Cancer Science & Therapy

The mammalian (mechanistic) target of rapamycin (mTOR) is a serine/threonine kinase that plays a key role in cell growth and proliferation and is regarded as an attractive therapeutic target for cancer therapy. Preclinical investigations have suggested that mTOR complex 1 (mTORC1) and mTORC2 are frequently activated in epithelial ovarian cancer, especially in clear cell carcinoma of the ovary. In mouse models of ovarian cancer, mTORC1 inhibitors have demonstrated promising antitumor activity against ovarian cancer both in the setting of monotherapy and when used in combination with cytotoxic agents. Based on these promising preclinical findings, mTORC1 inhibitors are currently being evaluated in phase I/II trials involving ovarian cancer patients. In an effort to overcome resistance to mTORC1 inhibitors, novel mTOR kinase inhibitors (TORKinib) that inhibit both mTORC1 and mTORC2 have recently been developed. In this report, we review the scientific rationale and evidence for the potential clinical benefits provided by mTOR inhibitors in patients with epithelial ovarian cancer.

Background: Published data suggest that diabetes influences survival of patients with lung cancer. The anti-cancer effect of metformin confounds this association. We sought to study the association of diabetes and metformin with survival in patients undergoing resection of stage I non-small cell lung cancer (NSCLC).

Methods: Pathologic stage I NSCLC patients undergoing anatomic resection from 2002 to 2011 were studied. A diagnosis of diabetes and diabetic medication use were identified through records. Univariate and multivariate analyses examined the association of diabetes and metformin usage with overall survival (OS).

Results: 409 eligible patients were included in the analysis - excluding patients with neoadjuvant therapy, more than one lung cancer, or resection less than lobectomy. 71 (17.4%) patients were diabetics and 41 (10.0%) used metformin. With a median follow up of 44 months, univariate analysis demonstrates that diabetes had no effect on OS (P=0.75); however, metformin use was associated with improved OS (median survival not reached vs. 60 months; P=0.02). Metformin use remained an important predictor of good survival in multivariate analysis (HR=3.08; P<0.01) after adjusting for age, gender, pathologic stage, histology and smoking status.

Conclusion: Metformin use rather than diabetes is associated with improved long-term survival in Stage I NSCLC patients.

Background: Antimitotic drugs represent some of the most popular vascular disrupting agents used today in the fight against cancer. Colchicine is the first known alkaloid. The drug binds to tubulin protein and depolymerizes microtubules. Despite the impressive therapeutic activity as an antimitotic agent, colchicine is fatally toxic when administered to cancer patients intravenously due to its low therapeutic index. This study supports the early development of a relatively safe and target-specific nanoparticle for the IV administration of colchicine to lung tumors.

Methods: For in vitro studies, lung cancer (LLC, Chago-k-1 and MCA-205), and endothelial cell lines (MS1- VEGF, HMEC-1) were employed. The qualitative and quantitative analyses of the cytoskeleton and nuclear areas were performed using FITC-labeled β-tubulin antibody; the mean area of cytoskeleton and nucleus per cell was determined by fluorescence microscopy and BIOQUANT. In vivo, the biodistribution and therapeutic efficacy studies of the pegylated cationic liposomes (PCLs) were performed in C57BL/6 mice bearing pseudo-orthotopic lung tumors. The biodistribution of colchicine and PCL-colchicine was determined by dual labeling. 111In labeled PCLs and 3H-Colchicine were employed to simultaneously track the vehicle and drug, respectively. The therapeutic efficacy was determined by monitoring animal survival.

Results: The disruption of microtubules was most evident when colchicine was loaded in DOTAP-PCLs. We report a ~2 fold (p=0.0214, 95% CI is 2.923 to 13.247) increase in the accumulation of PCL-colchicine in tumor-bearing lung compared to the normal lung, resulting in significantly extended survival times in PCL treated group (p=0.0052, Log Rank (Mantel-Cox test)).

Conclusions: The PCL-based colchicine-loaded nanosystem can renew the clinical potential of abandoned antimitotic agents such as colchicine. The PCL platform can enable the accumulation of clinically relevant doses of colchicine in solid tumors. This will ensure antimitotic activity while decreasing the uptake of the drug in healthy tissues.

Ovary cancer is a fullness paradigms disease and serious health problem Is important knows it’s natural history, because has multi-factor origins, and understood it’s behavior since risk factors until patient’s dead, metastatic disease in patient is reality to challenger for oncology group. Ovarian cancer screening is today difficult theme; almost patients with disease had advanced ovarian cancer in the first visit with oncology. In this work we made a bibliographic report about natural history, is an analytic review that’s brings up concepts since etiology theirs risk factors, evolution sources, preclinical horizon, clinical disease and related symptoms, without treatments, until host dead.

Many histopathologic parameters in head and neck squamous cell carcinoma have been identified as predictive factors for cervical metastasis. Several studies focused on tumor thickness, and the depth of invasion was suggested to have a relationship to the occurrence of cervical metastasis, therefore the aim of this study was to determine the relationship between tumor depth and clinically suspicious neck, as well as occult neck disease, and to determine the cutoff point for metastasis in Iraqi population, in addition, the study intended to identify further predictive factors for cervical metastasis in squamous cell carcinoma of the oral cavity.

Methods: The medical records of 80 patients operated on with oral squamous cell carcinoma between 1991 and 2000 were reviewed; each patient, age, sex, tumor location, tumor size, degree of differentiation, pattern of invasion; lymphoplasmocytic infiltration and tumor depth were evaluated. All slides were examined by the same pathologist, chi-square test was used to compare the impact of these parameters on nodal metastasis in the neck.

Results: In multivariate analysis the most important factors was tumor depth followed by pattern of invasion, tumor site, degree of differentiation, tumor size, and lymphoplasmocytic infiltration. Univariate analysis indicates that tumor depth is important predictive factor in cervical metastasis for oral squamous cell carcinoma P<0.001.

Conclusion: Tumor depth is a reliable factor to predict nodal metastasis and tumor depth of 4 mm can be considered as a suggested standard Iraqi cutoff number in staging and management of early oral squamous cell carcinoma.

Background and objective: Small cell lung cancer (SCLC) is one of the most challenging tumors to treat due to high proliferation rate, early metastatic dissemination and rapid development of chemotherapy resistance. The current treatment protocols involve the use of topoisomerase 1 (TOP1) poisons such as irinotecan and topotecan in combination with platinum-based compounds. TOP1 poisons kill cancer cells by trapping TOP1 on DNA, generating lethal DNA double-strand breaks. A potential mechanism employed by cancer cells to resist killing by TOP1 poisons is to overexpress enzymes involved in the repair of TOP1-DNA breaks. Tyrosyl DNA phosphodiesterase 1 (TDP1) is a key player in this process and despite its importance, no data is currently available to correlate TDP1 protein and mRNA levels with catalytic activity in SCLC. In addition, it is not known if TDP1 and TOP1 protein levels correlate with the cellular response of SCLC to TOP1 based therapies.

Methods and results: We report a remarkable variation in TDP1 and TOP1 protein levels in a panel of SCLC cell lines. TDP1 protein level correlates well with TDP1 mRNA and TDP1 catalytic activity, as measured by two newly developed independent activity assays, suggesting the potential utility of immunohistochemistry in assessing TDP1 levels in SCLC tissues. We further demonstrate that whilst TDP1 protein level alone does not correlate with topotecan sensitivity, TDP1/TOP1 ratio correlates well with sensitivity in 8 out of 10 cell lines examined.

Conclusion: This study provides the first cellular analyses of TDP1 and TOP1 in SCLC and suggests the potential utility of TDP1/TOP1 ratio to assess the response of SCLC to topotecan. The establishment and validation of an easy-to-use TDP1 enzymatic assay in cell extracts could be exploited as a diagnostic tool in the clinic. These findings may help in stratifying patients that are likely to benefit from TOP1 poisons and TDP1 inhibitors currently under development.