Interstitial methotrexate kinetics in primary breast cancer lesions

The transfer of cytotoxic agents across the tumor endothelium into the interstitial tumor space is considered a critical step in clinical resistance of solid tumors to antineoplastic chemotherapy. However, experimental data on drug transfer from the blood into the interstitium of solid tumors are scarce. Therefore, in this study, we used an innovative technique, in vivo microdialysis, for measuring interstitial tumor pharmacokinetics and plasma-to-tumor transfer rates of methotrexate (MTX) in breast cancer patients. Microdialysis probes were inserted into the primary tumor and the periumbilical s.c. adipose layer of nine previously chemotherapy-naive breast cancer patients to monitor interstitial concentrations following i.v. administration of MTX (40 mg/m2) during a three-drug treatment regimen. Mean interstitial MTX load in breast tumors, expressed as area under curve (AUC), was 60 +/- 20% (mean +/- SE; coefficient of variation = 100%) of mean plasma MTX load. There was no correlation between plasma AUC and the AUC in the interstitial space of tumor tissue (P = 0.93). Not one of the parameters plasma, interstitial tumor load, and transfer rate of MTX to the interstitial space was associated with favorable clinical response. In conclusion, plasma levels of MTX are not predictive of intratumor levels. There is a high interindividual variability in transendothelial MTX transfer. Under the present conditions, access of MTX to the interstitial space is not a rate-limiting step for clinical response to chemotherapy.     

Metabolic aspects of cardiac and skeletal muscle tissues in the condition of hypoxia, ischaemia and reperfusion induced by extracorporeal circulation

Extracorporeal circulation (ECC) during aortopulmonary bypass surgery allows the investigation of the metabolic and biochemical effects of hypoxia (skeletal muscle), ischaemia (cardiac muscle) and reperfusion (skeletal and cardiac muscle) in homogeneous groups of patients. In this study we examined the mitochondrial enzymic response to oxidative stress in 40 subjects, and analysis was carried out on heart and skeletal-muscle biopsies taken before, during and after aortic clamping and 115 min of ECC. The results obtained constitute a clinical and biochemical picture characterized by some peculiar adaptive changes of enzymic activities which thus antagonize the oxidative damage due to acute hypoxia, ischaemia and reperfusion. Consequently it seems that this cellular protective mechanism plays a crucial role in the reversibility of oxidative damage in hypoxic and ischaemic tissues.     

Lovastatin disrupts early events in insulin signaling: a potential mechanism of lovastatin's anti-mitogenic activity

The mechanism by which lovastatin lowers cholesterol levels is well characterized but little is known about its anti-mitogenic and anti-tumorigenic mechanism. Here we demonstrate that lovastatin disrupts early events in the mitogenic signaling pathways of insulin. Insulin treatment (200 mM) of quiescent HIR rat-1 fibroblasts results in an 8-fold stimulation of phosphatidylinositol-3-kinase (PI-3-K) activity. Overnight pretreatment of cells with lovastatin (20 microM) inhibits insulin stimulation of PI-3-K activity by 75%. Immunoprecipitation and immunoblotting experiments using antibodies against the regulatory subunit of PI-3-K (p85), phosphotyrosine, and insulin receptor alpha and beta subunits demonstrate that lovastatin inhibits the association of p85 with tyrosine phosphorylated insulin receptor substrate-1 and the beta subunit of the insulin receptor. Furthermore, lovastatin dramatically reduces (70-100%) the level of tyrosine phosphorylated insulin receptor beta subunit following insulin stimulation. These results clearly demonstrate that lovastatin disrupts early events of insulin mitogenic signaling by reducing the levels of tyrosine phosphorylated beta subunit and suggest that this disruption is a potential mechanism for the anti-mitogenic effect of lovastatin.     

Fate of the TRAM flap after abdominoplasty in a rat model

During a classical abdominoplasty, all musculocutaneous perforators from the deep inferior epigastric vessels are normally divided. Even if somehow neovascularization could relink the abdominal skin and rectus abdominis muscles, reestablishing these same discrete perforators would be unlikely because of the barrier effect of the abdominal wall fascia. Therefore, a lower transverse rectus abdominis musculocutaneous (TRAM) flap intuitively should not regain sufficient vascularity for viability after a prior abdominoplasty, and a history of the latter should be expected to be a major contraindication for this procedure. Nevertheless, anecdotal observations of successful lower TRAM flaps following abdominoplasty seem to contradict our basic principles, which may need better further elucidation. Consequently, this two-stage study in Sprague-Dawley rats was undertaken, initially performing an abdominoplasty in all rats. This was followed 1 or 10 months later by the creation of an unipedicled superiorly based TRAM flap that incorporated virtually all of the abdominal skin. From our identical historical TRAM flap control (n = 5) except without prior abdominoplasty, 72.8 +/- 12.83 percent of this area survived. TRAM flaps raised 1 month after the abdominoplasty (n = 6) had 2.2 +/- 3.4 percent or essentially no viability. Unexpectedly, the long-term group (n = 7) demonstrated 13.7 +/- 10.0 percent viability, ranging from 0 to 30 percent. Both groups of TRAM flaps after abdominoplasty had a flap survival area significantly less than that of the control by two-tailed group t test (p < 0.001), and that of the long-term group area was significantly greater than that of the short-term (p = 0.022). Lead oxide studies 10 months after abdominoplasty revealed no irrefutable evidence of the reestablishment of rectus abdominis perforators to the integument, although obviously some reconnections had formed at the microcirculatory level to partially revascularize some flaps. The range of viability of the long-term rat TRAM flaps documented that for the majority, surviving surface area was minuscule even following a delay equivalent to a human decade after abdominoplasty (1 rat month - 1.1 human years), yet rarely sufficient revascularization did indeed occur, which could explain the prior unusual clinical successes. However, the basic principle that a TRAM flap raised following a classical abdominoplasty at any time would be a risky maneuver seems to still be a valid concept.     

Phospholipid pool, lipid peroxidation, and superoxide dismutase activity under various types of oxidative stress of the brain and the effect of low-energy infrared laser irradiation

The effect of low-energy infrared laser irradiation on the phospholipid pool, lipid peroxidation, and superoxide dismutase activity in the brain of white rats was studied in experimental ischemia, reperfusion, and acute edema. These models are characterized by oxidative stress; the contents of tri- and diphosphoinositides and sphingomyelins were lowered, whereas the levels of phosphatidylserine and phosphatidylethanolamine did not change, and the amount of phosphatidylcholine was increased. In acute brain edema, the contents of hydroperoxides and malonic dialdehyde in enzymatic and nonenzymic lipid peroxidation systems were increased in mitochondrial and microsomal fractions and the level of arachidonic acid was significantly elevated. Infrared laser irradiation contributes to the correction of the changes in the phospholipid pool; laser irradiation lowered the increased levels of hydroperoxides and malonic dialdehyde and elevated superoxide dismutase activity in the brain during ischemia, reperfusion, and acute edema of the brain. The data suggest that low-energy infrared laser irradiation has certain neuroprotective activity in various types of oxidative stress including ischemia, reperfusion, and acute edema of the brain.     

Nuclear magnetic resonance measurement of skeletal muscle: anisotrophy of the diffusion coefficient of the intracellular water

Four cases of chiasmal syndrome resulting from chromophobe adenoma with normal-sized sella turcica are reported. The predominantly suprasellar growth of these tumors was probably the result of a well-pneumatized sphenoid sinus and/or a congenitally deficient diaphragma sellae. In patients with chiasmal syndrome, a high suspicion of a surgically treatable lesion must be maintained in spite of radiographs showing a normal-sized sella. In spite of the difficulties presented by normal variations, subtle findings should be searched for on the plain films and given additional weight in the patient with a chiasmal syndrome. An aggressive diagnostic work-up, including pneumoencephalography with thin-section tomography, should be pursued in all such patients before accepting some alternate explanation, such as demyelinating disease, for visual impairment.     

Specific glucocorticoid receptor in the iris--ciliary body of the rabbit

The cytoplasm of the iris--ciliary body of the rabbit contains a receptor capable of specifically binding dexamethasone. This binding protein has a high affinity for dexamethasone (average KD = 2.0 X 10(-8) M), a low capacity (average 4.8 X 10(-13) mol of steroid bound per milligram of protein), and extreme heat sensitivity; it exhibits a pattern of competition virtually identical to that obtained with glucocorticoid receptors from other tissues and shows characteristic physicochemical behavior in various salt concentrations. The demonstration of a specific dexamethasone receptor in the iris--ciliary body provides the first direct biochemical evidence that these tissues may function as a target organ for glucocorticoids.