Clinical Cancer Drugs - Volume 3, Issue 2, 2016

Background: Monoclonal antibodies have become attractive clinical anticancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.g. mesothelioma, pancreatic, ovarian, lung, triple negative breast and gastric cancers). Methods: Mesothelin is validated as a suitable antibody target for cancer therapy. A number of novel antibody therapeutics targeting mesothelin in development are compared and their mechanisms of action are also discussed. Both basic science and clinical data are provided to give a complete veiw of how an agent is developed from bench to bedside. Results: Novel antibody therapeutics, including unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates, targeting mesothelin exert anti-tumor activities by different mechanisms of action. Based on the convincing preclinical data generated with these molecules, the antibody therapeutics have been brought into early clinical evaluation where initial promising results were obtained. Conclusion: These antibody therapeutics directed against mesothelin are expected to have different safety profiles, based on their different mechanism of action. Further clinical development will reveal which of these molecules shows the best efficacy and widest therapeutic window and thus is best suited to bring benefit to the patients.

Background: The Mesenchymal Epithelial Transition factor (c -Met, MET) is the tyrosine kinase cell surface receptor, and the only known high affinity ligand is hepatocyte growth factor (HGF). HGF/MET pathway is required for not only normal physiologic development, but also a wide variety of human malignancies. More and more pieces of evidence have been identified for the treatment of a variety of malignancies with c-Met/HGF inhibitors. This review aims to more deeply understand the effects of c-Met/HGF inhibitors on patients with solid tumors and investigate the association between HGF/MET pathway biomarkers and survival. Methods: We carried out a review based on 24 published clinical trials to determine whether various kinds of c-Met/HGF inhibitors will benefit patients with solid tumors. We collected information about the tumor efficacy endpoint such as complete response, partial response, stable disease, objective responses and the objective response rate to assess clinical outcomes. Results: The biomarkers were analyzed for their relative efficacies. Interestingly, efficacy is quite different with each c-Met inhibitor, kind of solid tumor, and the combination with other antitumor agents and biomarkers. The outcomes of the biomarkers support the further exploration of c-Met/HGF as a prognostic marker. Conclusion: High quality studies with the identification and selection of the optimal patient populations are needed to further reveal the clinical effects of c-Met/HGF inhibitors and the development of a new generation of c-Met/HGF inhibitors is essential.

Background: Conventional cancer therapies such as chemotherapy and radiotherapy are often characterised by lack of tumor specificity, increased resistance of tumors to drugs, failure to detect metastases and undesirable side effects. Several years back, William Coley’s pioneering work on the use of bacteria opened up the new field of cancer immunotherapy. The search for alternative and better strategies in cancer treatment is an ongoing process. Methods: Articles related to the therapeutic efficacies of different bacterial species against cancer were searched in different scientific journals and databases. This review summarizes the studies on the expediency of different bacterial species in cancer treatment particularly the potential therapeutic efficiency of Mycobacteria. Results: A strain of Mycobacterium bovis, i.e. Bacillus Calmette Guerin, is approved for the treatment of bladder carcinoma. Also, treatment with Mycobacterium vaccae improves the quality of life of patients suffering from some tumors. Recent studies have revealed the efficacy of Mycobacterium indicus pranii in inducing a Th1 priming environment and reducing the in vivo tumor growth in several animal models. Conclusions: The immunotherapeutic potential of different mycobacterial species warrant clinical investigations for a wide range of tumors and may open up a new dimension in cancer therapy. Further studies and technological innovations are likely to shed new light on host responses to tumors, provide a promising regimen of cancer therapeutics and improve the quality of life of cancer patients.

Background: 5-Flurorouracil (5-FU) chemotherapy has been one of the extensively employed standard therapies for the treatment of colon cancer. Various molecular interventions and dose modulations in the form of adjuvant therapies has been exploited for better therapeutic efficacy and low adverse effects to improve overall survival rate in advanced colorectal cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) have shown huge potential to supplement the classical chemotherapeutic regimens in order to achieve better cytotoxic potency against cancer cells and specifically through targeting of multi apoptotic pathways and inflammatory markers. Methods: The present investigation was carried out to study the effect of etodolac (ETD) on the therapeutic spectrum of 5-FU in colon cancer in order to regress the dose related adverse potential by modulating the 5-FU dose in 1,2 dimethylhydrazine (DMH) induced colon cancer rats and to explore the molecular apoptotic pathways involved. Results: Diverse dose combination therapy of 5-FU plus ETD (FEC1; high dose combination of 5-FU and ETD in ratio of 4:1), FEC2; medium dose combination of 5-FU and ETD in ratio of 3:1) and (FEC3; low dose combination of 5-FU and ETD in ratio of 2:1) showed significant decrease in the tumor burden in a dose dependent manner (i.e. FEC1>FEC2>FEC3) in comparison to monotherapy. Further, the combination therapy also showed significantly enhanced apoptosis in DMH induced colon cancer rats in comparison to monotherapy. Conclusions: ETD could be a useful intervention as adjuvant therapy for increasing the cytotoxic potential of 5-FU at lower therapeutic dose. The present study showed the immense application and future role of ETD as an adjuvant agent in fluorouracil based combination strategy to widen therapeutic spectrum and increased apoptosis in cancer cells. To best of our knowledge, this report for the first time elucidates the enhanced therapeutic efficacy of low dose 5-FU in combination with ETD via nuclear factor kappa-B (NF-ΚB), peroxisome proliferator activator receptor-gamma (PPAR-γ), tumor necrosis factoralpha (TNF-α) and cyclooxygenase–II (COX-II) pathway in DMH induced colon cancer rats.

Background: Forskolin and Andrographolide are extensively used in many parts of Asia as traditional herbal medicines. Potato tumor bioassay has several advantages for pre-screening of antitumor molecules as compared to animal cell based bioassays. The present study was aimed to evaluate the antitumor potential, biochemical changes induced by the test compounds, and screening of their ability to interact with DNA. Methods: The preliminary screening for the selectivity of solvent and the antimicrobial activity of the test drugs against A.tumefaciens was carried out on the potato tumor bioassay. The antitumor activity and biochemical changes (total sugars and soluble protein) induced by test drugs were evaluated in comparison with 5-Fluorouracil that was used as a positive control, using potato tumor bioassay. Results: Both, Forskolin and Andrographolide inhibited tumor induction in potato tumor bioassay. Complete tumor inhibiton (100 %) was exhibited by Forskolin at a concentration of 40 μg/mL, Andrographolide at 70 μg/mL and 5-Fluorouracil at 60 μg/mL, respectively. The IC50 values were observed to be 5.7 μg/mL, 20.91 μg/mL and 24.55 μg/mL for Forskolin, Andrographolide and 5- Fluorouracil, respectively. The result suggests that Forskolin was a potent antitumor molecule as compared with 5-Fluorouracil. The interaction of Forskolin, Andrographolide and 5-Fluorouracil with B-DNA by molecular docking studies suggested that their binding was in close proximity with the GC rich region via non-covalent interactions, with Forskolin exhibiting the highest binding affinity of - 7.4 K cal mol-1 . The UV spectroscopic analysis using calf thymus DNA further revealed a hyperchromic effect with a red shift for Forskolin, 5-Fluorouracil and hypochromic effect for Andrographolide at 5 to 40 μg/mL concentrations tested. Conclusion: Using potato tumor bioassay, the antitumor potentials of Forskolin and Andrographolide have been assessed in comparison with an established antitumor drug, 5-Fluorouracil. Further, possible interaction of the compounds with DNA substantiates their role as antitumor molecules.

Background: A medical need exists for successfully treating patients afflicted with leukemia and especially those that relapse and ultimately become refractory to front line chemotherapies. Leukemia cases are particularly high within Hispanic populations where this disease is among the most frequently occurring cancer. A possible cause is somatic mutations in Janus tyrosine kinase (Jak3). Fourteen somatic mutations have been reported in Jak3, including M511I and A573V, from patients with various forms of leukemia. While several of these Jak3 mutations have been shown to possess transforming ability in cell lines, whether these mutations are susceptible to Jak3 selective inhibitors remains less clear. Methods: The IL-3 dependent pro-B cell line Ba/F3 was virally transduced with plasmids encoding GFP and different mutant forms of Jak3, some of which conferred IL-3 independence. Sensitivity to pre-clinical and clinical Jak3 selective inhibitors was assessed for cellular viability and growth. Results: Two Jak3 mutations conferred IL-3 independent growth in Ba/F3 cells. However, the level of drug sensitivity varied with respect to Jak3 inhibitors NC1153, CP-690,550, and EP-009. Conclusion: Jak3 inhibitors CP-690,550 and NC1153 showed efficacy in reducing viability of Ba/F3 cells transformed with mutant forms of Jak3, thus providing new therapeutic strategies to treat these types of cancer.

Background: A novel series of structurally divergent 1,5-diaryl-3-oxo- 1,4-pentadiene analogues 1-10 displayed marked cytotoxic potencies towards a number of human leukemia/lymphoma cells. Objective: To identify novel selective cytotoxic compounds that induce apoptosis. Methods: The Differential Nuclear Staining (DNS) screening protocol was utilized to measure the cytotoxicity of all experimental dienones on several cancerous cells. Additionally, the selective cytotoxicity index was calculated by comparing the dienone’s cytotoxicity between leukemia/lymphoma cells vs. non-cancerous cells. Furthermore, to discern whether a selected dienone induced cell death via apoptosis or necrosis on T-lymphocyte leukemia cells, diverse approaches were utilized to detect individual biochemical facets of apoptosis. Results: The dienones were tested for their anti-neoplastic efficiency on human leukemia/lymphomaderived cell lines. Special emphasis was applied on dienone 1, on the basis of its sub-micromolar cytotoxicity (CC50=0.43+0.02 μM) and high selective cytotoxicity index (11.1) exerted on T-leukemia cells. In general, dienone 1 showed the most potent cytotoxic properties as compared to other dienones and a related reference cytotoxin curcumin as well as the EF-24 curcumin analogue. Dienone 1 caused cell death by apoptosis in Jurkat cells as evidenced by inducing phosphatidylserine externalization, mitochondrial depolarization and caspase-3/7. These effects were mainly attributed to the induction of apoptotic pathways. Conclusion: The novel dienone 1 was found to exhibit potent anti-leukemia activity by inducing programmed cell death/apoptosis. Consequently, dionone 1 should be developed further to examine its potential efficacy to combat malignancies in a pre-clinical animal model.