Rationally designed anti-mitotic agents with pro-apoptotic activity

Agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and monotetrahydrofuran compounds (COBRA compounds), targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization and demonstrated potent cytotoxic activity against cancer cells. COBRA-1 inhibited GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other agents that have shown promise for cancer treatment include phorboxazoles, natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. In standard MTT assays, synthetic phorboxazole A exhibited potent cytotoxicity against NALM-6 acute lymphoblastic leukemia cells (IC50 = 1.7 nM), BT-20 breast cancer cells (IC50 = 3.4 nM), and U373 glioblastoma cells (IC50 = 6.7 nM). Structure-activity studies were reported for seven synthetic analogs of phorboxazole A. Out of these, two showed potent anti-cancer activity. Phorboxazole analog 2 was active against NALM-6 cells (IC50 = 4.8 nM), BT-20 cells (IC50 = 12.6 nM) and U373 cells (IC50 = 27.4 nM), as was analog 3 (NALM-6 IC50 = 5.2 nM, BT-20 IC50 = 11.3 nM, and U373 IC50 = 29.2 nM). Anticancer activity of the phorboxazole analogs was correlated to the presence of certain structural moieties such as portions of the macrolide group, the central oxazole group, and the polyene side chain. The requirement of more than one structural element for activity suggested that at least bimodal interactions of the natural product with key cellular components may occur. Promising anti-mitotic agents with pro-apoptotic activity include inhibitors of the tyrosine kinase BTK. The leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells (IC50 = 17 microM). Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.     

Mitotic drug targets and the development of novel anti-mitotic anticancer drugs.

Drugs that interfere with the normal progression of mitosis belong to the most successful chemotherapeutic compounds currently used for anti-cancer treatment. Classically, these drugs are represented by microtubule binding drugs that inhibit the function of the mitotic spindle in order to halt the cell cycle in mitosis and to induce apoptosis in tumor cells. However, these compounds act not only on proliferating tumor cells, but exhibit significant side effects on non-proliferating cells including neurons that are highly dependent on intracellular transport processes mediated by microtubules. Therefore, there is a particular interest in developing novel anti-mitotic drugs that target non-microtubule structures. In fact, recently several novel drugs that target mitotic kinesins or the Aurora and polo-like kinases have been developed and are currently tested in clinical trials. In addition, approaches of cell cycle checkpoint abrogation during mitosis and at the G2/M transition inducing mitosis-associated tumor cell death are promising new strategies for anti-cancer therapy. It is expected that this "next generation" of anti-mitotic drugs will be as successful as the classical anti-microtubule drugs, while avoiding some of the adverse side effects.     

New proposals for testing drugs with IKr-blocking activity to determine their teratogenic potential

Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.     

New findings with old drugs for osteoporosis

Background: Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods: This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results: Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions: As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.     

New antiplatelet drugs

Many clinical trials and pathologic analyses have clearly demonstrated a central role for platelets in the pathophysiology of major cardiovascular disorders, including unstable angina pectoris, acute myocardial infarction (MI), transient ischaemia, and stroke following thrombolytic therapy [1,2]. A meta-analysis of 25 randomised trials of various antiplatelet agents that included 29,000 patients revealed a highly significant decrease in non-fatal MI, stroke, total cardiovascular death, and overall mortality in patients treated with antiplatelet agents compared with placebo [3]. These data have triggered intense efforts over the past 10 years in studying the role of the platelet in cardiovascular disorders, and in developing more potent and selective antiplatelet agents. This discussion summarises recent advances in the development and evaluation of these newer agents with particular emphasis on antagonists of the glycoprotein (GP) IIb/IIIa receptor, since this protein plays a key role in the final common pathway of platelet aggregation.     

New antiarrhythmic drugs

While controversy still exists as to the precise indications for the treatment of all forms of ventricular arrhythmia, advances in the number and, more importantly, type of antiarrhythmic drugs can provide the clinician with a rational basis for selecting antiarrhythmic drug therapy. A host of new agents with different pharmacokinetic and electrophysiological actions are now available, and can be compared or contrasted to conventional antiarrhythmic agents such as quinidine, procainamide, disopyramide, lignocaine (lidocaine) and bretylium. This review summarises the electrophysiological, haemodynamic, pharmacokinetic, and efficacy and safety data of mexiletine, tocainide, flecainide, encainide, propafenone, amiodarone, sotalol, pirmenol, cibenzoline (cifenline) and ethmozine (moracizine, moricizine), and aims to provide a basis on which clinicians can compare and contrast these agents and form an algorithm for selection of antiarrhythmic drug therapy in the treatment of patients with ventricular arrhythmias.     

New anti-epileptic drugs

Epilepsy represents the most common serious neurological disorder, with a prevalence of 0.4 - 1%. Approximately 30% of patients are resistant to currently available drugs. New anti-epileptic drugs are needed to treat refractory epilepsy, improve upon current therapies, improve the prognosis of epilepsy and to prevent the epileptogenic process. Designing compounds with specific physiological targets would seem the most rational method of anti-epileptic drug development, but results from this approach have been disappointing; the widespread screening of compounds in animal models has been much more fruitful. Older methods of animal screening have used acute seizure models, which bear scant relationship to the human condition. More modern methods have included the development of animal models of chronic epilepsy; although more expensive, it is likely that these models will be more sensitive and more specific in determining anti-epileptic efficacy. In this review, we consider the possible physiological targets for anti-epileptic drugs, the animal models of epilepsy, problems with clinical trials and ten promising anti-epileptic drugs in development (AWD 131-138, DP16 (DP-VPA), ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, retigabine, rufinamide and soretolide). Perhaps the most important advances will come about from the realisation that epilepsy is a symptom, not a disease. Preclinical testing should be used to determine the spectrum of epilepsies that a drug can treat, and to direct later clinical trials, which need to select patients based on carefully defined epilepsy syndromes and aetiologies. Not only will such an approach improve the sensitivity of clinical trials, but also will lead to a more rational basis on which to treat.     

New anti-epileptic drugs

Epilepsy represents the most common serious neurological disorder, with a prevalence of 0.4 - 1%. Approximately 30% of patients are resistant to currently available drugs. New anti-epileptic drugs are needed to treat refractory epilepsy, improve upon current therapies, improve the prognosis of epilepsy and to prevent the epileptogenic process. Designing compounds with specific physiological targets would seem the most rational method of anti-epileptic drug development, but results from this approach have been disappointing; the widespread screening of compounds in animal models has been much more fruitful. Older methods of animal screening have used acute seizure models, which bear scant relationship to the human condition. More modern methods have included the development of animal models of chronic epilepsy; although more expensive, it is likely that these models will be more sensitive and more specific in determining anti-epileptic efficacy. In this review, we consider the possible physiological targets for anti-epileptic drugs, the animal models of epilepsy, problems with clinical trials and ten promising anti-epileptic drugs in development (AWD 131-138, DP16 (DP-VPA), ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, retigabine, rufinamide and soretolide). Perhaps the most important advances will come about from the realisation that epilepsy is a symptom, not a disease. Preclinical testing should be used to determine the spectrum of epilepsies that a drug can treat, and to direct later clinical trials, which need to select patients based on carefully defined epilepsy syndromes and aetiologies. Not only will such an approach improve the sensitivity of clinical trials, but also will lead to a more rational basis on which to treat.