Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models

Raf-1 protein kinase plays an important role in cell growth, proliferation and cell survival. We have previously described the use of liposome-entrapped antisense raf oligonucleotide (LErafAON) to inhibit Raf-1 expression resulting in tumor growth inhibition and radiosensitization. The present study was undertaken to evaluate the chemosensitization effects of LErafAON in combination with doxorubicin or paclitaxel on a panel of human tumor xenografts. LErafAON (25.0 mg/kg i.v. x 10) displayed significant antitumor activity (P<0.05) when administered as a single agent in prostate (PC-3), lung (A549) and breast (MDA-MB 231) carcinoma models. Doxorubicin (1.0-4.0 mg/kg i.v. per week x 3) and paclitaxel (1.0-4.0 mg/kg i.v. on alternate days x 3) were administered as single agents at non-toxic doses that led to only minimal to moderate antitumor activity. However, a combination of LErafAON with doxorubicin or paclitaxel led to significantly enhanced antitumor activity in all the tumor types tested (PC-3, P<0.03; A549, P<0.035; MDA-MB 231, P<0.045) as compared with LErafAON alone or chemotherapeutic agents alone treated groups. This effect of chemosensitization appeared to be sequence-specific because a mismatch control oligonucleotide continued to show significant tumor growth. Additionally, no inhibition in Raf-1 expression in MDA-MB 231 tumor tissue was observed with mismatch oligonucleotide treatment. On the other hand, LErafAON treatment led to >75% inhibition of Raf-1 expression in tumor tissue. These preclinical observations support the use of LErafAON in combination with chemotherapeutic agents to improve the treatment of human cancers.     

From PET detectors to PET scanners

This review describes the properties of available and emerging radiation detector and read-out technologies and discusses how they may affect PET scanner performance. After a general introduction, there is a section in which the physical properties of several different detector scintillators are compared. This is followed by a discussion of recent advances in read-out electronics. Finally, the physical performance of the several commercial PET scanners is summarized.     

Mycalosides B-I,eight new spermostatic steroid oligoglycosides from the sponge Mycale laxissima

New steroidal oligoglycosides mycalosides B-I (2-9) have been isolated from the polar extract of the Caribbean sponge Mycale laxissima, and their structures have been elucidated by 1D and 2D NMR ((1)H, (13)C, DEPT, COSY-45, COSY-RCT, HSQC, HMBC, and NOESY spectra) and MALDI-TOF mass spectrometry. Mycalosides B (2) and C (3) were shown to be 27- and 28-nor derivatives of the previously known tetraoside mycaloside A (1). Mycaloside D (4) differs from 1 only in the presence of an additional acetyl group in the carbohydrate moiety. Mycaloside E (5) was structurally identified as a 28-nor-4-dehydroxy derivative of 1. Mycalosides F-H (6-8), differing from each other by the structures of their side chains and nonacetylated (7, 8) or acetylated (6) tetrasaccharide carbohydrate moieties, have new 5(6)-unsaturated 3 beta,4 beta,21-trihydroxy-15-keto-steroidal aglycons. Mycaloside I (9) is a tetraoside of a new 7,24(28)-diunsaturated 3beta,15 beta,29-trihydroxystigmastane aglycon. It was established that the total fraction of the mycalosides as well as mycalosides A (1) and G (7) inhibit the fertilization of eggs by sperm of the sea urchin Strongylocentrotus nudus preincubated with these compounds.     

Free radicals potentiate the negative dromotropic effect of adenosine in guinea pig isolated heart

OBJECTIVE: Adenosine is released during myocardial ischaemia and delays atrioventricular nodal (AV) conduction. We hypothesized that free radicals present during reperfusion potentiate the negative dromotropic effect of adenosine on the AV node. METHODS AND RESULTS: Guinea pig hearts were prepared using the Langendorff technique, paced (200 beats/min), and instrumented to measure the atrium-to-His bundle (A-H) interval, an index of AV nodal conduction time. Adenosine (2 microM) prolonged the A-H interval by 5.7 +/- 0.5 ms from a control value of 35.7 +/- 1.3 ms. (n = 10, P < 0.05). In the absence of adenosine, the superoxide (O2-) generator pyrogallol (20 microM) did not affect the A-H interval (0.7 +/- 0.2 ms prolongation, n = 10). However, concurrent infusion of adenosine (2 microM) and pyrogallol (20 microM) lengthened the A-H interval by 11.0 +/- 0.8 ms from control (n = 10, P < 0.001). This A-H interval prolongation was reversed by cyclopentyl-1,3-dipropylxanthine (100 nM), a selective A1-adenosine receptor antagonist (P<0.001, n = 5). Similarly, A-H interval prolongation was decreased to 4.3 +/- 0.4 ms when NG-methyl-L-arginine (100 microM), a nitric oxide (NO) synthase inhibitor, was infused (n = 4). The superoxide scavenger superoxide dismutase (200 U/ml) also diminished the A-H interval prolongation to 7.1 +/- 0.6 ms (n = 4, P < 0.001). Ba2+ ( 100 microM), a blocker of the adenosine-induced inward potassium current (I(K,ADO)), did not significantly affect this potentiation (13.0 +/- 0.8 and 10.8 +/- 0.7 ms greater than control A-H interval in the absence and presence of Ba2+, respectively, n = 4). CONCLUSIONS: Superoxides and adenosine delay AV nodal conduction in a synergistic manner via a NO-dependent mechanism involving an I(K,ADO)-independent component. This phenomenon may contribute to the genesis of reperfusion arrhythmias.     

The influence of anticonvulsant and antioxidant drugs on nitric oxide level and lipid peroxidation in the rat brain during penthylenetetrazole-induced epileptiform model seizures

Nitric oxide (NO) generation in the brain cortex of Wistar rats was measured by direct method of electron paramagnetic resonance (EPR) spectroscopy. Dramatic (fivefold) elevation of NO production was found during penthylenetetrazole (PTZ)-induced epileptiform seizures. The level of secondary products of lipid peroxidation (LPO; thiobarbituric acid reactive substances, TBARS) was also significantly increased in the cerebral cortex of rats with PTZ-evoked seizures. The effects of anticonvulsant drugs phenobarbital, lamotrigine, phenazepam, as well as antioxidant substances alpha-tocopherol and novel original Russian synthetic drug mexidol (2-ethyl-6-methyl-3-oxypiridine succinate), were investigated. All the substances studied significantly decreased seizure manifestations and partially prevented both enhancement of NO generation and increase in TBARS formation. Mexidol and phenobarbital were found to be the most effective in the preventing of PTZ-induced seizures among all the substances studied. The data obtained support our speculation that neuroprotective action of mexidol may correlate with its ability to inhibit not only excessive reactive oxygen species (ROS) formation but also NO generation. While the molecular mechanism underlying action of mexidol and phenobarbital still remains unclear, it is likely that the effect of these drugs on NO production is contributing to their neuroprotective action. It might be concluded that both the suppression of seizure-induced NO generation and LPO enhancement may be involved in the mechanism of action of antiepileptic drugs.     

Tumor-targeted liposomes: doxorubicin-loaded long-circulating liposomes modified with anti-cancer antibody.

Commercially available doxorubicin-loaded long-circulating liposomes (Doxil, Alza Pharmaceuticals) were modified with the monoclonal nucleosome (NS)-specific 2C5 antibody (mAb 2C5) that recognizes a broad variety of tumors via the tumor cell surface-bound NSs. For incorporation into liposomes, mAb 2C5 was modified with poly(ethylene glycol)-phosphatidyl ethanolamine conjugate (PEG-PE) with the free PEG terminus activated with the p-nitrophenylcarbonyl group (pNP-PEG-PE). Derivatives of mAb 2C5 containing a variable number of PEG-PE residues (10-32) per protein molecule were prepared with a reasonably good preservation of the antibody specific activity even at the highest degree of modification. PEG-PE-modified antibody quantitatively incorporated into the liposomal membrane of doxorubicin-loaded liposomes with a loss of not more than 20% of the encapsulated doxorubicin. 2C5-targeted Doxil liposomes acquired the ability to recognize NSs and specifically bind to various tumor cells. Doxorubicin-loaded long-circulating liposomes modified with the mAb 2C5 kill various tumor cells in vitro with the efficiency higher than non-targeted doxorubicin-loaded liposomes.     

Micelles from polyethylene glycol/phosphatidylethanolamine conjugates for tumor drug delivery.

Micelles prepared from polyethylene glycols of various lengths conjugated with phosphatidylethanolamine (PEG-PE) were loaded with various poorly soluble anticancer agents. PEG-PE micelles selectively accumulated in Lewis lung carcinoma (LLC) tumors implanted in mice. Modification of the micelles with tumor specific antibodies further enhanced the efficiency of tumor accumulation.     

The Essence Trial: Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI: A Double-Blind,Randomized, Parallel-Group,Multicenter Study Comparing Enoxaparin and Intravenous Unfractionated Heparin: Methods and Design

Antithrombotic therapy reduces the risk of recurrent ischemic events in patients with unstable angina. The primary aim of the ESSENCE trial is to evaluate the efficacy of enoxaparin (low molecular weight heparin) versus unfractionated heparin, plus aspirin, in patients with rest angina or non-Q-wave infarction. This is a randomized, double-blind, placebo-controlled study of 3180 patients comparing enoxaparin, 1 mg/kg sc bid, with unfractionated heparin via continuous iv infusion to maintain the aPTT at 2 × control. Patients within 24 hours of the onset of acute myocardial ischemia without ST elevation are eligible, and trial therapy is administered for a minimum of 48 hours to a maximum of 8 days. Primary endpoints analyzed are death, myocardial infarction (MI), or recurrent angina at 14 days. Currently 3019 patients have been randomized in 10 countries. The mean age is 64 years, 33% are female, and 46% have had a prior MI. The overall event rates at 14 days are 1.7% mortality, 5.9% subsequent MI, and 17% recurrent angina. The composite triple endpoint rate is 23.6%. Recruitment should be complete by June 1996. The methods and design of the study are presented in this article.