Targeting Cancer-initiating Cells With Oncolytic Viruses

Recent studies in a variety of leukemias and solid tumors indicate that there is significant heterogeneity with respect to tumor-forming ability within a given population of tumor cells, suggesting that only a subpopulation of cells is responsible for tumorigenesis. These cells have been commonly referred to as cancer stem cells (CSCs) or cancer-initiating cells (CICs). CICs have been shown to be relatively resistant to conventional anticancer therapies and are thus thought to be responsible for disease relapse. As such, they represent a potentially critical therapeutic target. Oncolytic viruses are in clinical trials for cancer and kill cells through mechanisms different from conventional therapeutics. Because these viruses are not susceptible to the same pathways of drug or radiation resistance, it is important to learn whether CICs are susceptible to oncolytic virus infection. Here we review the available data regarding the ability of several different oncolytic virus types to target CICs for destruction.     

Anguidine potentiates cis-platinum in human brain tumor cells

Summary Anguidine pretreatment was previously shown to potentiate cis-platinum in Chinese hamster ovary cells by 100-fold, probably by enhancing cellular cis-platinum. uptake. Since both cis-platinum and anguidine have been reported to have clinical efficacy in human brain tumors, the present study was initiated to investigate whether anguidine's potentiation of cis-platinum was applicable to human brain tumor cells in culture. Using the colony formation assay, it was found that anguidine enhanced cis-platinum's cytotoxicity by ten-fold, producing a dose modification factor of 1.74. Alkaline elution analysis of cis-platinum-induced DNA crosslinks found that anguidine enhanced cross-linking by a factor of 1.55, 1.76, 1.63, and 1.48 at 0, 6, 24, and 48 hr, respectively, after cis-platinum treatment. This enhancement of cross-linking is evidence for anguidine increasing cis-platinum uptake. Thus, anguidine enhances cis-platinum-induced DNA cross-linking and subsequent cytotoxicity in human brain tumor cells, and may be clinically useful in combination with cis-platinum in those tumors.     

A randomized prospective comparison of oral versus intraperitoneal ofloxacin as the primary treatment of CAPD peritonitis

Summary: Oral ofloxacin has been successfully used in our centres for the primary treatment of peritonitis complicating continous ambulatory peritoneal dialysis (CAPD). In view of the progressive rise in the resistance rate to ofloxacin among peritoneal bacterial isolates, a study was conducted to determine if oral ofloxacin remains a viable first line treatment for CAPD peritonitis in our centres and if the result can be improved by changing from an oral to an intraperitoneal (i.p.) route. In patients on three 2 L daily CAPD exchanges, ofloxacin given at the i.p. dosage of 200 mg loading followed by 25 mg/L of peritoneal dialysate achieved overnight trough peritoneal levels which are at least four times the minimal 90% inhibitory concentration (MIC90) of most bacterial pathogens without significant accumulation in the systemic circulation. This i.p. dosage was therefore chosen for the clinical study and the result was compared to that using ofloxacin given in the oral dosage of 400 mg loading followed by 300 mg once daily as maintenance. of all the recruited episodes, 35 were eligible for analysis. the overall primary cure rate including primary failures and relapses was 55.6% (10/18) in the oral treatment group and 70.6% (12/17) in the i.p. treatment group. the corresponding figures for gram positive bacterial (g +) infections were 36.4% and 50%, for gram negative bacterial (g -) infections were 66.7 and 80% and for culture negative infections were 75 and 80%. In culture positive cases, all treatment failures were due to resistant infections which were observed in 42.3% of all bacterial isolates, 47.1% of g + isolates and 33.3% of g - isolates. Due to the high background level of bacterial resistance among our CAPD population, ofloxacin monotherapy given either by the oral or the i.p. route can no longer be recommended for the primary treatment of CAPD peritonitis.     

Ventricular septal defect with tricuspid pouch with and without transposition. Anatomic and surgical considerations.

In a 10-year review, patients operated on for ventricular septal defect and tricuspid valve pouch were divided into two groups, because the effect of the tricuspid valve pouch is influenced by which ventricle has the higher pressure. Group I comprised patients with ventricular septal defect without transposition of the great arteries and group II, ventricular septal defect with transposition. In 72 of 392 group I patients, the septal tricuspid valve leaflet was incised to expose the edges of the hidden ventricular septal defect to accomplish proper anatomic repair. Forty-eight patients had a tricuspid valve pouch, the diagnosis being established by angiography, echocardiography, or at operation. Ages at operation ranged from 5 months to 22 years and the pulmonary-systemic flow ratio ranged from 1 to 3.4, with 16 being less than 1.5. In one patient the pouch produced a 40 mm Hg pressure gradient in the right ventricular outflow tract. At operation, through a transatrial approach, the tricuspid valve pouch was opened radially, the actual ventricular septal defect patched, and the tricuspid valve leaflet repaired. There were no deaths, no significant intraoperative or postoperative morbidity, and no tricuspid valve dysfunction. The average postoperative hospital stay was 4.8 days. In group II, six of 83 patients operated on for transposition with ventricular septal defect had significant left ventricular outflow tract obstruction from the tricuspid valve pouch. Five of six had a Mustard procedure, two requiring a left ventricular-pulmonary artery conduit, and in two of the six the ventricular septal defect was closed through the pulmonary artery. One patient had heart transplantation after a Mustard repair and tricuspid valve replacement. The sixth patient in group II had a successful arterial switch at 9 years of age, after the presence of left ventricular outflow tract obstruction was proved to be due to the pouch. The presence of a tricuspid valve pouch in group I may lead the surgeon to close false small openings produced by the pouch rather than the actual ventricular septal defect. Incising the pouch is safe and essential for proper exposure and secure closure of the true defect. In group II, the systemic right ventricular pressure can push the pouch into the left ventricular outflow tract, causing significant obstruction, and may contribute to tricuspid valve insufficiency after atrial baffle repair. Arterial switch is preferred because it returns the obstructive tricuspid valve pouch and abnormal tricuspid leaflet to the lower pressure pulmonic right ventricle.     

High titer anti-HIV antibody reactivity associated with a paraprotein spike in a homosexual male with AIDS related complex

We observed a human immunodeficiency virus (HIV)-infected homosexual male with AIDS related complex (ARC) who had a serum globulin level of 80 g/L. Serum protein electrophoresis revealed a gamma globulin fraction of 40 g/L, of which 50% (20 g/L) was contained within a paraprotein spike, comprised predominantly of IgG kappa. This patient also had high titer anti-HIV antibodies in his serum, which were Western blot reactive at a final dilution of 1:500,000, and recognized gp120env, p66pol, p55gag, p53pol, p41gag, and p24gag. Because paraproteins in the past have been shown to be directed against specific antigens, we purified this patient's paraprotein using a modified high performance liquid chromatography (HPLC)-hydroxylapatite procedure and tested the purified paraprotein for anti-HIV antibody activity. The purified paraprotein retained anti-HIV antibody activity to a final dilution of 1:100,000, and recognized p66pol, p55gag, p53pol, p41gag, and p24gag. The recognition of both "gag" and "pol" gene products suggested that the purified paraprotein might not be monoclonal in origin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the purified paraprotein contained at least two immunoglobulin light chain species (Mol wt 30 to 33 Kd). Affinity chromatography of the purified paraprotein using a p24- Sepharose 4B matrix separated the "gag" and "pol" antibody activities. Immunoglobulin gene rearrangement analysis of a bone marrow aspirate (which contained 15% plasma cells) failed to reveal a clonal population of immunoglobulin producing cells. We conclude that this patient's paraprotein accounted for most of the anti-HIV activity present in whole serum, and that this paraprotein was not monoclonal in origin.     

Use of a counterpulsation balloon as a substitute for the pulmonic valve: a new application

An inflatable, 3-ml balloon positioned within the distal right ventricular outflow tract was used to restore pulmonic valve function in 8 dogs that had undergone open-chest valvectomy. Balloon inflation and deflation were accomplished with a counterpulsation console. Valvectomy produced loss of the pulmonic incisura, a decrease in pulmonary artery diastolic pressure (PADP; mean +/- standard error) (9.5 +/- 1.3 versus 4.4 +/- 0.6 mm Hg, p less than 0.01), and an increase in pulmonary artery pulse pressure (PAPP) (8.6 +/- 0.7 versus 19.1 +/- 1.9 mm Hg, p less than 0.01) without significantly affecting forward cardiac output (CO) (1,750 +/- 110 versus 1,880 +/- 230 ml/min, p is not significant). Properly timed counterpulsation restored the pulmonic incisura, raised the PADP from 6.1 +/- 0.8 to 9.5 +/- 0.8 mm Hg (p less than 0.01), lowered the PAPP from 15.1 +/- 1.4 to 10.6 +/- 1.0 mm Hg (p less than 0.01), and raised the forward CO from 1,850 +/- 260 to 1,920 +/- 260 ml/min (p less than 0.01). The injection of glass beads, 40 to 150 microns in diameter, into the right ventricular outflow tract increased pulmonary vascular resistance from 383 +/- 87 to 730 +/- 150 dyne . sec cm-5 (p less than 0.05) and decreased forward CO from 1,850 +/- 260 to 1,570 +/- 230 ml/min (p less than 0.05). Following this injection, counterpulsation again restored the pulmonic incisura, raised the PADP from 9.3 +/- 1.4 to 16.0 +/- 1.8 mm Hg (p less than 0.01), lowered the PAPP from 25.0 +/- 2.5 to 18.2 +/- 2.5 mm Hg (p less than 0.01), and raised the forward CO from 1,570 +/- 230 to 1,720 +/- 220 ml/min (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)