Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/ mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer.However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

Effect of Esmolol upon Sodium Nitroprusside-Induced Hypotension under Halothane Anesthesia in Dog : Impact on the Hemodynamic Parameters and the Sodium Nitroprusside Dose Requirement / 대한마취과학회지

BACKGROUND: The induced hypotension was used to decrease blood loss, thereby decreasing the need for blood transfusion and/or improving operating conditions at the surgical site. It was hypothesized that SNP-induced hypotension with fixed concomitant esmolol infusion(75 ug/kg/min) might prevent side effects such as reflex tachycardia and reduce SNP dose requirement during SNP-induced hypotension. METHOD: The concomitant infusion of 75 ug/kg/min esmolol was used to potentiate hypotension(30% reduction of mean arterial blood pressure) induced with sodium nitroprusside in six dog during halothane(lvo1%)-N2O(50%)-O2(50%) anesthesia. Mean arterial blood pressure, heart rate, cardiac output, mean pulmonary arterial blood pressure, central venous pressure, arterial blood gas analysis, and mixed venous oxygen saturation were measured and systemic vascular resistance was calculated in the each periods. RESULT: The results run as follows; 1) Compared to SNP-induced hypotension, there was significant reduction in SNP dose requirement to maintain a 30% reduction of mean arterial pressure at the concomitant infusion of 75 ug/kg/min esmolol. 2) There were significant reduction in heart rate, mixed venous oxygen saturation and cardiac output, but significant increase in systemic vascular resistance and mean pulmonary arterial pressure at the coneomitant infusion of 75 ug/kg/min esmolol. 3) No rebound hypertension was observed at 30 minute after SNP and esmolol infusions were simultaneously discontinued. CONCLUSION: The result of present study suggests that esmolol infusion is a safe and effective pharmacologic means of potentiating SNP-induced hypotension during halothane-N2O-O2 anesthesia. Probably esmolol may act by counteracting side effects such as acute tolerance during SNP-induced hypotension.

Epidural Anesthesia for Cesarean Section of Pregnant Woman with Lymphangioleimyomatosis / 대한마취과학회지

Lymphangioleiomyomatosis result from the proliferation of immature smooth muscle cells in the peribronchial, perivascular and perilymphatic areas of the lung. The disease primarily affects women of childbearing age, which has dyspnea, recurrent episodes of pneumothorax, pulmonary edema, chylous effusion and hemoptysis as symptoms. Most patients die from respiratory failure within 10 years after diagnosis. Definite diagnosis depends on histologic findings. We report our experience of anesthetic management for a pregnant woman with lymphangioleiomyomatosis which was confirmed with biopsy of inguinal lymph nodes.

Effect of Esmolol on Cardiovascular Responses to Extubation / 대한마취과학회지

Transient increases in blood pressure and heart rate(HR) at the end of anesthesia and during extubation are common. Tomori and Widdicombe observed that mechanical stimulation of four areas of the upper respiratory tract (nose, epipharynx, laryngopharynx, tracheobnchial tree) induced reflex cardiovascular responses associated with enhanced neuronal activity in the cervical sympathetic efferent fibers. In susceptible patients, even this short period of hypertension and tachycardia can result in myocardial ischemia or increased intracranial pressure. The purpose of present study was to evaluate the effect of esmolol in attenuating cardiovascular responses to extubation under general anesthesia with endotracheal intubation. A sixty healthy patients who underwent elective noncardiac operation under general anesthesia (N2O-O2-enflurane) with endotracheal intubation were randomly divided into two groups : one was placebo group that received intravenous injection of 0.1 cc/kg normal saline, the other was esmolol group that received intravenous injection of 1 mg/kg esmolol. Extubation was performed when the patients could breathe spontaneously and open their eyes on command. In practice extubation was done between 2 and 4 minutes after drug(esmolol or saline) injection. The measurement of systolic blood pressure and heart rate was obtained one minute before extubation and every minute for 5 minutes after extubation, then rate-pressure product was calculated. The results were as follows; 1) When compared to pre-extubation systolic blood pressure, systolic blood pressure for 2 minutes after extubation in both groups increased significantly but systolic blood pressure was more rapidly returned to pre-extubation level in the esmolol group than in the placebo group. When compared to pre-extubation systolic blood pressure, after extubation the number of patients in whom systolic blood pressure increased more than 20% was significantly fewer in the esmolol group than in the saline group. 2) When compared to pre-extubation heart rate, heart rate at 1 minute after extubation in the placebo group increased significantly but heart rate after extubation in the esmolol group did not change significantly. 3) When compared to pre-extubation rate-pressure product, rate-pressure product for 2 minutes after extubation in both group increased significantly. At 4 minutes after extubation, rate-pressure product in the saline group increased significantly when compared to rate-pressure product in the esmolol group. These results suggest that intravenous injection of 1 mg/kg esmolol before extubation blocks heart rate elevation following extubation under general anesthesia and is effective for rapid return to the pre-extubation level of systolic blood pressure.