depends on the arrangement of vessels (in series or in parallel) between the tumor and surrounding host tissues (Zlotecki et al., 1995).
Importantly, for some co-treatments, the increase in blood flow occurred concomitantly with a decrease in the rate of oxygen consumption by tumor cells. Irradiations further stimulate NO production through the ROS-dependent activation of the PI3 kinase pathway, a well described pathway supporting Akt-mediated eNOS phosphorylation (on Ser1177, human sequence) and activation (Sonveaux et al., 2003, 2007a). TICs are defined by in vivo experiments, and in vitro results always need to be validated in vivo. Tumor-selective vasodilation may also be used to improve the delivery of circulating anticancer agents to tumors.
Chronic hypoxia has classically been thought to result from long diffusion distances between tumor vessels as the consequence of the more rapid expansion of tumor cells than that of the supporting vasculature (Vaupel et al., 1989). Poor oxygen delivery has many causes in tumors, including high-rate of oxygen extraction at the tumor margin, decreased red blood cell deformability, and stacking, increased blood viscosity due to water extraction, vascular disorganization, and angiogenesis.
Modifiers of oxygen delivery tested in clinical trials included hyperbaric oxygen therapy (HBO), oxygen and carbogen breathing. The randomized multicentre phase III trial, designed and coordinated at Mount Vernon Cancer Centre, demonstrated a 13% benefit in overall survival when radiotherapy was combined with carbogen and nicotinamide compared to radiotherapy alone (Hoskin et al., 2009). Inhibition of tumor cell respiration is the main mechanism accounting for insulin-induced tumor reoxygenation (see below).
We documented that radiation-induced vasodilation takes an active part in the antitumor effects of X-rays by showing that eNOS inhibition between the first and second irradiation of a clinical regimen of fractionated radiotherapy results in the total loss of the antitumor efficacy of the second dose, whereas eNOS inhibition before a single dose does not preclude cytotoxic effects (Sonveaux et al., 2002). Further clinical applications are however confronted to financial issues: clinical trials are now warranted whereas nitrites or their use in cancer therapy can not be patented.
The bottom panel is a western blotting showing total 4EBP levels in the input lysates before in vitro kinase assay.
Imaging tumor perfusion and oxygenation is of importance not only for the development and validation of such combination treatments, but also to determine which patients could benefit from the therapy. It is now well established that steep longitudinal gradients of pO2 along the vascular tree, as opposed to radial diffusion of oxygen, can largely contribute to deficiencies in tumor oxygen supply (Dewhirst et al., 1999). Hypoxic cell radiosensitizers (possessing a selective toxicity for the radioresistant hypoxic cells) tested in clinical trials included metronidazole, misonidazole, nimorazole, and tirapazamine. Results from a large phase III trial launched to test this regimen will become available within the next 2 years. Treatment optimization would also require to monitor on individual bases the tumor response to treatment, preferentially using early surrogate, predictive, and non-invasive markers.
Active vasodilation after each of the consecutive doses of fractionated radiotherapy is associated with a window of tumor reoxygenation that offers a scientific rationale for the clinical use of radiotherapy in its fractionated mode. For advanced tumours with a large TIC burden, traditional models with standard end points (for example, tumour regression and metastasis) might be sufficient, whereas for other tumours, it might be necessary to focus on the tumour-initiating activity through administration of the agents before and following implantation of enriched or isolated TICs. In a systematic review, Overgaard (2007) identified 10,108 patients in 86 randomized trials designed to modify tumor hypoxia in patients treated with curative attempted primary radiation therapy alone.
Finally, Tirapazamine (TPZ) has attracted interest after preclinical studies showing that in addition to augmenting the cytotoxicity of both radiation and cisplatin, this compound selectively kills hypoxic cells (Rischin et al., 2001, 2005). TIC-related end points also include the effect on relapse after chemotherapeutic treatment or the ability of residual tumour cells after treatment to re-engraft in in vivo xenograft models.
Hence, this review also briefly describes both magnetic resonance and non-magnetic resonance in vivo methods and compares them in terms of sensitivity, quantitative or semi-quantitative properties, temporal, and spatial resolutions, as well as translational aspects. The commonly held view has been that acute hypoxia results primarily from vascular stasis, which stems from one of three causes: (1) vascular collapse in regions of high tumor interstitial pressure, (2) vessel plugging by leukocytes, and (3) impingement of tumor cells on the vascular lumen.
Overall modification of tumor hypoxia significantly improved the effect of radiotherapy for the outcome of locoregional control and with an associated significant overall survival benefit.
Phase I and II studies of the combination of TPZ with radiation and cisplatin were performed on patients with locally advanced head and neck carcinoma. To understand the effect of the drug on tumour hierarchy, immunochemistry using antibodies against TIC, lineage and EMT markers needs to be performed. No significant influence was found on the incidence of distant metastases or on the risk of radiation-related complications. On the basis of the phase II data, a large international phase III trial was launched (Peters et al., 2010).
To promote the tumour–host interaction, orthotopic models, subrenal capsule implantation and subcutaneous co-injection models that mix tumour cells with stromal cells have been explored. From this meta-analysis, the authors concluded in 2007 that “Ample data exist to support a high level of evidence for the benefit of hypoxic modification.
Surprisingly, the combination did not show any evidence of improvement in overall survival. More recent studies indicate a widespread presence of fluctuating hypoxia in solid tumors (Cardenas-Navia et al., 2008).
Nevertheless, patients were not previously screened for tumor hypoxia; the study was multicentric with some centers enrolling fewer than five patients and a consequent decrease in the quality of radiotherapy planning and delivery which can have dramatic consequences on outcome (Ang, 2010).



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