Targeted therapies by means of compounds that inhibit multiple target molecules represent a new perspective in the treatment and prevention of cancer. Vandetanib (Zactima ™ ) is an orally active, selective inhibitor of VEGFR-2 (vascular endothelial growth factor receptor-2) receptor tyrosine kinase that also demonstrates activity against EGFR (epidermal growth factor receptor) and RET (rearranged during transfection) tyrosine kinases. As there are indications of Vandetanib being effective in advanced NSLC patients for disease free survival, we have tested Vandetanib for efficacy in a primary rat tracheal epithelial (RTE) cell transformation model, which was originally developed for identifying potential chemopreventive agents belonging to different chemical classes/biological activity. RTE cells were treated with a tobacco-specific carcinogen, benzo[ a ]pyrene (B[ a ]P) alone or with five nontoxic concentrations of Vandetanib and the resulting transformed foci at the end of 30 days were scored for inhibition of transformation. In order to understand the mechanism(s) of this inhibition, the effect on biomarkers at different stages of RTE cell transformation was also tested. The results indicated that Vandetanib at half-log concentrations ranging from 0.003 – 0.3 μM, elicited an excellent dose-related inhibition of transformation (75- 93%) compared to B[ a ]P group (p = <0.0001). A significant dose-dependent inhibition (39- 93%) of phosphorylated tyrosine kinase activity was observed in Vandetanib-treated groups compared to B[ a ]P group. There was also an approximately 2-fold induction of apoptosis at 0.3 μM, and it inhibited survivin, a late stage biomarker, at all concentrations by 18-28%. In conclusion, the data shows that there is a very good correlation between the inhibition of B[ a ]P-induced transformation and corresponding inhibition of activated tyrosine kinase and other biomarkers. Based on this data, animal studies are planned to develop this drug for lung cancer prevention by administering it directly to the lungs as it was found to be very effective at lower doses compared to therapeutic doses.
Over-expression of FGF/STAT-3 signalling pathways or aberrant regulation of their activities has been implicated in many forms of human malignancies, including skin neoplasms. Therefore, targeting FGF/STAT-3 signalling pathways represents an attractive strategy for development of basal cell carcinoma (BCC) treatment by simultaneously inhibiting tumor cell growth and survival, and also tumor angiogenesis. Here, we describe the efficacy of a safe, potent and selective FGF inhibitor –dobesilate- in BCC patients. Anti-tumor effect of dobesilate correlates with promotion of apoptosis, and inhibition of both cell proliferation and angiogenesis. Our data support dobesilate as an agent for chemoprevention and therapy of skin cancers by inhibiting FGF/STAT-3 oncogenic signalling axis.
Objective: Given the economic burden of prostate cancer (PCa), a PCa risk-reduction medication would be desirable. A within-trial economic analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study was performed.
Methods: REDUCE, a 4-year, randomized, double-blind, placebo-controlled, parallel-group clinical trial, compared efficacy and safety of dutasteride 0.5 mg daily and placebo to reduce the risk of PCa in men at increased risk. Resource use was prospectively collected; costs from standard costing sources were applied. Utilities were obtained from published literature. Relative risks and Wilcoxon rank sums were used to examine differences between treatments.
Results: Placebo patients were at significantly higher risk (P < 0.05) for concomitant medication use; and health care visits related to surgical procedures, unscheduled biopsies, acute urinary retention, urinary tract infections, or macroscopic hematuria. Total costs were significantly lower (P < 0.001) in dutasteride patients ($1 300; 95% confidence interval: $806, $1 795). Incremental cost per quality-adjusted life-year (QALY) was $26 516; cost per PCa case avoided was $19.
Conclusions: During the 4-year trial period, men at increased risk for PCa receiving dutasteride incurred fewer health care costs than men receiving placebo, which helped offset dutasteride costs. Dutasteride was good value for money.
Sporadic colorectal cancer (CRC) represents 75% of the total of the CRC cases diagnosed and is the second leading cause of cancer death with a a 5-year survival rate of 62%. The development of colorectal cancer is a complex process involving multiple molecular pathways, since the formation of adenomas to the development of carcinoma in the digestive tract (the so-called “adenoma-carcinoma sequence”), in a process that can last several decades. Thus adenomas are considered a surrogate variable for the development of CRC in clinical trials. Although screening strategies (blood in stool, endoscopic and CT-colonoscopy) have supposed a great advance in the early detection of these tumours, they are associated with inconveniences such as their cost and associated morbidity. Moreover screening does not necessarily prevent the development of cancer or prevent mortality. Therefore, interest in primary prevention research has increased in recent years. In this regard, multiple attempts to modify lifestyle and dietary factors to try to reduce the incidence of cancer have been promoted. However, some studies, many of them observational or case-control, have yielded conflicting data. Consequently, in the past 20 years, chemoprevention studies have grown in importance.
Introduction:Garlic supplementation in diet has been shown to be beneficial to cancer patients. Recently, its pharmacological role in the prevention and treatment of cancer has received increasing attention. However, the mechanisms by which garlic extract (GE) induces cytotoxicity, oxidative stress, and apoptosis in cancer cells remain largely unknown.
Objective:The present study was designed to use HL-60 cells as a test model to evaluate whether or not GE-induced cytotoxicty and apoptosis in human leukemia (HL-60) cells is mediated through oxidative stress.
Methods:Human leukemia (HL-60) cells were treated with different concentrations of GE for 12 hr. Cell survival was determined by MTT assay. The extent of oxidative cell/tissue damage was determined by measuring malondialdehyde (lipid peroxidation biomarker) concentrations by spectrophotometry. Cell apoptosis was measured by flow cytometry assessment (Annexin-V and caspase-3 assays) and agarose gel electrophoresis (DNA laddering assay).
Results:Data obtained from the MTT assay indicated that GE significantly (p < 0.05) reduced the viability of HL-60 cells in a concentration-dependent manner. We detected a significant (p < 0.05) increase in malondialdehyde (MDA) concentrations in GE-treated HL-60 cells compared to the control. Flow cytometry data showed a strong concentration-response relationship between GE exposure and Annexin-V positive HL-60 cells. Similarly, a statistically significant and concentration-dependent increase (p <0.05) were recorded with regard to caspase-3 activity in HL-60 cells undergoing late apoptosis. These results were confirmed by data of DNA laddering assay showing a clear evidence of nucleosomal DNA fragmentation in GE-treated cells.
Conclusion: Our finding indicates that GE-induced cytotoxicity and apoptosis in HL-60 cells involve phosphatidylserine externalization, caspase-3activation, and nucleosomal DNA fragmentation associated with the formation of MDA, a by-product of lipid peroxidation and biomarker of oxidative stress. At therapeutic concentrations, GE-induced cytotoxic and apoptotic effects in HL-60 cells is mediated by oxidative stress.
Nagi Kumar, Theresa Crocker, Tiffany Smith, Julio Pow-Sang, Philippe E. Spiess, Shanjayla Connors, Ganna Chornukur, Shohreh Iravani Dickinson, Wenlong Bai, Christopher R. Williams, Raoul Salup and Wui Fu
Inspite of the large number of promising nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in high-risk cohorts are required to inform design of phase II clinical trials. Additionally, a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must be utilized to evaluate effectiveness in these trials. The goal of this paper is to provide a model, using a systematic approach for evaluating the safety, effectiveness and mechanism of action of a well characterized nutrient-derived agent- isoflavones - in a phase II clinical trial for prostate cancer (CaP) chemoprevention, targeting a population of African American (AA) and Caucasian men. Based on our previous observations, we hypothesize that the effects of isoflavones on prostate carcinogenesis are mainly mediated through the down regulation of androgen receptor (AR) and AR activity in AA men is higher due to its shorter length of Glutamine repeats in its N-terminus. We thus believe that isoflavones will exert a stronger protective effect for CaP in AA men and cause a higher activation of FOXO factors and their target genes. The aim of the study is to evaluate the comparative effectiveness of the study agent and placebo, in addition to a comparison of the effectiveness and safety in African American men compared to Caucasian men treated with this agent.