Browsing by Subject "Breast--Cancer--Chemotherapy"

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Investigation of the effects of [alpha]-TEA, 9-nitrocamptothecin and paclitaxel alone and in combination on 66cl-4-GFP murine mammary cancer cells in vitro and in vivo
(2007-12) Latimer, Paul Brian, 1976-; Sanders, Bob G.; Kline, Kimberly
Second only to lung cancer, breast is the leading type of cancer among women in the US. Despite all the medical advances over the past few decades, toxicity and increased resistance to standard drug therapy still remains a significant problem. The heterogeneic nature of all cancers has led to a shift in treatment approaches, in that more research is being carried out with combination treatments in the hope that a multidirectional targeting of cancer will be far more effective than the current single treatment options. Our goal was to gain a better understanding of the molecular mechanisms of a nonhydrolyzable ether analog of RRR-[alpha]-tocopherol, 2, 5, 7, 8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (abbreviated [alpha] -TEA), and to investigate its efficacy when used in combination with known chemotherapeutics 9-nitro-camptothecin (9NC), and Paclitaxel (Taxol). The data presented here looks encouraging as it shows a clinically relevant delivery method using [alpha]-TEA and 9NC has the unique ability to reduce primary tumor burden as well as macro and micrometastatic lung and lymph node lesions in an aggressive syngeneic mouse mammary model, while displaying no obvious toxic side effects. The effect of combination treatments on tumor volume appears in part to be moderated by an increase in tumor cell apoptosis and a decrease in tumor cellular proliferation. Next, the intricate molecular mechanism of how [alpha]-TEA alone and in combination with 9NC is able to induce apoptosis in 66cl-4-GFP murine mammary cancer was investigated. The data suggest that the signaling pathway that ultimately leads to apoptosis is caspase dependent, is able to upregulate pro-death players while at the same time downregulate pro-survival proteins such as c-Flip and survivin. Finally, we investigated the efficacy of [alpha]-TEA used in an allograft mouse model following treatment with Taxol. Combination treatments were able to significantly reduce primary tumor burden, decrease lung and lymph node micrometastases, tumor cell proliferation, tumor blood vessel density as well as increase tumor cell apoptosis. Based on the results presented, we propose that [alpha]-TEA when used alone and in combination is an effective, non-toxic option for cancer treatment which warrants further investigation.
Studies of the antitumor activity of [alpha]-TEA in human breast cancer cells
(2006) Wang, Pei; Sanders, Bob G.
Breast cancer is the most common cancer among women and is the second leading cause of cancer deaths among women in the United States. An effective chemotherapeutic drug is greatly needed for breast cancer. In order to develop a stable and clinically useful vitamin E-based chemotherapeutic agent, a nonhydrolyzable ether linked acetic acid analogue of RRR-a-tocopherol, namely, a-TEA has been produced. a-TEA exhibits strong antitumor activity in tumor cells but has no effect on normal cells. Since a-TEA is hydrophobic, formulation into appropriate carrier systems to potentiate delivery is needed. The anticancer efficacy of a-TEA formulated into liposomes or nanoparticles has been assessed in this study. a-TEA formulated in either nanoparticles or liposomes at 5 mg/day was very effective in inhibiting tumor growth and visible lung metastases, as well as lung and lymph node micrometastatic lesions. a-TEA at 2.5 mg/day formulated in nanoparticles was more effective than a-TEA at 2.5 mg/day formulated in liposomes in reducing tumor burden and lymph node and lung micro-metastatic tumor foci; however, the difference could be attributed to a nanoparticle effect rather than an a-TEA effect since nanoparticles alone significantly reduced tumor burden and metastases. These studies show that oral delivery of a-TEA at an appropriate dosage formulated in either liposomes or nanoparticles to be effective, clinically relevant means for administrating this hydrophobic drug. In the mechanistic studies of a-TEA, over 400 potential targets have been identified in a-TEA treated MDA-MB-435 cells using microarray analyses. Thirty four genes were of interest for their possible involvement in the known biological activities of a-TEA. Three genes, Arg, TSP-1 and NOXA were further studied. The proapoptotic BH3 only protein NOXA was studied in detail. Data show that NOXA induction was involved in a-TEA-induced mitochondria-dependent apoptosis in human breast cancer cells and NOXA expression was mediated through JNK-p73 signaling pathway. From the data reported in this thesis, we now have a better understanding of how a-TEA functions as a promising anticancer drug, and more importantly, how to efficiently use it as a chemotherapeutic reagent.
Utilities of metastatic breast cancer patients treated with taxanes compared to utilities of oncology nurses
(2001-08) Hauser, Robert Sean, 1972-; Koeller, Jim
Utility analyses are rapidly becoming a standard measure for many oncology studies. A recent publication in JCO reported utility scores obtained from 40 published studies and presented the results in a league table format (Earl et al. J Clin Oncl, 2000;18(18): 3302- 2217). The majority of the studies utilized healthcare professionals (nurses and physicians) as proxies for the patients with the disease state studied. The main objective of this study was to determine if there is a significant difference between utility scores obtained from metastatic breast cancer patients and oncology nurses. Using eight Markov modeled health states describing metastatic breast cancer; the standard gamble procedure was utilized to obtain utility scores from 45 patients and 57 oncology nurses. Utility values are measured on a scale between 0.0 and 1.0. Independent t-tests were used to test for differences between groups using an alpha level of 0.05. Significant differences (all p values <0.001) were found on all eight modeled health states. Patients reported a utility score of 0.84 (sd=0.11) compared to 0.71 (sd=0.22) reported by nurses on the “Partial Response (PR)” health state. Patients reported a utility score of 0.78 (sd=0.17) compared to 0.63 (sd=0.24) reported by nurses on the “PR with Severe Peripheral Edema” health state. Patients reported a utility score of 0.76 (sd=0.13) compared to 0.56 (sd=0.24) reported by nurses on the “PR with Severe Peripheral Neuropathy” health state. Patients reported a utility score of 0.73 (sd=0.16) compared to 0.59 (sd=0.22) reported by nurses on the “Before Second Line Treatment Begins” health state. Patients reported a utility score of 0.72 (sd=0.15) compared to 0.54 (sd=0.22) reported by nurses on the “Stable Disease” health state. Patients reported a utility score of 0.63 (sd=0.18) compared to 0.45 (sd=0.25) reported by nurses on the “Late Progressive Disease” health state. Patients reported a utility score of 0.40 (sd=0.26) compared to 0.19 (sd=0.21) reported by nurses on the “Terminal Disease” health state. Patients reported a utility score of 0.39 (sd=0.25) compared to 0.20 (sd=0.23) reported by nurses on the “Sepsis” health state. These results suggest that patients have a higher utility for health than nurses perceive the patients as having. Furthermore, these results may show that when performing cost-utility analysis, that a patient utility measure should be incorporated into the decision model rather than a proxy score obtained by a healthcare professional. Further studies should compare patients in other disease states with healthcare professionals to see if these results hold true for other disease states. These results also lead to the question of who’s utility values should we use for cost-utility analysis in oncology.