Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.

The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor reduction in tumor size (4 patients) to objective partial response (>50% reduction in tumor size, 2 patients). ISIS 3521 is tolerable at its recommended single-agent dose when given with 5-FU and LV. There is no apparent PK interaction between ISIS 3521 and 5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting.     

The prevention of tuberculosis in prison staff

The Joint Tuberculosis Committee of the British Thoracic Society (BTS) recommends that all new prison staff be screened for tuberculosis (TB) as 'at risk' health workers. This study of prisons in the West Midlands area of England shows that there are considerable variations in the practice of TB control amongst prison staff and that the recommendations of the BTS committee are not routinely implemented. The study highlights the need for a routine and robust system of TB surveillance and prevention amongst prison staff which can be applied nationwide.     

A prospective observational study comparing cardiac function of small for gestational age with appropriate for gestational age babies using serial echocardiographic studies

Background: Approximately 30% of babies born in India are low birth weight (LBW) and about 70% of LBW babies are small for gestational age (SGA). Though there are several trials that have evaluated cardiac function of intrauterine growth restricted (IUGR) babies in utero, there is limited data about postnatal cardiac function in SGA babies during early neonatal period. This study was conducted to evaluate the cardiac functions of SGA babies by serial echocardiographic measurements and compare this with appropriate for gestational age (AGA) babies during the early postnatal period.

Material and methods: Seventy babies were enrolled in this prospective observational study with 35 each in the SGA and AGA groups. Echocardiography was performed for all babies on days 1, 2, and 3 of life. Myocardial performance index (MPI) was used as the primary measure to compare cardiac function. MPI was calculated for both ventricles using pulse wave Doppler and tissue Doppler.

Results: MPI of the left ventricle was significantly higher in the SGA group as compared to AGA babies during all the three measurement periods with SGA babies having significantly higher MPI of right ventricle on day 1 and day 2 but not on day 3. Left ventricular internal diameter index during diastole and systole (LVIDD index and LVIDS index), left atrium: aortic root ratio (LA:AO ratio) were significantly increased in SGA babies on all the occasions. Fractional shortening, ejection fraction, and area shortening were similar in two groups.

Conclusions: Myocardial performance index of left and right ventricle, which evaluates both systolic and diastolic function of ventricles, was significantly increased in SGA babies in comparison to AGA babies during the first 3 days of life except MPI of the right ventricle on day 3. Thus, SGA babies have compromised cardiac function through all phases of the cardiac cycle with the performance improving spontaneously over time.     

Papillary fibroelastoma of the tricuspid valve presenting as neonatal pulmonary haemorrhage

Papillary fibroelastoma is a benign tumour of the cardiac valve apparatus. We present an unusual case of life-threatening pulmonary haemorrhage and disseminated intravascular coagulation in a neonate associated with this benign cardiac tumour. Papillary fibroelastoma of the tricuspid valve rarely presents in children and, to our knowledge, this is only the second reported case in a neonate. The patient was successfully managed by anticoagulation therapy followed by surgical excision of the tumour. This case illustrates the potentially fatal presentation of this benign cardiac tumour among neonates. Conclusion: Pulmonary haemorrhage of this degree is unusual in an otherwise healthy term neonate and needs careful investigation for unusual pathology including potential sources of pulmonary emboli in the heart. We emphasize the value of echocardiography in the evaluation of unexpected pulmonary haemorrhage in the newborn.     

Current approaches to novel therapeutics in pancreatic cancer

Pancreatic cancer is one of the most refractory neoplasms to medical treatment. Until now there has been only modest improvement in the treatment of this disease. Standards of care for combined-modality treatment of resectable as well as locally advanced, unresectable disease have not been uniformly accepted to date because of an equivocal or conflicting data. The inception of gemcitabine introduced the new era in the management of metastatic pancreatic cancer, however, new therapeutic approaches still need to be defined. The article discusses the current knowledge of the biology of this lethal disease, its impact on treatment options, and explores novel therapeutic modalities that are likely to improve outcomes and survival for patients in the future.     

New bivalent PKC ligands linked by a carbon spacer: enhancement in binding affinity

Protein kinase C (PKC) is known to play an important role in many signal transduction pathways involved in hormone release, mitogenesis, and tumor promotion. In continuation of our efforts to find highly potent activators of PKC for possible use as Alzheimer's disease therapeutics, we designed and synthesized molecules containing two binding moieties (amides of benzolactams or esters of naphthylpyrrolidones) connected by a flexible spacer chain, which could theoretically bind to both the C1a and C1b activator binding domains of the catalytic region or to the C1 domains of two adjacent PKC molecules. The dimers 2a-g of benzolactam showed a 200-fold increase in affinity to PKCalpha and -delta as the spacer length increased from 4 to 20 carbon atoms. Replacement of the oligomethylene chain with an oligoethylene glycol unit (compounds 2h, 2i) showed a 4000- to 7000-fold decrease in affinity to PKCalpha. The dimers of naphthylpyrrolidones 4a-g did not show any marked improvement in binding affinities to PKC in comparison to the monomers synthesized earlier. The dimer of benzolactam 2e did not show much selectivity for PKCalpha, -betaIota, -delta, -epsilon, and -gamma. The high binding affinity of compounds 2d-g to PKCs gives us the impetus to design additional molecules that would retain this enhanced activity and would also show selectivity for the PKC isoforms.     

The BCL2-family of protein ligands as cancer drugs: the next generation of therapeutics

Selective aberrant cell suicide (ie., apoptosis or programmed cell death) is a hallmark of "nonneoplastic" tissue. In cells that have clonally evolved or in common parlance "cancer cells", apoptosis is either itself aberrant or completely inhibited. Strategies to enhance apoptosis under conditions of cancer cellular stress is an evolving and actively investigated area of experimental therapeutics. Bcl2 proteins are key mediators of the process of apoptosis and ligands to these family of proteins have been described using modern combinatorial, computational and evolutionary small molecule screening approaches. Crystallization of several of the Bcl2 family members has provided clarification of the role of these ligands and provided a clearer mechanism of action for the consequences of ligand binding. In several cases, these ligands (e.g., HA14-1, 2-methoxy antimycin A) induce apoptosis even under conditions of Bcl2 overexpression and if developed preclinically will be promising anticancer agents. This rationale becomes even more striking when one observes overexpression of Bcl2 in 70% of breast cancer, 30-60% of prostate cancer, 80% of B-cell lymphomas, 90% of colorectal adenocarcinomas, and many other forms of cancer.