In the present study, the anti-tumor efficacy of α-TEA, a derivative of RRR-α-tocopherol, was investigated in LNCaP and PC-3-GFP human prostate cancer cells. Data show that α-TEA induced apoptosis in both cell lines in a time- and dose-dependent manner. Data show that α-TEA induces apoptosis through the activation of pro-apoptotic Fas signaling and inhibition of pro-survival Akt signaling pathways. The role of FADD and Daxx in α-TEA-induced apoptosis was determined. Data show that α-TEA promotes the association of FADD with Fas. FADD siRNA significantly reduced α-TEA-induced apoptosis in LNCaP cells. However, in PC-3-GFP cells, FADD siRNA caused apoptosis in the absence of α-TEA, and in the presence of FADD siRNA, α-TEA-induced apoptosis was significantly enhanced, indicating pro-survival activity of FADD in PC-3-GFP cells. Although α-TEA did not change the total protein levels of Daxx, it did promote the association of Daxx with Fas. α-TEA-induced apoptosis was significantly reduced by Daxx siRNA, and enhanced by overexpression of wild type Daxx, showing the pro-apoptotic role of Daxx in α-TEA-induced apoptosis. α-TEA inhibited phosphorylation of all three Akt isoforms; namely, Akt1, Akt2, and Akt3, thereby removed the phosphorylation inhibition on FOXO1 and FOXO1-mediated upregulation of FasL enhanced apoptosis through Fas signaling pathway. Studies have shown that selenium is of value in prostate cancer prevention. Here we document that methylseleninic acid (MSA) acts synergistically with α-TEA to induce apoptosis in LNCaP and PC-3-GFP human prostate cancer celld in culture. Western blot analyses indicate the involvement of caspases-8, -9, and -3, as well as Akt, in the synergistic effect of α-TEA and MSA. In a preclinical PC-3-GFP xenograft mouse model, α-TEA and MSC separately and together significantly reduced tumor burden and metastatic lesions in lungs and lymph nodes. However, synergism with the combination that in cell culture were not obtained in the animal study. α-TEA alone was as effective as, perhaps better than, the combination treatment in ruducing tumor burden and inhibiting metastases. Thus, data support α-TEA alone, rather than α-TEA plus selenium, as a treatment for human prostate cancer. / text

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Peritoneal carcinomatosis is a complex clinical-pathological condition and most patients with this disease would die within 6 months. The disadvantage of systemic cancer therapy is that only a small portion of the administered drug can reach the tumor cells, and side effects could occur due to its wide distribution in the body. In recent years, cytoreductive surgery combined with intraperitoneal chemotherapy has been the effective way for the treatment of peritoneal carcinomatosis. But the anticancer agents in aqueous form can be easily absorbed through capillaries below the large serosal surface into the systemic circulation, and it is difficult to retain the drug at a high concentration for a long time in the peritoneal cavity. The ideal drug for intraperitoneal chemotherapy should have a high molecular weight, a prolonged retention in the peritoneal surface, and increase drug exposure to tumor cells, decrease drug absorption and hence reduce systemic toxicity. ABZ (albendazole) with its properties of poor water solubility and strong anticancer effects could be a potential effective agent for the treatment of peritoneal carcinomatosis. The aims of this study are: to compare oral versus i.p administration of ABZ, study pharmacokinetic characteristics of ABZ in i.p administration; to study the efficacy ofABZ on early, middle and later stages of cancer development, to find out the possible antitumor effect of ABZ in suppressing cancer cell proliferation, ascites control and longer survival of mice with peritoneal carcinomatosis; to solve the occurring problems during ABZ i.p administration, reduce side effects and increase the drug efficacy; to investigate possible mechanisms ofABZ suppressing tumor proliferation and ascites formation. A series of experiments were designed in order to achieve the study objectives. The pharmacokinetic study of ABZ gives some dynamic characteristics by oral versus i.p administration in rabbits. Three sets of experiments of ABZ treatment were performed on different stages peritoneal carcinomatosis arising from the OVCAR-3 cancer cells in nude mice, from which the efficacy of ABZ in suppressing tumor growth and ascites formation by i.p administration is clearly demonstrated. The increased solubility of ABZ with three surfactants and in human ascites was carried out in different tests, and the combination of ABZ with Tween 80 has achieved better control of peritoneal carcinomatosis when given by i.p administration. The results from this study have revealed for the first time the capacity of ABZ suppressing VEGF (vascular endothelial growth factor) and ascites formation profoundly, confirmed that ABZ has potent anti-proliferation effects on ovarian cancer cells (OVCAR3); it suppressed tumor growth in early stage of cancer development; and prolonged survival of all ABZ treated mice by i.p administration. The major contributions from this study are: ABZ i.p treatment increases survival, inhibits ascites production, reduces tumor burden at relatively early stage of cancer, changes tumor morphology and reduces vascular density, reduces CA-125 (cancer antigen 125) and VEGF level, decreases in vitro VEGF secretion, and down regulates VEGF mRNA expression. The study results concluded that ABZ could be a potential anticancer agent for the treatment of peritoneal carcinomatosis by i.p administration. The significance of this study is that the fundamental results obtained from all experiments, including the major contributions and other associated works, have provided the scientific foundation for a clinical trial. Currently the maximum tolerated dose of ABZ i.p treatment in mice is on going before clinical trial and studies in related area of ABZ anticancer pathways are continuing in our laboratory.

The search for the cure for cancer is currently a multi-billion dollar industry and the search for the elusive “magic bullet”, i.e. the perfect cancer drug that would interact therapeutically with cancerous tissues while having a minimal effect on healthy cells, is the topic of many research studies in the world today. A large number of novel drugs or drug complexes and conjugates are being synthesized and subjected to rigorous evaluation in the race to find the perfect cure. ECDG (Ethylene diCysteine DeoxyGlucose) seems to have promising cancer targeting ability. Even though this compound has been described in a few publications, we could not find any reference to the current use of ECDG in oncology clinics, either as a therapeutic agent, or as a diagnostic tool for imaging purposes. It was also not possible to purchase pure ECDG anywhere in the world. This prompted us to further investigate ECDG as a possible candidate for cancer targeting research, either as an imaging agent for cancer diagnosis or complexed with an anti-cancer agent for therapeutic purposes. Detailed investigations done in our laboratory can be divided into the following categories: - Development of a synthetic method for ECDG on a multigram scale ; - Purification of prepared ECDG not using the described dialysis method that only allows the purification of small quantities of ECDG (mg scale) ; Detailed investigation of the chemistry involved in the preparation of pure ECDG and its metal complexes ; - Investigation of the stability of ECDG and its metal complexes that is essential data required for any pharmaceutical agent ; - Preparation of ECDG complexes for use as a diagnostic tool, i.e. complexation with 99mTc ; Investigation of the bio distribution of ECDG-ReO complexes ; - Preparation of an ECDG kit as a diagnostic tool for use in oncology clinics. The development of novel aromatic ligands having similar characteristics compared to ECDG, containing an N2S2 chromophore as donor atoms, to further investigate their targeting capabilities, have also been investigated. All intermediates and final compounds were characterized mainly by ESI MS, in some cases IR and NMR whenever available. Successful preparation and purification of ECDG ands its metal complexes was achieved and extensively characterized and evaluated. Efforts directed towards the development of ECDG at NECSA, South Africa, were also rewarded with significant success. Furthermore, significant development regarding the synthesis of two novel compounds with ECDG-like characteristics was also completed.

Micro ribonucleic acids (miRNAs) are pivotal post-transcriptional regulators of gene expression and if research continues to reveal positive results, they will soon be used as therapeutic targets in the clinical setting for the treatment of a variety of cancers. They are evolutionarily conserved small noncoding RNAs that range from 18 to 24 nucleotides in length. There are over 1,400 miRNAs for which abundant evidence has demonstrated fundamental importance in normal cell development and up- or downregulation when they become deregulated. The deregulation of miRNAs, which can function as tumor suppressors or oncogenes, contributes to the development of cancer, among other diseases. Deregulation of tumor suppressor miRNA can occur in many different tissues of the body and lead to a variety of cancers. Tumor suppressor let-7 negatively regulates expression of an oncogenic mRNA named RAS. In lung cancer, a decrease in let-7 produces an increase in expression of RAS, which contributes to cell proliferation and tumorigenesis. In chronic lymphocytic leukemia, Bcl2 protein becomes overexpressed due to the down-regulation of tumor suppressors miRNA-15 and miRNA-16. MicroRNA-34 plays an important role in neuroblastoma in which its expression is decreased due to mutations that decrease a tumor suppressor protein, p53. Upon deregulation of oncogenic miRNAs, tumor suppressor mRNA expression is decreased and leads to multiple types of cancer. Up-regulation of the miRNA-17-92 cluster in lung cancer leads to increased cell proliferation and contributes to angiogenesis in many cancers. In B cell lymphoma, miRNA-155 becomes up-regulated along with an RNA named BIC. This up-regulation accelerates pathogenesis and up-regulation of an oncogenic protein, c-myc. MicroRNA-21 acts as an anti-apoptotic factor by downregulating apoptosis-related genes and contributing to the development of human glioblastoma. This review summarizes the present understanding of how miRNAs function at the molecular level in the body, how their deregulation contributes to tumor formation, maintenance and metastasis and how they can be used for cancer diagnosis, prognosis and therapy. With the mass amounts of knowledge gained from the current research done on miRNAs, a cancer cure may soon be developed based on the targeting of specific miRNAs. The promise of miRNAs in cancer therapeutics will depend on the development of proper delivery strategies of miRNA mimics and inhibitors, in addition to evaluation of safe usage and toxicity of therapeutic dosages.

Increasing demands for hyperthermia (HT) as an adjuvant therapy is caused from the contributions of thermal therapy to the traditional treatments. Latest improvements in hyperthermia make it popular among thermal therapies to cure cancer in any organ or body parts. HT takes advantage of EM radiation inside the tumor that provides temperature and blood perfusion increment that helps radiation therapy and chemotherapy to be more efficient. Therefore, some advantages makes HT preferred when compared to similar treatments. Being noninvasive and painless with an efficient cooling system, and helping to shorten the application period and session number of conventional treatments are most important advantages of HT. However, existing HT systems require high input power per elements on the applicators and long application time. Designing conformal and patient specific applicators with mild application can solve this issue. Moreover, mild HT application can make cancer treatment cheaper and more accessible. The main goal in this study is to design conformal HT applicators through optimization for liver and provide a patient specific and cost-effective local hyperthermia treatment that can be widely used in local clinical cancer treatment centers without expensive applicators.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science, 2017 / Aim: The aim of this study was to quantify random and systematic setup errors in a population of head and neck cancer patients for the purposes of evaluating departmental positioning and immobilization techniques, verification and treatment protocols, as well as validating the treatment margins used. Methods and Materials: All patients had more than one phase of radiation, each consisting of different megavoltage photon field arrangements. Some phases were also treated with electron fields in addition to the photon fields. Random and systematic setup errors in all three principal directions were calculated for two groups of patients, using record and verify system couch position data. For one group (20 patients) the positioning and immobilization device system was mechanically localized to the treatment couch, and for the other group (38 patients), it was visually centered on the treatment couch. Within both groups of patients, the patient position was either verified online with portal imaging or verified offline on a conventional radiotherapy simulator. Results: For the patient group treated with the base plate visually centered on the treatment table the population random and systematic setup errors calculated for the photon fields were only indicative of setup uncertainties in the anterior-posterior direction. For the patient group treated with the base plate localized to the treatment couch, the population random and systematic setup errors were found to be within the 5 mm clinical to planning target volume expansion margin used at Livingstone Hospital. Due to treatment couch position differences from fraction to fraction, setup errors made during this study could not reliably be determined for electron field treatments Conclusions: Results indicate that the base plate should be localized to the treatment couch when calculating random and systematic setup errors for photon fields using the couch position as a surrogate for patient position. For this method to be used to calculate setup errors for electron fields, shielding should always be fastened to the same position at the endface of the applicator. Offline and online verification did not significantly influence systematic setup errors. / XL2018