Anti-invasion drugs

Summary Most of the pharmaceuticals in clinical practice today for treatment of breast and other cancers are cytotoxic or cytostatic inhibitors of tumor growth. While this type of drug has found its place, along with surgery and radiotherapy, in treatment of disease, the breast cancer death rate has not decreased. This appears to be the result of rising incidence, resistance to therapy, and metastasis of the disease. Since distant metastasis (usually indicated by lymph node involvement) of breast cancer is related only indirectly to tumor size, it would appear that a concerted effort should be made to discover drugs which directly interfere with this complex process. Metastasis appears to depend upon tumor cell motility, dedifferen-tiation, local invasion, and angiogenesis. Significant progress has been recently made in the creation of new animal models of metastasis and in identifying several new drugs which may be suitable for clinical inhibition of this process. This article reviews current findings on anti-invasion/metastasis drugs with a focus on breast cancer.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

Linear model for visual-vestibular interaction.

The results of experiments are evaluated in terms of a simple model for the interaction of eye movement responses to simultaneous optokinetic and vestibular stimuli. The model predictions agree with the results of these experiments and explain many clinical observations concerning the effect of vision on nystagmus. The model accounts for the dominance of the visual system's response over the vestibular system's response at low frequencies. It also accounts for the inability of patients with decreased smooth pursuit system response to suppress the vestibulo-ocular reflex during simultaneous optokinetic and vestibular stimulations. The model provides useful information for the design of combined optokinetic and vestibular stimuli for test vestibulo-ocular reflexes.     

Plasma catecholamines and oxygen consumption during weaning from mechanical ventilation

Previous studies on oxygen consumption ( ) during weaning from mechanical ventilation assumed that an increase in ( ) reflected oxygen consumption by respiratory muscles ( ), and proposed as a weaning predictor. We measured CO₂ production ( ) and plasma catecholamines in 20 short-term ventilated patients during weaning by SIMV and CPAP. as a percentage of during spontaneous ventilation ( %) ranged from 4.8% to 41.5%. also increased and correlated with . Plasma adrenaline and noradrenaline increased significantly to levels known to produce considerable increases in metabolic rate. Mean arterial pressure and heart rate concomitantly increased, but spontaneous minute ventilation decreased. Thus, since the increased plasma catecholamines are calorigenic, the assumption that represents is incorrect. Although mean % of successfully weaned patients was significantly less than that of failure-to-wean patients, the wide scatter of individual values in the latter group excludes % as an accurate weaning predictor.     

Sinus node-atrioventricular node isolation: long-term results with the "corridor" operation for atrial fibrillation

The "corridor" operation is designed to restore sinus rhythm to patients with atrial fibrillation by electrically isolating the sinus node, a band of atrial tissue and the atrioventricular (AV) node from the remaining atrial tissue. Nine patients with drug-refractory atrial fibrillation underwent this operation; four patients had chronic atrial fibrillation and five had paroxysmal atrial fibrillation; the mean duration of symptoms was 12 +/- 8 years. Patient ages ranged from 25 to 68 years (mean 48 +/- 12). At preoperative electrophysiologic study, no patient had evidence of an accessory AV pathway or AV node reentry. Sinus node recovery time could not be determined in five patients because of recurrent atrial fibrillation during or before programmed stimulation. At operation the corridor of atrial tissue connecting the sinus and AV nodes was successfully isolated from the remaining left and right atrial tissue in all patients. One patient required early reoperation for recurrent atrial fibrillation before hospital discharge. At the predischarge electrophysiologic study, the corridor remained isolated in all patients except for one patient who had intermittent conduction between the corridor and excluded right atrium. One patient had nonsustained atrial fibrillation and one had atrial tachycardia evident in the corridor. Atypical AV node reentry of uncertain significance was induced in one other patient. Over a total follow-up of 191 patient months (mean 21 +/- 20), seven patients remained free of atrial fibrillation. Two patients had recurrent atrial fibrillation, which in one patient was effectively controlled by a single antiarrhythmic agent. A permanent pacemaker was implanted in four patients for sinus node dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

Hamster ependymomas produced by intracerebral inoculation of a human papovavirus (MMV).

Ependymomas were produced in 3 of 11 newborn hamsters inoculated intracerebrally with a human papovavirus (MMV) isolated from a malignant lymphoma of the brain of a child with Wiskott-Aldrich syndrome. One of the tumors was serially transplanted into weanling hamsters. Cells from the transplanted tumors and from cell cultures derived from these tumors contained an intranuclear "T" antigen that reacted with simian virus 40 T antibody.     

Role of neutrophils in the synergistic liver injury from monocrotaline and bacterial lipopolysaccharide exposure.

Synergistic liver injury develops in Sprague-Dawley rats from administration of a small, noninjurious dose (7.4 x 10(6) EU/kg) of bacterial lipopolysaccharide (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid, monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated through inflammatory factors, such as Kupffer cells and tumor necrosis factor alpha (TNF-alpha), rather than through simple interaction between MCT and LPS. In the present study, the hypothesis that neutrophils (polymorphonuclear leukocytes or PMNs) are causally involved in this injury model is tested, and the interdependence between PMNs and other inflammatory components is explored. Hepatic PMN accumulation and the appearance of cytokine-induced neutrophil chemoattractant-1 in plasma preceded the onset of liver injury, suggesting that PMNs contribute to toxicity. Hepatic PMN accumulation was partially dependent on TNF-alpha. Prior depletion of PMNs in MCT/LPS-cotreated animals resulted in attenuation of both hepatic parenchymal cell (HPC) and sinusoidal endothelial cell (SEC) injury at 18 h. PMN depletion did not, however, protect against early SEC injury that occurred before the onset of HPC injury at 6 h. This observation suggests that SEC injury is not entirely dependent on PMNs in this model. In vitro, MCT caused PMNs to degranulate in a concentration-dependent manner. These results provide evidence that PMNs are critical to the HPC injury caused by MCT/LPS cotreatment and contribute to the progression of SEC injury.