Preclinical antitumour activity of F 11782, a novel dual catalytic inhibitor of topoisomerases

F 11782 is a novel inhibitor of topoisomerases I and II, with an original mechanism of action (Perrin et al, 2000). This study, aimed to define its anticancer efficacy against a series of murine and human tumour models, has provided evidence of major antitumour activity for F 11782. This was demonstrated as a high level of activity against the P388 leukaemia, as reflected by increased survival of 143–457%, when administered i.p., p.o. or i.v. as single or multiple doses, and proved consistently superior to etoposide or camptothecin tested concurrently. Single or multiple i.p. doses of F 11782 also proved highly active against the s.c. grafted B16 melanoma, significantly increasing survival (P < 0.001) and inhibiting tumour growth (T/C of 0.3%), again superior to etoposide tested concurrently. Furthermore, F 11782 inhibited the number of pulmonary metastatic foci of the B16F10 melanoma by 99%. In human tumour xenograft studies, multiple i.p. doses of F 11782 resulted in major inhibitory activity against MX-1 (breast) tumours (T/C of 0.1%), as well as causing definite tumour regressions, whereas none resulted from similar experimental treatments with etoposide. Significant activity was also recorded with F 11782 against the relatively refractory LX-1 (lung) xenografts, with an optimal T/C value of 19%. It was notable that the antitumour activity of F 11782 was consistently demonstrated over a wide range of 2–6 dose levels, providing evidence of its good overall tolerance. In conclusion, these results emphasize the preclinical interest of this novel molecule and support its further preclinical development. © 2000 Cancer Research Campaign http://www.bjcancer.co

Nebulized heparin in burn patients with inhalation trauma : safety and feasibility

Background: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin. Methods: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility. Results: The study was prematurely stopped after inclusion of 13 patients (heparin N = 7, placebo N = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations. Conclusion: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients

Cushny, 1913; Eckenhoff and Oech

ABSTRACT This report describes a systematic analysis of opiate drug effects on ventilation and its components tidal volume and frequency in intact, awake and unrestrained rats. A whole-body plethysmo graphic method was used to measure these parameters of respiration while animals breathed air or various concentrations of CO2 in air. Subcutaneous doses of morphine lower than 40 mg/kg exerted little or no apparent effect in rats breathing air; in rats breathing 4 to 8% of CO2 these doses of morphine also failed to depress any of the ventilatory parameters below the level of saline controls breathing air. Doses (0.16 to 160 mg/kg) of morphine blunted the frequency response to CO2in a biphasic manner. The effects of morphine on tidal volume consisted of a slight increase at 0.16 and 0.63 mg/kg, a dose-dependent de crease at 2.5 to 40 mg/kg and a paradoxical nse at 160 mg/kg. These complex effects of morphine on tidal volume and fre quency resulted in a simple sigmoid depression of minute vol ume. The slope of this sigmoid dose-response curve varied with the inspirate; it increasedas the concentration of CO2was higher. Naloxone antagonized the frequency depression produced by 40 mg/kg of morphine in a dose-dependent manner at doses ranging from 0.01 to 0.16 mgfkg, but frequency decreased again at 0.63 mg/kg. The effects of naloxorte on the tidal volume depression consisted of a paradoxical further decrease at 0.01 mg/kg, a dose-dependent antagonism of depression at 0.04 to 0.16 mg/kg and a stimulation above the normal control level at 0.63 mg/kg. These complex effects of naloxone on tidal volume and frequency resulted in a simple sigmoid antagonism of the minute volume depression produced by morphine. These and other experiments support the hypothesis that opiates depress the ventilatory response to C02, but several experimental con ditions were identified in which the opiate action on minute volume was effected by intricate and perhaps paradoxical effects on tidal volume and frequency. The assumptions 1) that tidal volume is the sole directly controlled output vaviableof the CO2 controller and 2) that opiates decrease the sensitivity of the CO2 controller, do not seem to account in a parsimonious manner for all of the complex effects which opiates may exert on tidal volume and frequency of breathing in rats. opiates in subjects that are being exposed to a CO2 challenge (e.g., Lai et at., 1978). Intact and unanesthetized subjects were used 1) to match the conditions in which the analgesic effects of opiates are typically examined and 2) to avoid the confound ing influence that surgery, restraint, handling and anesthesia may have on ventilation (Borison, 1978

Prognostic value of nonangiogenic and angiogenic growth patterns in non-small-cell lung cancer

An essential prerequisite of nonangiogenic growth appears to be the ability of the tumour to preserve the parenchymal structures of the host tissue. This morphological feature is visible on a routine tissue section. Based on this feature, we classified haematoxylin and eosin-stained tissue sections from 279 patients with non-small-cell lung cancer into three growth patterns: destructive (angiogenic; n=196), papillary (intermediate; n=38) and alveolar (nonangiogenic; n=45). A Cox multiple regression model was used to test the prognostic value of growth patterns together with other relevant clinicopathological factors. For overall survival, growth pattern (P=0.007), N-status (P=0.001), age (P=0.020) and type of operation (P=0.056) were independent prognostic factors. For disease-free survival, only growth pattern (P=0.007) and N-status (P&lt;0.001) had an independent prognostic value. Alveolar (hazard ratio=1.825, 95% confidence interval=1.117-2.980, P=0.016) and papillary (hazard ratio=1.977, 95% confidence interval=1.169-3.345, P=0.011) growth patterns were independent predictors of poor prognosis. The proposed classification has an independent prognostic value for overall survival as well as for disease-free survival, providing a possible explanation for survival differences of patients in the same disease stage

Allelic imbalances of chromosomes 8p and 18q and their roles in distant relapse of early stage, node-negative breast cancer

INTRODUCTION: Identification of breast cancer patients at risk for postoperative distant relapse is an important clinical issue. Existing pathological markers can predict disease recurrence only to a certain extent, and there is a need for more accurate predictors. METHODS: Using 'counting alleles', a novel experimental method, we determined allelic status of chromosomes 8p and 18q in a case-control study with 65 early stage, node negative, invasive ductal carcinomas (IDCs). The association between allelic imbalance (AI) of both chromosomal markers and distant relapses was examined. RESULTS: Eighty percent of tumors contained 8pAI and sixty-eight percent of tumors contained 18qAI. However, none of the tumor samples retained both chromosome 8p and 18q alleles. More importantly, tumors with 8pAI but not 18qAI were more likely to have distant relapse compared to tumors with 18qAI but not 8pAI. CONCLUSION: Our finding suggests that differential allelic loss of chromosomes 8p and 18q may represent subtypes of early stage IDC with different tumor progression behaviors