The combination of hormonal treatment based on a long-acting delivery system for the agonist [6-D-
Binding capacities and apparent dissociation constants of receptors for luteinizing-hormone-releasing hormone (LHRH) were investigated in estrogen-independent MXT mammary cancers of untreated mice and after in vivo treatment with agonistic or antagonistic analogs of LHRH containing cytotoxic radicals: AJ-04 (agonist [D-Lys6]LHRH linked to methotrexate), T-98-([D-Lys6]LHRH coupled to glutaryl-2-(hydroxmethyl)anthraquinone (G-HMAQ)) and T-121/B (LHRH antagonist T-147 containing two residues of G-HMAQ), which induced tumor growth inhibition. The effects were compared to LHRH agonist [D-Trp6]LHRH and carriers [D-Lys6]LHRH, LHRH antagonist T-147, as well as to methotrexate, G-HMAQ and surgical bilateral overiectomy. Analysis of the binding data revealed that in control tumors the interaction of 125I-[D-TRP6]LHRH was consistent with the presence of one class of saturable, specific, noncooperative, high-affinity and low-capacity binding sites. Chronic treatment of mice bearing MXT tumors with LHRH analogs AJ-04 and T-121/B carrying cytotoxic radicals, but not with T-98 produced significant down-regulation of membrane receptors for LHRH. The largest decrease in dissociation binding constant and Bmax of receptors for LHRH was also found in animals treated with T-121/B. Specific, high affinity binding of 125I-labelled epidermal growth factor (EGF) was detected in the membranes from control and treated MXT tumors. Treatment with cytotoxic LHRH analogs, AJ-04, T-98 and especially with T-121/B, reduced maximal binding capacity of EGF receptors. Our results indicate that LHRH analogs carrying cytotoxic radicals retain their hormonal activity and inhibit tumor growth while inducing down-regulation of LHRH receptors. In addition, probably both components of the cytotoxic LHRH analog, peptide carriers and cytotoxic radicals, reduce the binding capacity of EGF receptors, which might be useful in the treatment of breast cancer.
Catecholamines facilitate ventricular defibrillation in animals. We examined the effects of beta-adrenergic stimulation and blockade on ventricular defibrillation threshold in anesthetized dogs. Calibrated shocks were delivered between epicardial and superior vena caval electrodes, and defibrillation threshold was measured before and after administration of isoproterenol and propranolol. Eight dogs (group 1) received isoproterenol before propranolol. Nine dogs (group 2) received propranolol before isoproterenol. In group 1, the minimum energy required to defibrillate before isoproterenol was 10.6 +/- 1.7 (SE) J and decreased to 5.9 +/- 1.3 with isoproterenol (P less than 0.001). In group 2, the minimum energy required to defibrillate was 8.3 +/- 2.4 J before propranolol and increased to 10.7 +/- 2.2 after propranolol (P less than 0.001). In group 1, propranolol after isoproterenol increased defibrillation threshold (P less than 0.07), whereas in group 2 isoproterenol after propranolol produced no significant change in defibrillation threshold. Thus beta-stimulation decreased defibrillation threshold significantly in the anesthetized dog heart, an effect that was blocked by propranolol. Conversely, propranolol increased defibrillation threshold, an effect that occurred despite prior beta-stimulation, probably because of the short half-life of isoproterenol.
Morphological changes produced by the treatment with the D-tryptophan-6 analog of luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) and mitoxantrone (novantrone) were studied in the Dunning R3327H rat prostate cancer model. Microcapsules of D-Trp-6-LH-RH, calculated to release a controlled dose of 25 micrograms/day, were injected intramuscularly once a month. Novantrone (0.25 mg/kg body weight) was injected intravenously once every 3 weeks. The pathology of tumors was studied in two experiments. In the first experiment, the treatment was started 135 days after tumor transplantation, and the therapy was continued for 105 days. In the second experiment, the treatment was initiated 45 days after tumor transplantation, and was carried on for 70 days. The rats were divided into four groups: 1) untreated control, 2) microcapsule-injected, 3) novantrone-injected, and 4) combination of microcapsules and novantrone-injected. In both experiments, similar results were obtained, which included significant reduction in the tumor volume and weight, a very striking decrease in the number of epithelial tumoral cells with atrophy of the glandular epithelium, and an increase in the stromal connective tissue. All these changes were more prominent in the group treated with the combination of microcapsules and novantrone than in the groups treated with microcapsules or novantrone alone. Pathological results support the view that combined therapy may be more efficacious than the treatment with single agents.
The day-to-day variations in epicardial defibrillation threshold (DFT) were examined in closed-chest, unanesthetized dogs. In 11 animals, DFT decreased from 15.8 -+-2.1 J (mean SE) at the beginning of the study (day 1), to 7.4 + 1.7 J on day 2 (p < .0001). DFT measured daily for 5 consecutive days in seven dogs decreased from 22.1 + 3.1 J on day 1 to 9.3 + 2.3 J on day 2 (p < .01) and remained stable from day 2 to day 5. Transcardiac impedance, measured in six dogs, decreased from 112 + 6 Q on day 1 to 100 + 6 Q on day 2 (p = NS). Propranolol given on day 2 in 14 dogs increased DFT from 12.0 + 2.2 to 18.0 ± 3.1 J (p < .05). The effects on DFT of sequential administration of isoproterenol and propranolol were examined in 10 dogs. Isoproterenol decreased DFT from 10. O + 1. 9 to 5.5 + 1. 5 J when given before propranolol (p < .001, n = 10), and from 1 1. 7 -+ 3.0 to 9.7 + 3.1 J when given after propranolol (p < .05, n = 9). Propranolol increased DFT from 10.6 + 3.0 to 14.6 + 3.9 J when given before isoproterenol (p < .02, n = 9), and from 10.7 + 1.4 to 14.4 + 1.5 J when given after isoproterenol (p < .01, n = 10). These experiments demonstrate a sustained cardiac effect of epicardial defibrillation reflected by a decrease in DFT that is partially reversible by propranolol. A similar decrease was produced by /3-adrenergic stimulation, an effect that was partially blocked by propranolol. Thus, variations in the autonomic state of the heart may be an important modulator of cardiac DFT. extends these initial observations to a closed-chest, nonanesthetized preparation, and examines the pattern of DFT measurements repeated daily over several days. Material and methodsDogs weighing between 11 and 19 kg were anesthetized with 22.5 mg/kg pentobarbital and ventilated with a Harvard respirator using room air. A left thoracotomy was performed on each, and the left ventricular free wall was exposed. A 2.5 cm diameter cupped electrode (Parsonnet Porous Epicardial Electrode) was sutured on the anteroapical surface of the left ventricle, and its cable was extended through the rib cage and tunneled under the skin onto the left infrascapular area. The thoracotomy was closed in layers, the skin was sutured, and the dogs were taken back to their cages. Several days after thoracotomy, and after the dogs' complete recovery from the operation, experiments were begun. Each animal was sedated with 2.25 mg/kg subcutaneous morphine sulfate and placed on a rubber thermal blanket to prevent current leakage. This amount of morphine sulfate produced enough sedation to allow placement of the dogs on their sides, loosely restrained, for the duration of the experiment. The animals, however, were awake, responsive, and did not require respiratory support.
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