Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity.

LU 79553 is a novel bis-naphthalimide which is highly cytotoxic in vitro with EC50 (concentration required for 50% inhibition of growth) ranging from 2 x 10(-7) to 5 x 10(-10) M. A number of studies were conducted to examine its antitumor activity in human xenograft models. In addition, we wanted to explore the possible schedule dependency of LU 79553 cytotoxicity in these xenograft models. Complete regression of MX-1 (mammary carcinoma) xenografts was observed when LU 79553 was administered i.v. daily for 5 doses at 20 mg/kg (2 cycles starting on Days 6 and 20) or every 3 days for 2 doses at 55 mg/kg (2 cycles starting on Days 6 and 13) or every 7 days for 4 doses. Complete regression was also seen in the MX-1 model when tumors were staged at 1-2 g prior to the initiation of treatment. Regressions (complete or partial) were observed in the LX-1 (lung), CX-1 (colon), DLD (colon), and LOX (melanoma) xenograft models. A significant increase in the median survival time of OVCAR-3- (ovarian carcinoma) bearing mice was noted in LU 79553-treated animals (treated/control = 195%). The excellent activity of this compound in such a wide variety of tumor types suggests LU 79553 merits further investigation in clinical trials.

In vivo phosphorylation and membrane association of the fyn proto-oncogene product in IM-9 human lymphoblasts.

The protein product of the src-related proto-oncogene, fyn, was isolated from IM-9 cells with antibodies specific for the amino-terminal 22 residues of the fyn protein. Peptide mapping demonstrated that the fyn protein was distinct from the closely related c-src and c-fgr proteins. The fyn protein from IM-9 cells incorporated [3H]myristate in vivo and was found to be membrane associated. Phosphoamino acid analysis demonstrated that the fyn protein from IM-9 cells was phosphorylated in vivo predominantly on tyrosine and threonine with only a small amount of phosphoserine detected. the major chymotryptic phosphopeptide of the fyn protein was phosphorylated exclusively on tyrosine. This peptide was specifically precipitated by antibodies directed against a peptide modeled on the closely related carboxy termini of the c-src and fyn proteins. These results provide direct evidence for phosphorylation of tyrosine-531 in the carboxy-terminal chymotryptic peptide of the fyn protein. Phosphorylation of the corresponding site in the closely related c-src protein (tyrosine-527) represses src kinase activity and transforming ability. Loss of the phosphorylation site at tyrosine-531 may similarly contribute to the transforming abilities of carboxy-terminal deletion mutants of the fyn protein.

Chromophore-modified bis-naphthalimides: synthesis and antitumor activity of bis-dibenz[de,h]isoquinoline-1,3-diones.

The bis-dibenz[de,h]isoquinoline-1,3-diones are a new series of antitumor agents that consist of two chromophores bridged by an alkylamino linker. In the present study we have explored the effect produced by the presence of two dibenz[de,h]isoquinoline-1,3-dione moieties with different polyamine chains on cellular cytotoxicity. Bis-dibenz[de,h]isoquinoline-1,3-diones with the bridge (CH2)2-NH-(CH2)n-NH-(CH2)2, where n = 2-5, showed optimum cytotoxicity with IC50's around 10 nM. Compound 16, which has the (CH2)2-NH-(CH2)3-NH-(CH2)2 bridge, altered DNA mobility and topoisomerase I and II activity at approximately 5 microM. When tested in vivo, compound 16 increased the median survival time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma.

Early disruptive behavior, poor school achievement, delinquent behavior, and delinquent personality: longitudinal analyses.

Three alternative models concerning the causal links between early disruptive behavior, poor school achievement, and delinquent behavior or antisocial personality were tested with linear structural equation modeling. Subjects were boys and girls followed from first grade to age 14. Disruptive behavior was assessed in Grade 1; school achievement was assessed in Grades 1 and 4; delinquent behavior and antisocial personality were assessed at age 14. With regard to self-reported delinquent behavior at age 14, results indicate that the best model for boys was a direct causal link between Grade 1 disruptive behavior and delinquent behavior. Poor school achievement was not a necessary causal factor. For girls, none of the tested models were a good fit to the delinquent behavior data. As for delinquent personality, results indicate that, for both boys and girls, poor school achievement was a necessary component of the causal path between Grade 1 disruptive behavior and age 14 delinquent personality.

[Conservative surgery of the mitral valve. Immediate and late results]. / Chirurgie conservatrice de la valve mitrale. Résultats immédiats et à distance.

A consecutive series of 130 cases of pure or predominant mitral regurgitation underwent conservative mitral valve surgery between January 1975 and January 1982. The mean age of the patients was 30 +/- 17 years; 25 patients were under 15 years of age. The most common aetiology was rheumatic fever (112/130). Fifty nine patients had associated valvular lesions requiring surgical correction. The patients were divided into 4 groups, according to the surgical technique: Group I: valvular mobilisation (35 cases); Group II: reduction of the amplitude of valvular excursion (48 cases); Group III: mixed valvular mobilisation and reduction of amplitude of excursion (45 cases); Group IV: isolated annuloplasty (2 cases). Hospital mortality was 2.3% (3 patients). Five patients (3.8%) were lost to follow-up. The mean follow-up period was 38 +/- 27 months for the 122 patients followed-up. Seven patients needed reoperation. The long term mortality was 3.1% (4 patients). Four late thromboembolic episodes were observed; they were all transient and regressive in patients with atrial fibrillation. The 7 year actuarial survival rate for the whole series, including hospital mortality, was 92% (1.0 +/- 0.5 patients/year). It was 93.7 +/- 4.9% at 7 years for isolated mitral valvuloplasty and 89.9% +/- 5.6% at 5 years for combined mitro-tricuspid procedures. The actuarial percentage of patients without thromboembolic complications was 91.2% at 7 years with a thromboembolic risk of 1.0 +/- 0.5% patients/year. Eighty eight per cent of patients were not reoperated at 7 years and the reoperation rate was 1.7 +/- 0.7% patients/year.(ABSTRACT TRUNCATED AT 250 WORDS)

[Treatment of anterior mitral valve prolapse by partial transposition of the posterior leaflet. Apropos of 7 cases]. / Traitement des prolapsus de la valve antérieure de la mitrale par transposition partielle de la valve postérieure. A propos de 7 cas.

Seven patients aged 8 to 62 years with massive mitral regurgitation due to anterior leaflet prolapse related to rupture or elongation of the chordae tendinae underwent reconstructive mitral valvuloplasty between June 1984 and September 1985, consisting in transposition of a bandlet of the posterior leaflet and its chordae to the free edge of the anterior leaflet. Medium term results with 2 to 16 months follow-up (average 8 months) showed all patients to have returned to Class I of the NYHA Classification; 5 patients had no systolic murmur, a mild systolic murmur 1 and 2/6 was present in 2 cases. The quality of the repair was confirmed by pulsed Doppler examination in all patients and by catheterisation and angiography in 3 cases. This surgical technique offers a good solution to the problem of mitral regurgitation due to severe prolapse of the anterior leaflet caused by rupture or elongation of the chordae tendinae.

[Postoperative infections after heart surgery under extracorporeal circulation]. / Infections postopératoires après chirurgie cardiaque sous circulation extracorporelle.

Postoperative infection is still an important cause of mortality and morbidity after cardiac surgery. The aim of this study was to assess its incidence and causes in order to optimise treatment. Between January 1996 and December 1997, 1,000 consecutive patients (253 women and 747 men) were operated for cardiac aortic pathology under cardiopulmonary bypass. The mean age was 66 +/- 11 years. The initial pathology was coronary artery disease (N = 663), valvular heart disease (N = 193), an association of the two (N = 94), thoracic aortic pathology (N = 38) or other pathologies (N = 12). The global postoperative infection rate was 4.9% (N = 49). The incidence of sternal and/or mediastinal infections was 0.7%, of bronchopneumonia 0.9%, urinary infection 2.1%, and septicaemia 1.7%. Nine patients died of the consequences of an infection. The hospital stay was significantly longer in infected patients, irrespective of the site of infection. Statistical analysis of the whole population did not show any predictive factor related to the preoperative clinical status of the patients. The only predictive factor demonstrated was the day on which surgery was performed: the infection rate in patients operated during the first 4 days of the week was 2.2% compared with 7.3% for the patients operated during the last 3 days (p = 0.004, odds ratio (OR) = 3.57). In those patients who had an urinary infection, the two identified risk factors were the female gender (p = 0.006, OR = 3.34) and an operation performed at the end of the week (p = 0.017, OR = 3.77). In patients with sternal and medistinal infections, the only identified predictive factor was combined coronary artery and valvular surgery (p = 0.009, OR = 7.43). With respect to pulmonary infections, the only predictive factor was recent preoperative myocardial infarction (< 1 month) (p = 0.004, OR = 7.5). Finally, no predictive risk factors were identified in those patients who developed septicaemia. In conclusion, this study showed that postoperative infection remains a serious complication of cardiac surgery. The prevention of these complications should be a priority for quality health care.

Histopathological observations of ultrasound treatment in Ménière's disease: case report.

The temporal bones of a patient with unilateral Ménière's disease were studied. Two weeks before death, the patient had an ultrasonic treatment through the lateral semicircular canal. The only histopathological finding attributed to the ultrasound irradiation is the degeneration of the sensorineural epithelium and crista of the lateral and vertical anterior canal ampulla. The other vestibular sense organs are normal, giving rise to several hypotheses. Electron microscopy might have discovered some changes in the utricular and saccular maculae and in the posterior and superior ampulla. The presence of a normal ampulla of the posterior semicircular canal has led us to modify our surgical technique so that we now routinely irradiate both the lateral and vertical posterior canals in labyrinthine destruction of the labyrinth by ultrasound.

Detection of rotavirus in human stools by using monoclonal antibody.

A monoclonal antibody, 3F7, that reacts with the common rotavirus antigen on the sixth viral gene product was prepared. It was used in a direct monoclonal antibody radioimmunoassay (RIA) as a diagnostic reagent for detection, in 3.5 h, of rotavirus in human pediatric stool specimens. In the 177 samples tested, a concordance of 96% was seen between the monoclonal RIA and the well-established and commonly used commercially available Rotazyme test. Six discrepant specimens that were positive by monoclonal RIA but negative by Rotazyme were shown to be positive by either electron microscopy or confirmatory blocking immunoassay. A seventh discrepant specimen was positive by Rotazyme and negative by monoclonal RIA as well as by both direct and immune electron microscopy. The monoclonal RIA test appears to be highly sensitive and specific, and merits additional evaluation as a rapid, convenient diagnostic assay that can reduce currently encountered problems associated with diagnosing rotavirus infection by immunoassay.

Detection of rotavirus with a new polyclonal antibody enzyme immunoassay (Rotazyme II) and a commercial latex agglutination test (Rotalex): comparison with a monoclonal antibody enzyme immunoassay.

A total of 176 human fecal specimens were examined for the presence of rotavirus by four different assays: a monoclonal antibody enzyme immunoassay; the original polyclonal antibody enzyme immunoassay marketed by Abbott Laboratories, North Chicago, Ill. (Rotazyme I); a modification of this assay which is now commercially available (Rotazyme II); and a latex agglutination test (Rotalex) recently introduced by Medical Technology Corp., Somerset, N.J. In addition, selected specimens were examined for the presence of rotavirus by electron microscopy, immune electron microscopy, and RNA gel electrophoresis. A total of 40 specimens were positive in the monoclonal antibody enzyme immunoassay, and 136 were negative. Using the results obtained with this procedure as the reference standard, we found the sensitivities of the Rotazyme I, Rotazyme II, and Rotalex tests to be 97.4, 100, and 81.6%, respectively. The specificities of these three procedures were 88.8, 83.9, and 100%, respectively.

cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18.

We examine the effects of IL18 on monocytes by performing microarray experiments using cell line KG1. Based on sensitivity to IL18, we identified three functionally distinct gene expression clusters (EC). We see little proinflammatory gene induction at low IL18 concentrations, but instead observe induction of diverse NF kappa B signaling inhibitors. Conversely, intermediate concentrations of IL18 induced proinflammatory genes including the activating subunits of NF kappa B. At the highest IL18 concentration, we observe a third gene cluster containing the proapoptotic Fas gene among others. Clustering of IL18-responsive genes based on cis-elements in their promoters agreed well with the ECs. We conclude that IL18 produces a dose-dependent transcriptional response that can in part be attributed to the composition of cis-elements in the promoters of IL18-responsive genes. These results also support a model for regulatory mechanisms that prevent spurious immune response due to weak cytokine fluctuations and a separate mechanism enabling induction of proinflammatory functions by higher levels of cytokine.

Bis-naphthalimides 3: synthesis and antitumor activity of N,N'-bis[2-(1,8-naphthalimido)-ethyl] alkanediamines.

The bis-naphthalimides are a new class of antitumor agent. Previously, we have described initial synthetic series which established that two naphthalimide chromophores joined by polyamine linkers can produce agents with antitumor activity. We now extend these studies to describe the synthesis of a N,N'-bis[1,8-naphthalimido)-ethyl]alkanediamine series and examine the alkyl linker and chromophore substitution requirements for optimal antitumor activity. As a result, a bis-naphthal-imidoethyl derivative with no chromophore substitution and a NH-(CH2)3-NH bridge was identified. This agent (LU 79553) had both potent cellular cytotoxicity (IC50 = 0.014 microM) and was curative against MX-1 tumors grown in athymic mice. It has now been selected for clinical development.