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The purpose of this project is to explore the benefit of using prodrugs in chemotherapy, as well as to explain the concept of angiogenesis and the importance of this process to tumor development. Angiogenesis is the formation of new blood capillaries that are necessary for the survival of a

The purpose of this project is to explore the benefit of using prodrugs in chemotherapy, as well as to explain the concept of angiogenesis and the importance of this process to tumor development. Angiogenesis is the formation of new blood capillaries that are necessary for the survival of a tumor, as a tumor cannot grow larger than 1-2 mm3 without developing its own blood supply. Vascular disrupting agents, such as iodocombstatin, a derivative of combretastatin, can be used to effectively cut off the blood supply to a growing neoplasm, effectively inhibiting the supply of oxygen and nutrients needed for cell division Thus, VDAs have a very important implication in terms of the future of chemotherapy. A prodrug, defined as an agent that is inactive in the body until metabolized to yield the drug itself, was synthesized by combining iodocombstatin with a β-glucuronide linker. The prodrug is theoretically hydrolyzed in the body to afford the active drug by β-glucuronidase, an enzyme that is produced five times as much by cancer cells as by normal cells. This effectively creates a “magic-bullet” form of chemotherapy, known as Direct Enzyme Prodrug Therapy (DEPT).
ContributorsClark, Caroline Marie (Author) / Pettit, George Robert (Thesis director) / Melody, Noeleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2015-05
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The anthracycline drug Doxorubicin (DOX) is a highly effective treatment for breast cancer, but its clinical utility is limited by dose-dependent cardiovascular toxicity. The toxic effects are partly attributed to DOX-induced generation of reactive oxygen species, which may impair nitric oxide-mediated vasodilation. Exercise training activates antioxidant defense mechanisms and is

The anthracycline drug Doxorubicin (DOX) is a highly effective treatment for breast cancer, but its clinical utility is limited by dose-dependent cardiovascular toxicity. The toxic effects are partly attributed to DOX-induced generation of reactive oxygen species, which may impair nitric oxide-mediated vasodilation. Exercise training activates antioxidant defense mechanisms and is thus hypothesized to counteract oxidative stress when initiated prior to DOX administration. Adult 8-week old, ovariectomized female Sprague-Dawley rats were divided into 4 groups: sedentary + vehicle (Sed+Veh); Sed+DOX; exercise + veh (Ex+Veh); and Ex+DOX. Rats in the exercise groups were preconditioned with high intensity interval training consisting of 4x4 minute bouts of exercise at 85-95% of VO2peak separated by 2 minutes of active recovery performed 5 days per week. Exercise was implemented one week prior to the first injection and continued throughout the study. Animals received either DOX (4mg/kg) or veh (saline) intraperitoneal injections bi-weekly for a cumulative dose of 12 mg/kg per animal. Five days following the final injection, animals were anesthetized with isoflurane, decapitated and aortas and perivascular adipose tissue (PVAT) were removed for western blot analyses. No significant differences in aortic protein expression were detected for inducible nitric oxide synthase (iNOS) or the upstream activator of endothelial nitric oxide synthase (eNOS), Akt, across groups (p>0.05), whereas eNOS protein expression was significantly downregulated in Sed+DOX (p=0.003). In contrast, eNOS expression was not altered in Ex+DOX treated animals. Protein expression of iNOS in PVAT was upregulated with exercise in the DOX-treated groups (p=0.039). These findings suggest that exercise preconditioning may help mitigate vascular effects of DOX by preventing downregulation of eNOS in the aorta.
ContributorsO'Neill, Liam Martin (Author) / Sweazea, Karen (Thesis director) / Angadi, Siddhartha (Committee member) / Dickinson, Jared (Committee member) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
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Description
Currently, treatment for multiple myeloma (MM), a hematological cancer, is limited to post-symptomatic chemotherapy combined with other pharmaceuticals and steroids. Even so, the immuno-depressing cancer can continue to proliferate, leading to a median survival period of two to five years. B cells in the bone marrow are responsible for generating

Currently, treatment for multiple myeloma (MM), a hematological cancer, is limited to post-symptomatic chemotherapy combined with other pharmaceuticals and steroids. Even so, the immuno-depressing cancer can continue to proliferate, leading to a median survival period of two to five years. B cells in the bone marrow are responsible for generating antigen-specific antibodies, but in MM the B cells express mutated, non-specific monoclonal antibodies. Therefore, it is hypothesized that antibody-based assay and therapy may be feasible for detecting and treating the disease. In this project, 330k peptide microarrays were used to ascertain the binding affinity of sera antibodies for MM patients with random sequence peptides; these results were then contrasted with normal donor assays to determine the "immunosignatures" for MM. From this data, high-binding peptides with target-specificity (high fluorescent intensity for one patient, low in all other patients and normal donors) were selected for two MM patients. These peptides were narrowed down to two lists of five (10 total peptides) to analyze in a synthetic antibody study. The rationale behind this originates from the idea that antibodies present specific binding sites on either of their branches, thus relating high binding peptides from the arrays to potential binding targets of the monoclonal antibodies. Furthermore, these peptides may be synthesized on a synthetic antibody scaffold with the potential to induce targeted delivery of radioactive or chemotherapeutic molecular tags to only myelomic B cells. If successful, this would provide a novel alternative to current treatments that is less invasive, has fewer side effects, more specifically targets the cause of MM, and reliably diagnoses the cancer in the presymptomatic stage.
ContributorsBerry, Jameson (Co-author) / Buelt, Allison (Co-author) / Johnston, Stephen (Thesis director) / Diehnelt, Chris (Committee member) / School of Molecular Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Division of Teacher Preparation (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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Description
Estimates indicate that in the United States 1 in 8 women will develop breast cancer in their lifetime. Improved cancer screenings, early detection, and targeted treatments have increased breast cancer survival rates. However, breast cancer patients treated with chemotherapy are at an increased risk for cardiovascular disease, functional impairments, and

Estimates indicate that in the United States 1 in 8 women will develop breast cancer in their lifetime. Improved cancer screenings, early detection, and targeted treatments have increased breast cancer survival rates. However, breast cancer patients treated with chemotherapy are at an increased risk for cardiovascular disease, functional impairments, and loss of cardiorespiratory fitness. These negative outcomes have implications for early morbidity and mortality. The purpose of this thesis was to test the hypothesis that high-intensity exercise preconditioning (exercise commenced prior to initiating chemotherapy and continued throughout treatment cycles) preserves health-related outcomes in breast cancer patients treated with anthracycline-containing chemotherapy. Here, we present a subset of preliminary data from an ongoing trial (NCT02842658) that is focused on VO2peak and skeletal muscle outcomes from the first 10 participants that have enrolled in the trial. Breast cancer patients (N=10; 50 ± 11 y; 168 ± 4 cm; 92 ± 37 kg; 32.3 ± 12.3 kg/m2) scheduled to receive anthracycline-containing chemotherapy were randomly assigned to one of two interventions: 1) exercise preconditioning, (3 days per week of supervised exercise throughout treatment) or 2) standard of care (attention-control). Pre-testing occurred 1-2 week prior to chemotherapy. The interventions were initiated 1 week prior to chemotherapy and continued throughout anthracycline treatment. Post-testing occurred 3-7 days following the last anthracycline treatment. VO2peak (L/min) was reduced by 16% in the control group (P < 0.05), whereas VO2peak was preserved in the exercise preconditioning group. Trends for greater preservation and/or improvement in the exercise preconditioning group were also observed for lean body mass and peak heart rate. Hand grip strength was not changed in either group (P > 0.05). Both groups demonstrated an increase in ultrasound-derived echogenicity measures of the vastus lateralis (P < 0.05), indicating changes in the composition of the skeletal muscle during treatment. These preliminary data highlight that exercise preconditioning may serve as a strategy to preserve cardiorespiratory fitness and perhaps lean mass during anthracycline treatment of breast cancer. There remains a need for larger, definitive clinical trials to identify strategies to prevent the array of chemotherapy-induced toxicities that are observed in breast cancer patients treated with anthracyclines.
ContributorsCasey, Kathleen (Author) / Angadi, Siddhartha (Thesis director) / Gaesser, Glenn (Committee member) / Dickinson, Jared (Committee member) / College of Health Solutions (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05