Browsing by Subject "Chemotherapy"
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Item Development of an inhalational formulation of Coenzyme Q₁₀ to treat lung malignancies(2011-12) Carvalho, Thiago Cardoso; McConville, Jason ThomasCancer is the second leading cause of death in the United States and its onset is highly incident in the lungs, with very low long-term survival rates. Chemotherapy plays a significant role for lung cancer treatment, and pulmonary delivery may be a potential route for anticancer drug delivery to treat lung tumors. Coenzyme Q₁₀ (CoQ₁₀) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. In this work, we hypothesize that formulations of CoQ10 may be developed for pulmonary delivery with a satisfactory pharmacokinetic profile that will have the potential to improve a pharmacodynamic response when treating lung malignancies. The formulation design was to use a vibrating-mesh nebulizer to aerosolize aqueous dispersions of CoQ₁₀ stabilized by phospholipids physiologically found in the lungs. In the first study, a method was developed to measure the surface tension of liquids, a physicochemical property that has been shown to influence the aerosol output characteristics from vibrating-mesh nebulizers. Subsequently, this method was used, together with analysis of particle size distribution, zeta potential, and rheology, to further evaluate the factors influencing the capability of this nebulizer system to continuously and steadily aerosolize formulations of CoQ₁₀ prepared with high pressure homogenization. The aerosolization profile (nebulization performance and in vitro drug deposition of nebulized droplets) of formulations prepared with soybean lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) were evaluated. The rheological behavior of these dispersions was found to be the factor that may be indicative of the aerosolization output profile. Finally, the pulmonary deposition and systemic distribution of CoQ₁₀ prepared as DMPC, DPPC, and DSPC dispersions were investigated in vivo in mice. It was found that high drug amounts were deposited and retained in the mouse lungs for at least 48 hours post nebulization. Systemic distribution was not observed and deposition in the nasal cavity occurred at a lower scale than in the lungs. This body of work provides evidence that CoQ₁₀ may be successfully formulated as dispersions to be aerosolized using vibrating-mesh nebulizers and achieve high drug deposition in the lungs during inhalation.Item Impact of age on the chemotherapy treatment and outcomes of advanced colorectal cancer int he community oncology setting(2007-08) McKibbin, Trevor; Koeller, JimPurpose: Current literature regarding the treatment of advanced colorectal cancer (CRC) suggests elderly patients receive the same benefits from treatment as younger patients with a slightly higher of incidence of hematologic toxicity. However, the clinical trials on which this suggestion is based enrolled a small number of elderly patients and were not powered to determine differences based on age group. Clinical trials often maintain strict inclusion and exclusion criteria and may not be representative of the general population treated in community oncology practices. This study evaluated the treatment of advanced CRC in community oncology practices focusing on age-related differences in treatment and outcome. Methods: The primary objective was to compare the proportion of patients receiving combination chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age ≤ 65 years) and elderly (age > 65 years) patients. Secondary objectives included an age based comparison of: 1) the addition of bevacizumab to the initial regimen; 2) overall chemotherapy and monoclonal antibody utilization; 3) death due to advanced CRC; 4) toxicity-related dose changes, delays, chemotherapy and monoclonal antibody therapy changes, hospitalizations and additional clinic visits; and 5) toxicity leading to one of the events listed in the preceding endpoint. Medical records of patients receiving chemotherapy for advanced CRC in community oncology clinics after January 1, 2003 were reviewed. Patient demographics, prior therapy history, chemotherapy regimens, monoclonal antibody therapies, toxicity data, and date of last follow-up or death were collected. Results: Overall, 444 patients (203 ≤ 65 years and 241 > 65 years) with a median follow-up of 303 days, receiving 5,305 cycles of chemotherapy were included. Of the younger patients, 81% received first-line combination chemotherapy compared to 61% of elderly patients (p<0.0001). The utilization of each of the medications: irinotecan, oxaliplatin and bevacizumab was lower in the elderly patients compared to the younger patients (p<0.0001). Progression-related mortality was higher in the elderly cohort compared to the younger patients, 41% and 32% respectively (p=0.02). In the multivariate regression model, age group was no longer predictive of mortality. Better performance status and shorter follow-up were significantly associated with improved survival. Diarrhea was reported significantly more frequently in the elderly population, whereas neutropenia and neurotoxicity occurred more frequently in the younger patients. Conclusions: Elderly patients were less likely to receive first-line combination chemotherapy compared to younger patients and were more likely to experience progression-related mortality.Item Induction of apoptosis and cell cycle arrest in renal carcinoma cells by phenethyl isothiocyanate and the mechanisms involved(2011-05) Khan, Maruf; DeGraffenried, Linda; Ciolino, Henry P.; Sanders, Bob G.; Nunez, Nomeli P.; Fischer, Susan M.Renal Cell Carcinoma (RCC) has low 5 year survival rate and is resistant to radiation and chemotherapy. Phenethyl Isothiocyanate (PEITC) is a naturally occurring phytochemical that has a variety of anti-cancer properties. Here we explore two anti-cancer properties of PEITC: induction of apoptosis and induction of cell cycle arrest in RCC cells and the underlying mechanisms. We used two human RCC cell lines Caki-1 and Caki-2. Survival and cell proliferation was assayed using Calcein AM. Annexin V staining was used to measure apoptosis. Caspase-3/7 induction was measured using a fluorescent substrate. Cell cycle was studied using Propidium Iodide staining. DNA damage was determined using phospho [gamma]-H2AX antibody. Protein expression and phosphorylation was determined using immunoblotting. PEITC significantly reduced survival of Caki-1 and Caki-2 cells and inhibited their proliferation as determined by Calcein AM. 15 and 20 [mu]M PEITC induced apoptosis in both cell lines and induced caspase-3/7 activity. Western blot analysis revealed caspase-8, caspase-9 and Bid cleavage as well as upregulation of the death receptors Fas and DR5. Lower doses (up to 10 [mu]M) arrested Caki-1 cells in G2/M phase, and this was associated with increased p38 and MK2 (Thr334) phosphorylation. The p38 inhibitor SB203850 inhibited this G2 arrest induced by PEITC. 15 and 20 [mu]M PEITC treatment resulted in increased [gamma]-H2AX phosphorylation suggesting DNA damage, but this was completely blocked by caspase inhibitor. In summary, our study shows that PEITC induces apoptosis in Caki-1 and Caki-2 cells by upregulating Fas and DR5 and activating the downstream apoptosis cascade. PEITC does not cause direct DNA damage to the cells; the observed DNA damage is a result of the apoptotic process and is blocked by caspase inhibitor. PEITC induces G2/M arrest in Caki-1 cells and the mechanism involves p38 phosphorylation which activates MK2. Inducing cell cycle arrest and apoptosis may play an important role in the anti-cancer properties of PEITC. Fully understanding the mechanism by which PEITC induces apoptosis and cell cycle arrest in RCC cells may lead to development of novel chemotherapeutic drugs against RCC.Item Mechanisms and dynamics of survival in the treatment of ovarian cancer(2022-10-25) Vilas, Caroline Kate; Lee, Seongmin; Brock, Amy; Matsui, William; Dalby, Kevin; Iyer, VishwanathHigh-grade serous ovarian cancer (HGSOC) accounts for up to 80% of deaths from ovarian cancer, and overall survival has not improved much in decades. This is largely due to vast genome instability and genetic heterogeneity in HGSOC which contribute to chemoresistance. This substantial heterogeneity has been shown to result in the presence of rare pre-existing resistant clones in the tumor and the development of acquired resistance. Alongside paclitaxel, mutagenic platinum-based drugs remain the treatment mainstay for HGSOC. While cytotoxic, platinum-based drugs also increase genome instability, heterogeneity and chemoresistance. Such extensive heterogeneity promotes unique evolutionary trajectories that warrant detailed characterizations. In a multi-scale analysis, this dissertation leverages approaches from two disciplines to better understand the mechanisms and dynamics of survival in the treatment of ovarian cancer. The cisplatin-1,2-d(GpG) (Pt-GG) intrastrand cross-link is the major lesion produced by cisplatin and carboplatin and contributes to a predominant C:A mutation signature through the misincorporation of dATP opposite Pt-GG by polymerases such as DNA polymerase β (polβ). Using X-ray crystallography, we report the first structures of polβ misincorporating dATP opposite Pt-GG and demonstrate Pt-GG behaves like an abasic site to promote the misinsertion of dATP in a non-instructional manner, elucidating a molecular mechanism contributing to platinum-induced mutagenesis. We also conduct a systems level study of the clonal dynamics and mechanisms underlying HGSOC survival to chemotherapy using a multi-functional lineage tracing approach, ClonMapper, which combines clonal tracking with single-cell RNA sequencing and clonal isolation for further characterizations. We demonstrate that pre-existing features drive survival of clones, enabling a shift to a treatment-induced cell state characterized by cell growth (mTORC1, TNF-α signaling via NF-κB, Hedgehog signaling, androgen response), stress response (EMT, hypoxia, mitotic spindle, interferon response), and metabolism (glycolysis, oxidative phosphorylation). Genetic features underlie a rapid transition to this cell state in rare clones of one cell line. We also demonstrate successful isolation of a rare pre-existing resistant clone from pre-treatment for genomic and epigenetic characterizations. By harnessing two separate approaches, we gain a more holistic understanding of the mechanisms and dynamics underlying HGSOC survival to chemotherapy and provide insights into improving drug design and therapeutic strategies.Item Nanosystems for combined therapy and imaging of pancreatic cancer(2010-12) Homan, Kimberly Ann; Brannon-Peppas, Lisa, 1962-; Emelianov, Stanislav Y.; McGinity, James; Tunnell, James; Stevenson, Keith; Brown, Richard; Sokolov, KonstantinPancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. The objective of this thesis is to create innovative tools to better understand and improve chemotherapeutic treatment of pancreatic cancer. Towards this end, nanosystems were designed with a dual purpose: to carry chemotherapeutic drugs and act as photoacoustic imaging contrast agents. The overarching hypothesis is that these nanosystems can provide enhanced therapy for pancreatic cancer and enable visualization of drug delivery. Demonstrated in this dissertation is the design, synthesis, and characterization of two such nanosystems built to carry the chemotherapeutic agent gemcitabine while acting as a photoacoustic imaging contrast agent. The nanosystems were also shown to be multifunctional with possible application as photothermal therapy agents and cellular functional sensors. Although future research is required to fully investigate the clinical potential of these systems for pancreatic cancer, the work presented in this dissertation is a step towards creation of multifunctional nanosystems that will enable non-invasive, in vivo photoacoustic imaging of drug delivery.Item Physical forces from the extracellular matrix influence breast cancer cell response to doxorubicin(2018-12-07) Joyce, Marshall Hunter; Brock, Amy; Suggs, Laura; Rylander, Marissa N; Zoldan, JanetCancer is a complex disease capable of affecting multiple organs and is driven by numerous factors. Certain ‘hallmarks of cancer’ have been identified which describe biological conditions that lead to tumor development and characteristics that often follow tumorigenesis. These hallmarks have been revisited to describe the role that the extracellular matrix (ECM) plays in each. Such observations make it evident that the ECM is an important factor in tumor initiation, progression, and metastasis and can no longer be ignored in the search for a cure. Studies aimed at characterizing the role physical cues play in tumor development have considered ligand variety, ligand density, substrate composition, and substrate stiffness. These studies frequently utilize hydrogels as a culture platform given the biological relevance and diversity achievable through such a platform. Though the stiffness of hydrogels can be attenuated at the onset of an experiment, few systems are able to alter stiffness once gelation is complete. This makes any study of progressive changes in ECM stiffness difficult and largely restricts the study of certain temporal aspects of tumor progression in vitro. Recently, a Matrigel-alginate hydrogel system has been described whereby progressive modulation of hydrogel stiffness can be achieved using liposomes loaded with gold nanorods and near infrared light. In this study we utilize this hydrogel system to thoroughly investigate the role that ECM stiffness has on breast cancer response to doxorubicin. We sought to observe how progressive stiffening of the ECM affected breast cancer cell response to clinically relevant chemotherapeutics in a system that allows for minimal perturbation of cells during the stiffening process. Our results showed that breast cancer cells exhibiting a mesenchymal phenotype had a stiffness-dependent resistance to the chemotherapeutic doxorubicin. Mathematical modeling was used to determine reduced growth rate alone was not sufficient to explain this stiffness-dependent resistance, suggesting an additional mechanism associated with the mesenchymal phenotype is responsibleItem Treatment patterns and healthcare resource utilization and payments in patients with lung cancer in the Texas Medicaid program(2023-08) Ma, Xiaojing, M.S.P.S.; Lawson, Kenneth Allen, 1952-; Barner, Jamie C.; Richards, Kristin M.; Novak, SuzanneThe economic burden associated with the treatment of lung cancer is substantial. With the introduction of targeted therapy and immunotherapy, treatment options for lung cancer management have expanded in recent years. However, little is known about treatment patterns and healthcare utilization and payments for lung cancer patients enrolled in the Texas Medicaid program. The objective of this study was to evaluate treatment patterns and healthcare resource utilization and payments for lung cancer patients enrolled in Texas Medicaid. A total of 453 newly diagnosed lung cancer patients were identified between 2004 and 2021. There were significant differences in proportions of patients receiving chemotherapy, targeted therapy, and immunotherapy by treatment line (p<0.0001). Chemotherapy was the most frequently prescribed first-line treatment for enrollees with lung cancer (363, 80.1%). Immunotherapy (53, 11.7%), the second most used first-line treatment, exceeded targeted therapy (37, 8.2%). Only one-third (146) of patients received subsequent-line treatment, in which immunotherapy increased greatly. Platinum-based doublets were the main first-line treatment while single-agent chemotherapy dominated in subsequent line. Office visits (mean=19.5) and outpatient visits (mean=13.6) accounted for the majority of healthcare resource utilization during the 1-year follow-up period. Compared to the chemotherapy group, immunotherapy had a significantly higher number of office visits while targeted therapy had a significantly lower number of office visits. Targeted therapy also had a significantly lower number of ED visits. Consistent with healthcare resources utilization, payments associated with office visits and outpatient visits were primary drivers of payments. Compared to the chemotherapy group, the immunotherapy group had 160.93% higher total payments (p<0.0001), while the targeted therapy group had 29.99% lower total payments (p=0.1818). Findings from our study showed that although chemotherapy was still the mainstream treatment for lung cancer, the treatment landscape has shifted to immunotherapy. This could be attributed to a decreased utilization of chemotherapy and increased utilization of immunotherapy in subsequent-line treatment. Meanwhile, the greater use of immunotherapy might be a driving factor for more outpatient visits and office visits associated with higher payments. Future studies of real-world use of immunotherapy are needed to better understand the economic burden.