In vitro and in vivo anticancer potential and molecular targets of the new colchicine analog IIIM-067 / 中西医结合学报

OBJECTIVE@#The current study evaluated various new colchicine analogs for their anticancer activity and to study the primary mechanism of apoptosis and in vivo antitumor activity of the analogs with selective anticancer properties and minimal toxicity to normal cells.@*METHODS@#Sulforhodamine B (SRB) assay was used to screen various colchicine analogs for their in vitro cytotoxicity. The effect of N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(pyrrolidine-1-yl)5,6,7,9-tetrahydrobenzo[a] heptalene-7-yl] acetamide (IIIM-067) on clonogenicity, apoptotic induction, and invasiveness of A549 cells was determined using a clonogenic assay, scratch assay, and staining with 4',6-diamidino-2-phenylindole (DAPI) and annexin V/propidium iodide. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were observed using fluorescence microscopy. Western blot analysis was used to quantify expression of proteins involved in apoptosis, cell cycle, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Pharmacokinetic and in vivo efficacy studies against Ehrlich ascites carcinoma (EAC) and Ehrlich solid tumor models were conducted using Swiss albino mice.@*RESULTS@#IIIM-067 showed potent cytotoxicity and better selectivity than all other colchicine analogs screened in this study. The selective activity of IIIM-067 toward A549 cells was higher among other cancer cell lines, with a selectivity index (SI) value of 2.28. IIIM-067 demonstrated concentration- and time-dependent cytotoxicity against A549 cells with half-maximal inhibitory concentration values of 0.207, 0.150 and 0.106 μmol/L at 24, 48 and 72 h, respectively. It also had reduced toxicity to normal cells (SI > 1) than the parent compound colchicine (SI = 1). IIIM-067 reduced the clonogenic ability of A549 cells in a dose-dependent manner. IIIM-067 enhanced ROS production from 24.6% at 0.05 μmol/L to 82.1% at 0.4 μmol/L and substantially decreased the MMP (100% in control to 5.6% at 0.4 μmol/L). The annexin V-FITC assay demonstrated 78% apoptosis at 0.4 μmol/L. IIIM-067 significantly (P < 0.5) induced the expression of various intrinsic apoptotic pathway proteins, and it differentially regulated the PI3K/AKT/mTOR signaling pathway. Furthermore, IIIM-067 exhibited remarkable in vivo anticancer activity against the murine EAC model, with tumor growth inhibition (TGI) of 67.0% at a dose of 6 mg/kg (i.p.) and a reduced mortality compared to colchicine. IIIM-067 also effectively inhibited the tumor growth in the murine solid tumor model with TGI rates of 48.10%, 55.68% and 44.00% at doses of 5 mg/kg (i.p.), 6 mg/kg (i.p.) and 7 mg/kg (p.o.), respectively.@*CONCLUSION@#IIIM-067 exhibited significant anticancer activity with reduced toxicity both in vitro and in vivo and is a promising anticancer candidate. However, further studies are required in clinical settings to fully understand its potential.

Impact of multidisciplinary care in gynecological cancer patients

Objective: To determine the impact of multidisciplinary care in Gynecological cancer patients through multidisciplinary meetings [MDM] at MCH centre, Pakistan Institute of Medical Sciences [PIMS], Islamabad

Study Design: A pre and post intervention comparative study

Place and Duration of Study: The study was conducted at MCH centre, PIMS and Nuclear Oncology and Radiotherapy Institute, Islamabad from 1[st] April 2009 to 31[st] Mar 2010

Material and Methods: MDM is a regularly scheduled meeting of core and limited team members for the purpose of prospective treatment and care planning of newly diagnosed cancer patients. It was started in 2009 in order to improve the management of the cancer patients according to the international recommendations. In a total of 1 year study period 24 meetings were held. The major audit tool was the documentation of the meeting and its outcomes, patient communication and record of the Nuclear Oncology and Radiotherapy Institute of Islamabad [NORI]. A postgraduate student was deputed for documentation

Results: The study identified that MDM helped in achieving many of the best practices of international recommendations which include team approach to treatment planning as well as to care provision, throughout the complete patient pathway. The workload almost doubled as regards the surgery and outdoor cancer claims. There was a shorter delay to first seen in the cancer clinic and shorter duration from diagnosis to treatment. Team members were present in 90-100% of the meetings

Conclusion: MDM has swiftly improved the quality of care and follow up of patients with gynecological cancers and should be conducted at all tertiary care hospitals. Problems of access to high quality and timely care of poor patients in public sector should be addressed as poor patients are not compliant to timely follow-up

Influence of circadian variations on onset and in-hospital outcome of first acute myocardial infarction

To evaluate the influence of circadian variations on the onset and in-hospital outcome of first acute myocardial infarction [AMI]. After fulfilling the inclusion criteria 425 patients presenting with new onset acute myocardial infarction were studied. The study patients were divided into 4 groups according to time of onset of symptoms. Group I consisted of 67[15.8%] patients presenting during 0-6 hours interval, Group II 118[27.7%] patients presenting during 6:0l-12 hours, Group III 144[33.9%] patients presenting in 12:01-18 hours and Group IV comprised of 96[22.6%] patients having onset of AM1 during 18:0l-24 hours. Cardiovascular risk factors and in-hospital outcome were compared between the groups by applying Chi Square test. Two peaks of onset of symptom were observed, first between 12:0l-18 hours 144[33.9%] patients and the second between 6:0l-12 hours 118[27.7%] patients. The trough was early morning time 0-6 hours when only 67[15.8%] patients had acute MI. Mean age of the study population was 54.5 +/- 12.3 years. There were 337[79.3%] males and 88[20.7%] females. There were 114[26.8%] diabetics, 138[32.5%] hypertensives and 215[50.6%] smokers. Majority of patients 168[39.5%] presented 3-6 hours after the onset of symptoms. Overall 100[23.5%] patients presented to the hospital within 3 hours of onset of symptoms. Overall 173[40.7%] patients had anterior wall myocardial infarction followed by Anterospetal wall myocardial infarction in 147[34.6%] patients. In Group IV patients there was more 9[6.3%] tendency of presenting in advanced Killip class followed by Group I1 7[5.9%] and 4[2.8%] in Group 111 p<0.485. Overall 201[47.3%] patients received streptokinase therapy. Overall in-hospital mortality was 62[14.5%], mortality was higher 22[18.6%] in Group 11, followed by 14[14.6% in Group IV, 19[13.2%] in Group III and 8[11.9%] in Group I p<0.113. Left ventricular failure was the common cause 45[10.6%] of in-hospital mortality. The onset time of AMI has bimodal appearance with an early peak at 12:0l-18 hours and a second lesser peak at 6:0l-12 hours. In-hospital mortality was higher in patients presenting between 6:0l-12 hours because of more frequency of advanced killip class at the time of presentation in this Group