New Active Drugs Research Articles

A computational approach to compare microvessel distributions in tumors following antiangiogenic treatments

Experimental approaches currently used to quantify the activity of antiangiogenic treatments in cancer therapy do not generally address the importance of spatial distribution of microvessels in target tissues. We report a new computerized method to assess tumor vascularization by quantifying the distribution of functional microvessels as revealed by in vivo staining with sulfosuccinimidyl-6-(biotinamido) hexanoate. Our approach was based on pixel dilation of digital images of blood vessels and addressed the space-filling property of the vessel layouts. This was practically achieved computing the number of dilation cycles (Halo index) needed to permeate a pre-defined amount of each image. Our approach was validated on human tumor xenografts in nonobese diabetic/severe combined immunodeficient mice treated with the antiangiogenic drug sorafenib. For each experimental model, area normalization allowed the unbiased comparison of several hundreds of images showing different amounts of vascular tissue. In two different tumor types, comparison of Halo values showed statistically significant differences between control and sorafenib-treated samples. Conversely, this effect was not observed in samples from an additional xenograft known to resist the antiangiogenic treatment. By separating the analysis of vessel area from the quantification of vessel distributions, our approach can potentially contribute to a better evaluation of the antiangiogenic or vascular-disrupting activity of new drugs or treatments.

Second- and Third-line Treatment in Advanced Non-small-cell Lung Cancer

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of patients present with locally advanced or metastatic disease. First-line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine or vinorelbine) that results in less than 5% five-year survival. In recent years advances in second- and third-line treatment have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved in NSCLC second-line treatment, and a new class of drugs against specific molecular targets – tyrosine kinase inhibitors – has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in association, or new combinations of third-generation chemotherapeutic agents.

Novel Therapies and Role of Transplant in the Treatment of Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCL) are an uncommon, heterogeneous group of non-Hodgkin lymphomas that carry a much poorer prognosis than their more common B-cell counterparts. The most commonly used treatment is CHOP or its variations. However, while the results with CHOP are inadequate, there is little compelling data to suggest a preferred alternate strategy. Many of these alternate strategies have been assembled from retrospective data, small case series, subset analyses, phase II studies and individual experience. The greatest experience with alternative treatments has been with the use of high-dose therapy as consolidation. These approaches are promising, but most of the studies are retrospective and include patients with diverse prognoses, making interpretation difficult. Preliminary results of prospective trials in PTCL are only recently being reported. Perhaps more exciting have been the increasing numbers of new therapies being studied for patients with PTCL. The activities of new drugs are being described in studies specifically for PTCL, and attempts at novel combinations are beginning.

Chemistry and pharmacology of anticancer drugs

Chemistry and Pharmacology of Anticancer Drugs by David E Thurston has tackled a mountain of information that exists regarding the current state of cancer chemotherapy. The sheer volume of information published on both cancer and chemotherapeutics is frequently discouraging to novice cancer researchers and often turns them away from investigations on the action or activity of new drugs alone or in the combination. This book is written in a style that is easily understood and fairly comprehensive without delving into elaborate dosing tables and various regimens for delivery. As written, the book does an excellent job for its intended target audience of advanced undergraduates and health-care professionals in training or those with only peripheral exposure to cancer therapy. The book begins with a very brief introduction to cancer that includes: basic terminology of cancer and metastasis, staging and grading, treatment options, evaluation of chemotherapeutics, limiting toxicity and mechanisms of chemotherapy that are sufficient but will not impress the professional cancer researcher or clinician. However, the information is presented in a manner that will appeal to professionals or students who desire a rapid overview in this area. After this introduction, the book discusses chemotherapeutic compounds by class, in a manner reminiscent of more clinically rich clinical oncology texts: anti-metabolites, DNA interactive, anti-tubulin, molecular pathway targets and hormonal pathway targets. The author discusses each compound of every class; the class of compound is followed by detailed descriptions of the structure and mechanism of each drug in its class. Toxicities, side effects and current proscribed uses are included, but only as used in the United Kingdom. For those readers who are interested in a source that compiles chemotherapeutics by class and mechanism in a single table, keep waiting. This is one big deficiency of the text. Typically, these tables were provided with administration routes and scheduling information that made them too cumbersome for all but the clinical user. The author has missed a major opportunity to simplify a summary presentation. After this, the book takes a turn towards an examination of more novel and experimental therapies, something usually not found in books that are targeted at the advanced undergraduate to early graduate student level. Essentially, the book handles topics on tumour targeting strategies using antibodies and antivascular approaches as well as bioreductive agents. This trend is continued in the chapter on biological agents, which includes information on biological response modifiers and modulation of the immune system including vaccines. The book then delves into treatments on the horizon that are based upon fairly recent basic and translational research. The author provides a very nice overview of the number of strategies and the specificity for targeting cancer resistance, growth factor signalling pathways and the integration of genomics and proteomic responses for tailoring or determining if treatments are successful. This is followed-up in a later chapter on personalised medicine, which also includes a section on predicting adverse effects to chemotherapy. This section concludes with a brief overview of chemoprevention strategies and the most favoured chemoprevention agents that are used currently; the section also includes a discussion, or at least a speculation, of their mechanism of action. The book concludes with a section on adjunct therapies to ease major side effects and improve patient tolerance of therapy. It is a minor source of irritation that once drugs have been discussed at length they are no longer page referenced in the text and are referred to only by the trade name and not by the compound name, which is how they are listed most commonly in the index. This has the reader referring to the table of contents and the individual drug sections to try to refresh their memory of drugs as they come back into discussion in the text through a different context. Better cross-listing of compounds and a more complete index is needed but is not a major distraction. In short, the back jacket description is quite accurate and the book does not disappoint given the target audience. Finding drugs through the table of contents or through the index is sufficient. Overall, the book is easy to read and manages to not be redundant. This is all quite an accomplishment considering the topic.

Anti-Acute Myeloid Leukemia Activity of Chaetocin, a Novel Epigenetic Drug Inhibitor Inducing Oxidative Stress.

Recent studies have highlighted the importance of epigenetic modifications in the pathogenesis of Acute Myeloid Leukemia (AML). This results have been confirmed by the activity of new drug like DNA demethylating agents and histone deacetylase (HDAC) inhibitors in both in vivo and in vitro studies. Recently, Chaetocin, a natural fungal compound, has been identified as the first specific inhibitor of the histone methyltransferase SU(VAR)3–9 which plays a role in heterochromatin gene silencing. In this study, we decided to evaluate Chaetocin as a therapeutic agent in AML in vitro and to explore the related mechanisms. We show that Chaetocin induce dramatic cell death at nanomolar concentrations in U937 and HL60 (97.2% ± 0.4 and 91.6% ± 9 cell death at 100 nM chaetocin, respectively), and to a lesser extend in K562 (67.3% ± 1.6 cell death at 100 nM chaetocin), cell cultures. Cell death occurred at 24 h incubation time which correlated with induction of apoptosis as assessed by Annexin V/7-AAD staining and activation of downstream executioner caspase-3/7. Using transcription low-density array and quantitative RT- PCR, Chaetocin was showed to up-regulate gene transcription such as of the cell cycle inhibitor p21/WAF1 consistent with a role for the targeted SU(VAR)3–9 in heterochromatin gene silencing. In agreement with the recent report of Chaetocin being a promising new antimyeloma agent acting via imposition of oxidative stress, intracellular levels of oxidative species were increased in Chaetocin treated U937 cells in a time- and dose-dependent manner that correlated with induction of cell death. Furthermore, incubation of cells with N-acetyl cysteine, a cell-permeable precursor of intracellular glutathione reductant, prevented chaetocin-induced accumulation of oxidative species, transcription of selected genes (e.g. p21/WAF1), activation of caspase-3, and cell death. Finally, Chaetocin was found to increase the antileukemia activity of HDAC inhibitors and Aracytin, and thus appears as a promising agent for further study as a potential anti-AML therapeutic. Preliminary results obtained in vivo in xenograft models and ex vivo, using blasts of a panel of patients with AML, will be presented.

Growing opportunities for adjuvant therapy of renal cell carcinoma: targeted drugs and vaccines

The management of advanced renal cell carcinoma (RCC) is undergoing a revolution, with the introduction of new agents and surgical paradigms. Thoughtful integration of diagnostic, surgical and medical approaches to the patient is paramount for disease control. Methods of risk stratifying kidney cancers are reviewed, as well as mechanisms of action of newer drugs approved in advanced metastatic kidney cancer. These drugs present opportunities for application to patients in an earlier stage of disease, and adjuvant RCC trials designs are discussed. Improvements have been made in the understanding of the molecular and genetic basis of RCC, both for causative and prognostic markers, with models addressing prediction of tumor behavior and therapeutic targets. Practice patterns have shifted from cytokine therapies to targeted molecular approaches, particularly emphasizing the VEGF pathway, related intracellular kinases and the mammalian target of rapamycin. Autologous vaccine adjuvant studies are maturing. In conclusion, elucidation of specific genes, proteins and aberrant molecular pathways associated with kidney cancer are ongoing. These new agents may lead to opportunities to improvement of disease-free survival through therapy in the adjuvant setting.

Cibles des médicaments antithrombotiques

New antithrombotic agents are being developed not only to improve efficacy, but also to increase safety in comparison with widely used conventional agents such as the oral anticoagulants. New anticoagulant, antiplatelet, and profibrinolytic compounds are currently under study in drug development programs, and most of those in phase II or III of development are derived from the observation of natural phenomena and merely mimic processes developed by mammalians, including humans, to avoid thrombosis, or by blood-sucking insects or animals to prevent coagulation of the blood their are feeding on. By contrast, drug candidates identified by means of rigorous research and designed to target new pathways and achieve direct and specific inhibition of factors that are presumed to play an important role in thrombogenesis have generally failed to show any benefit and sometimes even induce deleterious effects. The clinical development of new drugs, even those mimicking natural phenomena, improves our knowledge of the pathogenesis of thrombosis and sheds light, retrospectively, on previous conceptual errors. The improvement in our basic knowledge and the development of new types of drugs suggest that, in contrast to the current antithrombotic compounds that are used in a broad range of clinical settings, use of new drugs should be restricted to specific situations in which their mechanisms of action are predicted to deliver the highest medical benefit. A major obstacle resides in the fact that current drug development programs are still required to comply with long obsolete guidelines based on the characteristics of first-generation antithrombotic agents, and that do not take into account the specific mechanisms of action of new drugs. This situation should change, however, and new antithrombotic drugs should soon be able to benefit from adapted development programs that will make it possible to determine their optimal risk-benefit ratio.

Preoperative Radiochemotherapy in Gastric Cancer: Another Ongoing Shift From Adjuvant to Neoadjuvant?

TO THE EDITOR: I read with interest the article by Ajani et al on preoperative radiochemotherapy in gastric cancer published in the July 15, 2004, issue of the Journal of Clinical Oncology. Since a similar experience published recently by our Geneva group apparently escaped the authors’ attention, I thought it worthwhile to call it to the attention of the Journal’s readers. Indeed, the approach and the chemotherapeutic agents used were quite similar, though the schedule of administration was different. In both series, preoperative radiochemotherapy was associated with remarkably low locoregional recurrence rates, with the peritoneum becoming a major site of failure. The survival rates were also comparable, with approximately 40% overall survival at 5 years. However, as the rate of distant metastases in the Ajani et al series remained very high (distant 45% peritoneum 21%), one might question the value of upfront chemotherapy. Moreover, this approach was associated with two treatment-related deaths (7%), making it difficult to recommend. Based on the results of the two series, future trials might favor concomitant radiochemotherapy using newer active drugs such as taxanes, and the use of intraperitoneal chemotherapy under hyperthermic conditions might be envisioned in case of peritoneal involvement. Finally, I seriously question the authors’ conclusions that major tumor response translates directly into a significant survival advantage. In fact, the overall survival and disease-free survival rates of the whole group were not different compared with the rates reported in the randomized trial of Macdonald et al using postoperative radiochemotherapy. Indeed, good response may reflect less aggressive biologic characteristics of the particular tumor, whose outcome would be favorable regardless of response to adjuvant treatment. The latter argument is clearly supported by the results of the recent randomized trial on preoperative radiochemotherapy in esophageal carcinomas, where similar overall and event-free survival rates were reported. Nevertheless, the results of the Ajani et al add to the evidence suggesting that neoadjuvant radiochemotherapy may be a good option to deal with the problems associated with administration of adjuvant treatment in some tumor locations where we know that surgery alone is inadequate.

HEK293 cell line: A vehicle for the expression of recombinant proteins

The HEK cell line has been extensively used as an expression tool for recombinant proteins since it was generated over 25 years ago. Although of epithelial origin, its biochemical machinery is capable of carrying out most of the post-translational folding and processing required to generate functional, mature protein from a wide spectrum of both mammalian and non-mammalian nucleic acids. Though popular as a transient expression system, this cell type has also seen wide use in stably transfected forms (i.e. transformed cells) to study a variety of cell-biological questions in neurobiology. The principal attributes which have made the HEK cell a popular choice among electrophysiologists to study isolated receptor channels include; its quick and easy reproduction and maintenance; amenability to transfection using a wide variety of methods; high efficiency of transfection and protein production; faithful translation and processing of proteins; and small cell size with minimal processes appropriate for voltage-clamp experimentation. These, and other attributes, also mean that complementary biochemical/cell biological evaluations of expressed proteins can be performed in concert with functional analyses to establish detailed pharmacological and biophysical profiles for the action of new drugs and their targets. The increased amount of sequence information available from the human genome has placed greater emphasis upon heterologous cell expression systems as targets for high throughput structure–function evaluation of novel drug targets and disease markers. Here we have highlighted some of the innate characteristics of the HEK cell in order that its suitability as a vehicle for the expression of a gene product can be assessed for particular needs. We have also detailed some of the standard methods used for transfection and obtaining functional data from electrophysiological recording techniques.

The clinical and nutritional implications of lipid-lowering drugs that act in the gastrointestinal tract

A new class of cholesterol-lowering therapy that reduces intestinal sterol absorption has recently been introduced. This increases the number of classes of lipid-lowering agents that directly affect gastrointestinal function and raises questions concerning the overall effect of these agents on absorption and nutritional status. A recent assessment notes a paucity of information concerning the factors that affect the bioavailability and intestinal absorption of lipophilic nutrients. By contrast, the specificity of the mechanisms of action of new drugs acting on the gastrointestinal tract may circumvent some of the detrimental effects on nutrient and drug bioavailability that have been noted with older forms of treatment. The clinical imperative for aggressive control of lipid and metabolic risk factors makes widespread use, alone or in combination, of lipid-lowering agents that affect the gastrointestinal tract seem increasingly likely. Whilst the opportunity for therapeutic synergy is attractive, care will be required to avoid interference with intestinal absorptive function.

Neoadjuvant therapy before radical prostatectomy in high-risk localized prostate cancer: defining appropriate endpoints

High-risk localized prostate cancer remains a vexing problem for clinicians. Definitive local treatments such as surgery and radiation therapy cure only a minority of these patients. As a result, efforts are being made to reduce the risk of recurrence by using chemotherapy and new agents before, during or after definitive local therapy. Neoadjuvant androgen deprivation therapy has yielded disappointing results when combined with surgery. Chemotherapy in the management of localized disease is evolving, and preliminary studies are just now being completed. Although these agents have established activity and acceptable toxicity in the hormone-refractory setting, more extensive use of them in patients with androgen-dependent disease will require data from randomized studies to determine overall efficacy. New molecular-targeted therapies are promising and hold the greatest hope that outcomes in early disease may be improved with early use of systemic therapy. The neoadjuvant surgical model also has promise in assessing the activity of new drugs, because it provides a means to determine molecular effects of specific agents, along with standard pathologic and clinical parameters of efficacy.

Objective response to treatment as a potential surrogate marker of survival in breast cancer.

Until recently, objective tumor response to chemotherapy was used as the primary endpoint in phase II trials aimed at assessing the anti-tumor activity of new drugs. However, it was not accepted as a surrogate endpoint of survival for efficacy trials in solid tumors, and it was not believed to be associated with survival benefit. The recent demonstration that objective response is indeed a valid surrogate endpoint of survival in colorectal cancer, together with strong indirect evidence supporting a similar role of response in breast cancer, opens new possibilities for both the design of trials in metastatic breast cancer and the clinical decision in individual patients with the disease.

The genetic basis of the pharmacological effects of anxiolytics: a review based on rodent models.

Anxiolytic drugs exert their pharmacological actions by binding to molecular targets, such as benzodiazepine receptors or 5-hydroxytryptamine (5-HT) receptors. Specific genes encode these receptors, or the subunits of which they are formed. Therefore, genetic factors may influence strongly the ability of anti-anxiety agents to produce their behavioural effects. The literature on this subject is reviewed here, with emphasis on data derived from studies with rodents. We present in a critical way the animal models used in the studies aimed at investigating the genetic basis of the action of anxiolytic compounds, including inbred mice, selected lines, linkage strains or mice generated by targeted mutation. Data show that increased anxiety-like behaviour is not a predictive factor for increased sensitivity to anxiolytic treatment, and it is possible that gene deletion might not be isomorphic to pharmacological antagonism. It is suggested that the strain differences in anxiety-like behaviour may be used as a tool in assaying anxiolytic activity of new drugs.

Optimization of metabolic stability as a goal of modern drug design.

Metabolism and other pharmacokinetic (PK) studies have always played a critical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of automated combinatorial synthesis, high-throughput pharmacological testing, and the ability to create extensive databases in the past decade, drug discovery has undergone an amazing evolution. With the increased throughput of drug discovery, metabolism and other PK studies have evolved to keep pace. Often called "early ADME" studies, these studies are characterized by parallel processing and higher throughput than before. This article focuses on a particular class of early ADME (absorption, distribution mechanism, and excretion) studies known as "metabolic stability" studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic intrinsic clearance is briefly presented. Some key relationships between structure and metabolism are summarized. Several case studies from recent medicinal chemistry literature are reviewed to exemplify how metabolic stability studies influenced drug design and led to improvements in bioavailability and half-life. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

Vinorelbine + Mitomycin C as Second-Line Treatment of Metastatic Breast Cancer: A Two-Stage Phase 2 Study

Second-line treatment of patients with metastatic breast cancer resistant to anthracyclines is an important clinical issue. The aim of the present two-stage phase II study was to evaluate activity and toxicity of vinorelbine + mitomycin C (VM) in such patients. Fifty-five patients were entered and received vinorelbine 30 mg/m² on days 1 and 8 + mitomycin C 10 mg/m² on day 1, every 4 weeks, up to 9 cycles. Two complete and 23 partial responses were observed for an overall response rate of 45.4% (95% CI 32.0–59.4). Median survival was 13 months and probability of surviving after a 1-year follow-up was 58%. Toxicity was never life-threatening, but G-CSF was used in 45% of cycles to contrast neutropenia that was the most frequent side effect. These results are consistent with previous studies and strongly support VM being considered among the optimal polychemotherapy regimens for second-line treatment of metastatic breast cancer in clinical practice; for clinical research aims, VM should be used as control arm for randomized trials evaluating the activity of new drugs against breast cancer.

Orthotopic Models of Human Pancreatic Cancer

Orthotopic transplantation of solid tumor fragments of human tumors in nude mice reproduces their pattern of local growth and distal dissemination. While lymphatic, hepatic or peritoneal dissemination can be reproduced, perineural invasion is absent. Early passages (less than 3) of xenografts show a high degree of stability regarding K-ras, p53 and p16 gene status. On the other hand, advanced passages of tumors acquire additional alterations in the p15 and Smad4 genes. Mutations in K-ras, p53, p15 and Smad4 genes can be acquired, in this model system, in the more advanced stages of pancreatic tumor dissemination. Finally, it is also possible to standardize local growth of these tumors as well as its dissemination pattern giving us a preclinical tool to evaluate the anticancer activity of new drugs.

Neurophysiology of Cancer Pain: From the Laboratory to the Clinic.

Pain is one of the most distressing symptoms associated with cancer. Basic science research has provided much insight into the mechanisms of peripheral and central pain and the actions of new drugs. Despite these advances, pain accompanying malignancy can be difficult to treat. Pain most commonly presents when the tumor has invaded somatic,visceral, or neural structures. An understanding of pain mechanisms is essential when deciding on the appropriate treatment. New therapeutic options have been developed and will hopefully provide clinicians with tools to successfully alleviate cancer pain.

New approaches to adjuvant chemotherapy for breast cancer.

Adjuvant chemotherapy improves the disease-free and overall survival of patients with resectable, early-stage breast cancer. However, the effect is modest, and we need means of increasing its impact. Retrospective and prospective studies on the effects of increased drug dosage have demonstrated that within some dose ranges, increasing the dose intensity (total drug dose divided by total treatment time) improves the outcome of treatment. Dose escalation to higher levels, sufficient to require growth factor and autologous stem cell support, is the subject of ongoing randomized study. Because there are both theoretical and practical limits on the potential effectiveness of single-cycle, high-dose chemotherapy, researchers are developing alternative means of increasing the effect of chemotherapy. One theoretically advantageous approach, predicted to be superior by kinetic models, is "dose-dense" chemotherapy administration. This approach consists of multiple cycles of escalated-dose chemotherapy administered at very short intervals. When administering presumed non-cross-resistant regimens or agents with overlapping toxicity, clinicians can increase dose density by using the sequential treatment plan. Furthermore, this plan can also facilitate the addition of new active drugs.

State-of-the-Art Review: Usefulness of Laboratory Techniques for Evaluating Antithrombotic Efficacy of New Therapeutic Strategies

New drugs and new therapeutic strategies are being introduced for the prevention and the management of cardiovascular and thromboembolic disorders. Extensive clinical studies and large-scale epidemiological investigations are conducted to demonstrate the efficacy of these therapeutic approaches. Laboratory assays are invaluable tools for this exploration. We discuss how the new understanding concerning the regulation of the coagulolytic equilibrium offers novel investigation tools. Parameters reflecting the activities of new drugs targeted to their impact site and presenting few side effects are available. In addition to global clotting methods and chromogenic substrate-based assays, introduction of immunoassays has allowed measurement of most of the molecular markers of hemostatic activation. We recommend use of a panel of markers exploring the endothelial damage, the blood cell involvement, the early coagulant pathways' activation (XIIa and VIIa), the thrombin-formation pathways, the fibrin formation, and the evaluation of the global fibrinolytic capacity. When related to the clinical end points, all these laboratory assays offer useful and reliable monitoring of new drugs. They contribute to the establishment of new therapeutic strategies. Key Words: Hemostasis—Activation—Antithrombotic—Therapy— Laboratory monitoring.

Evaluation of WR250417 (A Proguanil Analog) for Causal Prophylactic Activity in the Plasmodium cynomolgi-Macaca mulatta Model

The Plasmodium cynomolgi-Macaca mulatta model has been used to test the antimalarial activity of new drugs for both radical cure and casual prophylaxis. The proguanil analog WR250417 (also known as PS-15) was evaluated for causal prophylactic activity in rhesus monkeys infected with P. cynomolgi bastianelli. Four monkeys were orally dosed with 40 mg/kg/day of WR250417 over three days (-1, 0, and +1). Sporozoite-induced infection of P. cynomolgi was initiated on day 0 with 1 x 10(6) sporozoites to each monkey. Compound WR250417 extended the prepatent period from an average of 8.5 days for controls (n = 2) to a mean of 18.3 days (range 18-19 days, n = 4) for drug-treated monkeys. Analysis of plasma drug concentrations by high-performance liquid chromatography showed that the monkeys converted the WR250417 to its putative principal active metabolite WR99210 (a dihydrotriazine). These findings demonstrate that WR250417 and its principal metabolite do not prevent primary infection by P. cynomolgi.