Pancreatic cancer (PC) is known to be highly resistant to chemotherapy. Transporters, which regulate the influx and efflux of substrates across the plasma membrane, may play a role in PC drug resistance. ABC transporters are a large family of transmembrane proteins with diverse physiological functions, several of which play major roles in cancer drug resistance. Given that 90% of PC express a mutant K-ras oncogene and that PC are highly hypoxic, I postulated that constitutive K-ras activation and/or hypoxia may correlate with ABC transporter expression, which in turn may promote drug resistance in PC. Using normal and PC cell lines either overexpressing mutant K-ras or subjected to hypoxic treatment, mRNA expression was profiled for 48 ABC transporters. My findings indicate that expression of mutant K-ras and hypoxic treatment, as well as long-term exposure to chemotherapy, may contribute to the development of drug resistance in PC cells in part by inducing the expression of ABC transporters. Similar to ABC transporters, I investigated whether amino acid transporters would mediate drug resistance in PC. The Xc⁻ amino acid transporter (Xc⁻) mediates cellular uptake of cystine for the biosynthesis of glutathione, a major detoxifying agent. Because the Xc⁻ has been regulates the growth of various cancer cell types, and Xc⁻ is expressed in the pancreas, I postulated that the Xc⁻ may be involved in growth and drug resistance in PC. The Xc⁻ transporter is differentially expressed in normal pancreatic tissues and is overexpressed in PC in vivo. Using PC cell lines, I found that cystine uptake via the Xc⁻ was required for growth and survival in response to oxidative stress, and that expression of the Xc⁻ correlated with gemcitabine resistance. Accordingly, inhibition of Xc⁻ expression via siRNA reduced PC cell proliferation and restored sensitivity to gemcitabine. I also identified the anti-inflammatory drug sulfasalazine as a mixed inhibitor of the Xc⁻, which acts to inhibit cell proliferation via reducing Xc⁻ activity and not by reducing NFKB activity. My findings thus indicate that the Xc⁻ plays a role in PC growth in partby contributing to glutathione synthesis to promote PC cell proliferation, survival, and drug resistance.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 6 uppsatser.

Diss. (sammanfattning) Umeå : Umeå universitet, 2005. / Härtill 5 uppsatser.

Thesis (Ph. D.)--Drexel University, 2007. / Includes abstract and vita. Includes bibliographical references (leaves 120-128).

Resumo: Câncer é essencialmente caracterizado pelo crescimento desordenado de células que invadem órgãos e tecidos, sendo considerado atualmente um sério problema de saúde pública mundial. A despeito do atual e bem sucedido combate à doença, ainda permanecem em aberto questões relativas ao bom desempenho de suas modalidades de tratamento. Em particular, a quimioterapia anti-neoplásica carece de maior entendimento quantitativo e analítico. Assim sendo, propomos aqui um modelo matemático de equações diferenciais ordinárias, com o intuito de analisar as estratégias de administração de agentes quimioterápicos. Focamos nossa investigação nos protocolos antiangiogênicos e, a fim de aproximar-se da prática clínica, utilizamos dados experimentais, quando disponíveis, para simulações numéricas. Frente às implicações do tratamento oncológico, nossos resultados indicam que a administração de baixas doses e longos intervalos de tempo entre as dosagens estão relacionados ao fracasso terapêutico. Além disso, segundo o modelo proposto, a quimioterapia metronômica, se comparada ao regime convencional de tratamento, confere ao paciente um aumento de sobrevida. Por assim dizer, os protocolos antiangiogênicos podem ser uma alternativa aos pacientes oncológicos sem perspectiva de cura do câncer / Abstract: Cancer is essentially characterized by the uncontrolled growth of cells that invade organs and tissues and it is now considered a serious public health problem worldwide. Despite the current and successful fight against the disease, there are some important questions concerning the efficient performance of its treatment modalities. In particular, the anti-cancer chemotherapy requires further quantitative and analytical understanding. So, we described here a mathematical model of ordinary differential equations, in arder to analyze the chemotherapeutic schedules. We focus our research on antiangiogenic schedule and, in order to get closer to clinical practice, we use some experimental data for numerical simulations. At the implications for cancer therapy, our results indicate that administration of low doses and longer intervals between doses are related to therapeutic failure. Moreover, according to the model, metronomic chemotherapy, compared to the conventional treatment, gives the patient an increased survival. Thus, the antiangiogenic scheduling can be an alternative to cancer patients with no prospect of curing cancer / Orientador: Paulo Fernando de Arruda Mancera / Coorientador: Suani Tavares Rubim de Pinho / Banca: Hyun Mo Yang / Banca: Marcelo Messias / Mestre

The incidence of nasopharyngeal carcinoma (NPC) is high in Southeast China, including Hong Kong. Current therapy on NPC relies largely on radiotherapy and chemotherapy, but treatment failures remain the major challenge for advanced stage and recurrent/metastatic NPC. Previous studies indicated that after completion of primary treatment, the tumor recurrent rate for NPC was between 15% and 58%. Recent researches suggest the existence of cancer stem cells (CSCs). CSC refers to a sub-population of cells within the bulk tumor. CSCs exhibit the stem cell property of self-renew and differentiation, and are responsible for sustaining tumorigenesis and establishing the heterogeneity in the tumor. CSCs are generally more resistant to conventional treatment methods and might be responsible for tumor recurrent after treatment. Therapies that can eliminate cells with CSCs-characteristics might provide a more durable response and better prognosis. Sulforaphane (SFN) is a natural compound present in Cruciferous vegetables. SFN has been shown to inhibit the in vitro and in vivo growth of various types of tumor cells through the (i) induction of cell cycle arrest and apoptosis, (ii) inhibition of angiogenesis and metastasis, and (iii) suppression of cancer stem cells (CSCs). However, the effects of SFN on NPC have not been examined in detail. The present study aims to study the anti-tumor activities of SFN on NPC. In the first part of this study, the effects of SFN on the in vitro growth of NPC cells were examined. The growth of both EBV-negative HONE-1 and EBV-positive C666-1 cells was found to be inhibited by SFN. The growth inhibition was associated with the induction of G2/M cell cycle arrest and apoptosis. The effects of SFN on the growth of NPC cells with CSCs characteristics were also examined by the tumor spheres formation assay. SFN was found to reduce the capacity of both HONE-1 and C666-1 cells to form CSCs-enriched tumor spheres. The population of cells with high expression of NPC CSCs-associated markers (Sox2 and ALDH) was found to be reduced after SFN treatment. Under the culture conditions for CSCs, ALDH inhibitor was found to reduce the capacity of NPC cells to form tumor spheres. Similarly, the capability of Sox2 siRNA-treated NPC cells to form tumor spheres was also reduced in the spheroids assay. Results from these studies indicated that the growth of NPC cells with CSCs characteristics could be reduced by SFN. After the in vitro study of SFN on the growth of NPC cells, mechanisms that are associated with the SFN-induced growth inhibition on NPC cells were examined. MIF is a NPC biomarker that is highly expressed in NPC patients. Previous study has shown that SFN could interact with MIF and affect the biological function of MIF. In the present study, SFN was found to down-regulate the expression of MIF in NPC cells. One of the receptors of MIF, CXCR2, was found to be down-regulated after the SFN treatment. The downstream Akt signaling was also inhibited. Results from the second part of this study indicated that SFN-mediated inhibition of MIF/CXCR2/Akt signaling was involved in the growth inhibitory effects of SFN on NPC cells. In NPC, many genes were found to be down-regulated through hypermethylation and such down-regulation contributed to NPC development. In the present study, DNMT1 was found to be down-regulated after SFN treatment, and the effect was accompanied with the restored expression of WIF1 and Rassf1a. Further mechanistic study showd that siRNA-mediated DNMT1 knock-down could reduce the capacity of tumor spheres formation of NPC cells. Interestingly, the expression of the tumor suppressor genes WIF1 and Rassf1a was restored. In addition, exogenously added WIF1 could reduce the formation of tumor spheres. These findings suggested that SFN-mediated down-regulation of DNMT1 was associated with the growth inhibitory effects of SFN on NPC cells. Finally, the in vivo efficacy of SFN alone or SFN in combination with cisplatin on the growth of NPC xenograft was examined. SFN was found to inhibit the growth of C666-1 xenograft and enhance the anti-tumor effects of cisplatin on the C666-1 xenograft. Taken together, results from this study demonstrated the anti-tumor effects of SFN in NPC and suggested that SFN could be a potential therapeutic drug for NPC.

Master of Science / Department of Kinesiology / Carl Ade / Background – Chemotherapy-induced left ventricular cardiotoxicity is associated with many cancer treatments; however, what is less known is how these treatments affect vascular health and autonomic control of blood pressure. Arterial stiffness and cardiovagal baroreflex sensitivity (BRS) are indicators of cardiovascular health and may provide insight into the adverse effects of anti-cancer chemotherapy. Therefore, the primary aims of the present study were to evaluate carotid artery stiffness and arterial BRS in cancer patients currently being treated with adjuvant chemotherapy. Methods – We performed a cross-sectional, case-control study involving 9 cancer patients and 9 age- and sex-matched controls. Carotid artery stiffness was assess via 2D ultrasonography. Cardiovagal BRS was assessed from the spontaneous changes in beat-to-beat time series of R-R interval and systolic blood pressure via the cross correlation technique. Results – Our findings indicated a significant decrease in cardiovagal BRS in cancer patients compared to controls (4.7 ± 0.6 vs 9.2 ± 1.7 msec mmHg⁻¹ respectively, P = 0.02). Carotid artery β-Stiffness was significantly higher in the cancer patients compared to control participants (9.2 ± 1.2 vs 6.6 ± 0.74 U respectively, P = 0.05). Conclusions – These data suggest that anti-cancer chemotherapy elicits significant decreases in the autonomic control of blood pressure and arterial stiffness, leaving cancer survivors with an increased risk of future cardiovascular disease.

Ipratropium bromide is a short-acting, non-selective, muscarinic antagonist frequently prescribed for the treatment of Chronic Obstructive Pulmonary Disease (COPD) and as an emergency adjunct therapy for acute asthma. Within the past decade, there has been an accumulating wealth of clinical evidence which indicates that anti-muscarinic drugs, such as ipratropium, are responsible for an increased risk of stroke or, an adverse cardiovascular outcome (including increasing the risk and severity of myocardial infarction (MI)). MI remains the highest risk factor of death for COPD patients due to the systemic co-morbidities associated with COPD, which includes ischaemic heart disease (IHD). Despite the knowledge that approximately 22% of COPD patients also suffer from underlying IHD, the cardiovascular safety of muscarinic antagonists, such as ipratropium, has not been tested in a non-clinical setting of IHD or MI. In order to address this, the current project was designed to investigate, for the first time, the effects of ipratropium on the myocardium in a non-clinical setting. It was identified that under normoxic conditions, ipratropium did not have a significant effect on cardiac myocyte viability or infarction, from 3 month Sprague Dawley rats. In addition to this, following simulated ischaemia, ipratropium also did not appear to exacerbate myocardial injury. However, when ipratropium was administered in the context of simulated ischaemia followed by reperfusion, there was a significant exacerbation in myocardial injury which was characterised by increases in infarction, apoptosis, necrosis and a loss of resilience of oxidative stress. In order to characterise the mechanism by which ipratropium exerts the observed cardio-toxic effects, it was investigated whether acetylcholine (ACh) or cyclosporin A (CsA) were capable of attenuating the ipratropium induced cardiotoxicity. Both agents showed significant limitation of injury when co-administered with ipratropium indicating that ipratropium exerts its cardio-toxic effect through a mechanism which links muscarinic signalling to the mitochondrial permeability transition pore (mPTP). This supports previously published work where the protective signalling of ACh has been shown to promote the phosphorylation of pro-survival kinases, such as Akt and Erk1/2 and that this provides inhibition of the mPTP. Western blotting was employed to identify whether there was an involvement of the pro-survival kinases Akt and Erk1/2, as well as the stress induced kinase JNK. Ipratropium significantly increased levels of phospho-Akt and phospho-Erk1/2. However, JNK levels appeared to be insignificantly altered in comparison with the control groups. Both ACh and CsA were capable of limiting these increases. Further to this, an aged study was carried out, which showed that, within the aged myocardium, ipratropium is capable of eliciting further injury in comparison with the 3 month age groups. The effect of ipratropium on tolerance of oxidative stress was not significant, but, also, ACh and CsA were shown as unable to protect. Significant levels of JNK were also observed in the aged animals in comparison with the 3 month groups. In combination, the results presented here demonstrate, for the first time, that ipratropium is capable of exacerbating ischaemia/reperfusion injury in in vitro models of myocardial ischaemia/reperfusion. In addition, ACh and CsA are capable of limiting this injury, implying a role for pro-survival kinases and the mPTP in ipratropium induced myocardial injury. In the aged study, ipratropium still exacerbated injury, however, ACh and CsA appeared unable to protect, therefore promoting previous work that cellular signalling is altered in the senescent myocardium. In conclusion, further studies must be carried out in order to fully characterise the cardio-vascular safety profile of ipratropium.

Breast cancer in South Africa has become one of the most prominent cancers affecting women. Worldwide, breast cancer results in more deaths amongst women than any other cancer (Vorobiof, 2001). Chemotherapy has become one of the most effective and commonly used adjuvant forms of treatment in breast cancer. However, despite its effectiveness, it has a variety of side effects ranging from nausea, fatigue, vomiting, alopecia to many others. Due to the significant levels of discomfort and disability associated with chemotherapy, patients often seek additional treatment to assist with these side effects. Many individuals combine complementary and alternative therapies with conventional treatment of their cancer (Breasthealth, 2005). Homoeopathy is often used to alleviate the side-effects resulting from the chemotherapy treatments (Diamond and Crowden, 1997). This research involved the individualized treatment of patients experiencing side effects from chemotherapy, employing homeopathic medicine. The study involved ten participants who had been diagnosed with breast cancer and who were scheduled for at least four chemotherapy treatments. The participants did not receive any homoeopathic remedies to assist with the side effects following the first chemotherapy treatment. The results from the first chemotherapy treatment were utilized to establish each individual’s control results against which, future results would be compared. Participants received their homoeopathic similimum remedies to assist with their second, third and fourth chemotherapies. The appropriate homoeopathic remedy was determined using each patient’s distinguishing, mental, emotional and physical symptoms following each chemotherapy treatment. Each participant completed the Researcher’s Questionnaires (Appendix B) following their chemotherapy treatments and recorded the severity of their nausea, fatigue, vomiting and general symptoms experienced after each of the four chemotherapies. These were handed to the researcher at each follow-up consultation. These results, together with the holistic progress as noted by the researcher at every consultation, were used to determine the efficacy of homoeopathy on the side effects of chemotherapy treatment. This study aimed to reduce the severity and duration of side effects resulting from chemotherapy treatment using individual homoeopathic remedies prescribed. The severity of side effects was graded and monitored for each patient following each chemotherapy session. Of the ten participants involved in this study, eight participants completed all their scheduled chemotherapy sessions. Two of the participants completed only three chemotherapies as their conditions had improved drastically and were not compelled to complete their remaining chemotherapies. Compliance with the homoeopathic treatments was thus effectively 100%. The results of this study indicated that all of the participants reported a statistically significant decrease in side effects after taking the similimum homoeopathic remedies and they also experienced a shorter duration of side effects. All patients in this study were better able to cope with the side effects of chemotherapy whilst taking the similimum Homoeopathic remedies. / Dr. N. Wolf Dr. C.A. Benn Dr. K. Peck

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