Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references. / viii, 12 leaves, bound ill. 29 cm

published_or_final_version / abstract / Medicine / Master / Doctor of Medicine

The emergence of multidrug resistant tumours during the course of chemotherapeutic treatment of cancer patients is a major obstacle in cancer chemotherapy. Although several mechanisms may contribute to the appearance of multidrug resistance phenotype (MDR) in tumour cells, reduced drug accumulation and the ability of cells to undergo apoptosis are thought to be very important in expression of MDR. The work in this thesis focuses on the mechanism responsible for the reduced drug accumulation in tumour cells, mainly the multidrug resistance protein (MRP1). / The molecular mechanism underlying the binding and efflux of drugs by the MRP1 is currently not well understood. Several studies have now demonstrated that the cysteinyl leukotriene C$ sb4$ (LTC$ sb4$) and other glutathione (GSH) S-conjugated anions are substrates for the MRP. To learn more about MRP-drug interactions, we characterized the binding of MRP to a non-glutathione photoactive quinoline compound (abbreviated, ASA-AQ) (Chapter II). Since MRP mediated multi-drug resistance can be modulated by the anionic quinoline LTD$ sb4$ cysteinyl leukotriene receptor antagonist (MK571), we speculated that other quinoline-based compounds are likely to interact with MRP. In Chapter III, we show that MDR cells that express MRP1 are more resistant to the antimalarial drug, chloroquine. We also show that. chloroquine is a substrate for MRP1 drug efflux. / Taken together, the results of this thesis describe the interactions of MRP1 with a quinoline-based photoactive drug and the antimalarial drug chloroquine.

M.Tech. (Radiography) / This was a prospective, quantitative comparative study. The aim of the study was to evaluate acute toxicity of radical combination therapy, in the form of radiotherapy and chemotherapy, in HIV +ve patients on HAART and HIV -ve patients for cervical cancer at CDH, Lusaka, Zambia. The specific objectives were to compare acute toxicity in HIV +ve on HAART and HIV -ve patients and to assess the level of severity in the levels of toxicity. The study was conducted from January 2010 to December 2010. A hundred and twenty stage IB₂-IIIB cervical cancer patients were serially recruited and assigned study numbers for identification and confidentiality. Participants received Cisplatin based radical chemoradiation for five to six weeks during which time they were assessed for acute reactions and data was prospectively collected. Four systems namely Genitourinary, Haematopoietic, Skin, and Gastrointestinal were used for the assessment of toxicity in the study. Toxicity was scored using the NCI CTC v2.0. The results of this study showed that, major acute reactions in the CDH study participants were grade 3 leucopoenia (five in each study arm) and one grade 3 acute skin toxicity in the HIV +ve arm. Results also revealed that there were three HIV +ve study participants with grade 3 vomiting and one HIV –ve. There was one grade 3 anaemia in the HIV +ve arm, one grade 3 anaemia in the HIV –ve arm and one grade 4 anaemia in the HIV +ve arm. However, only the incidence of grade 3 leucopoenia in both study arms and vomiting in the HIV +ve study participants was significantly higher. This study demonstrated that radical chemoradiation is well tolerated by HIV +ve patients with intact immunity. Toxicity was usually mild and reversible and no exaggerated toxicities beyond those generally associated with single-agent Cisplatin were observed in the HIV +ve study participants. Therefore, radical chemoradiation in conventional doses can safely be given to cervical cancer HIV +ve patients who are on HAART.

No description available.

Chemotherapy in childhood cancer patients is associated with reduced bone density that can result in osteoporotic fracture in survivors. A significant proportion of paediatric patients experience a reduction in plasma 25 - hydroxyvitamin D3 [ 25 ( OH ) D3 ] and 1,25 - dihydroxyvitamin D3 [ 1,25 ( OH ) 2D3 ] levels during treatment, the basis of which is unknown. A balance between the bioactivation and degradation of 1,25 ( OH ) 2D3 is responsible for maintaining homoeostatic levels of 1,25 ( OH ) 2D3 at the correct set - point. Whereas the cytochrome P450 enzyme, CYP27B1 ( 25 - hydroxyvitamin D3 1 α - hydroxylase ), catalyses the hydroxylation of the precursor 25 ( OH ) D3 to generate 1,25 ( OH ) 2D3, catabolic inactivation and cleavage of 1,25 ( OH ) 2D3 is achieved by the mitochondrial cytochrome P450 enzyme, 25 - hydroxyvitamin D3 24 - hydroxylase ( CYP24 ), which is highly expressed in bone and kidney cells. Since many of the signalling pathways which regulate the expression of CYP24 are also activated by chemotherapeutic drugs, we hypothesised that the drugs could cause the degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 by increasing CYP24 expression, the principal means of facilitating the bio - inactivation and degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3. Using the kidney cell - lines, COS - 1 and HEK293T cells, we now report that chemotherapeutic drugs, represented by daunorubicin hydrochloride ( an anthracycline antibiotics ), etoposide and vincristine sulphate ( vinca alkaloids and related compounds ) and cisplatin ( an alkylating agent ), were able to enhance CYP24 promoter activity in kidney cell lines transfected with a CYP24 promoter - luciferase construct, either by themselves or in the presencedaunorubicin hydrochloride and etoposide, two of the strongest inducers of CYP24 promoter activation under our experimental conditions, demonstrate that these drugs acted in a concentration - dependent manner. In addition to stimulating promoter activity on their own, the drugs also amplified the induction of the CYP24 promoter by 1,25 ( OH ) 2D3. Synergistic increases were generally observed when the cells were treated simultaneously with 1,25 ( OH ) 2D3 and a drug. The two kidney cell lines generally responded in a similar manner when challenged with the drugs, either in the presence or absence of 1,25 ( OH ) 2D3. Interestingly, the hydroxylated derivative of daunorubicin hydrochloride, doxorubicin hydrochloride which is also a commonly used chemotherapeutic drug, had no effect of promoter activity. Further studies with daunorubicin hydrochloride demonstrated that the effects of the drug per se were not mediated by oxidative stress and the vitamin D receptor was not required for daunorubicin hydrochloride per se to stimulate CYP24 promoter activity. However, daunorubicin hydrochloride caused a modest increase in the expression of the vitamin D receptor and this could contribute to its synergistic activity with 1,25 ( OH ) 2D3. In the presence of etoposide, there was also a tendency for the kidney cells to express higher levels of the vitamin D receptor. A key role for the extracellular signal - regulated protein kinase ( ERK ) 1, ERK2 and ERK5 mitogen - activated protein ( MAP ) kinases was demonstrated for the inductive action of daunorubicin hydrochloride and etoposide, with CYP24 promoter - specific transcription factors located in the first - 298bp being likely targets of the ERK activity. Studies with a dominant negative mutant of MKK4, one of the two immediate upstream activators of the c - jun N - terminal kinase isoforms, demonstrated that this MAP kinase also played a crucial role in inductive actions of the of 1,25 ( OH ) 2D3. Dose - response studies with drugs. Consistent with their use in anti - cancer therapy, all of the above drugs killed the human promyelocytic HL60 leukaemic cells at very low concentrations but had no effect on the viability of kidney or liver cells, either at concentrations used in our experiments or at higher levels. Our data provide novel biochemical evidence that some of the commonly used chemotherapeutic drugs could cause an increase in the transcriptional activation of the promoter, most likely via the MAP kinases activating the transcription factors which bind to the CYP24 promoter. Such an effect could contribute to the reduction in plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 in some of the patients undergoing chemotherapy. / Thesis (Ph.D.)--School of Paediatrics and Reproductive Health, 2005.

Indiana University-Purdue University Indianapolis (IUPUI) / Although cancer and treatment-associated cognitive dysfunction has been well-documented in the literature, much work remains to elucidate the biological mechanisms driving this effect, hampering current therapeutic efforts. To address this gap, we first reviewed studies utilizing neuroimaging to characterize cognitive dysfunction in cancer, as studies of neurodegenerative diseases point to neuroimaging as a sensitive measure of cognitive dysfunction. This review highlighted the need for longitudinal imaging studies of cancer and treatment-related changes in cerebral structure and function. Subsequently, we utilized multimodal neuroimaging techniques in a female breast cancer cohort to investigate the longitudinal impact of cancer and chemotherapy treatment on cerebral perfusion and gray matter. Our findings indicate that chemotherapy is associated with elevated perfusion, primarily in posterior brain regions, as well as depressed frontal perfusion associated with decreased frontal gray matter density. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. We also investigated the relationship of cognitive dysfunction and chemotherapy-induced peripheral neuropathy (CIPN), another type of chemotherapy-related nervous system sequelae, again utilizing multimodal, longitudinal neuroimaging, and found that peripheral neuropathy symptoms following chemotherapy were associated with changes in cerebral perfusion and gray matter density. Together, these findings support the hypothesis that multiple biological mechanisms drive cancer and treatment-related cognitive dysfunction. Interestingly, although cancer is associated with cognitive dysfunction, epidemiological studies have shown that cancer and Alzheimer's disease (AD) are inversely correlated. To extend our imaging analysis beyond breast cancer, we leveraged the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate the inverse relationship of cancer and AD and investigate the impact of both of these diseases on gray matter density. We found that though the inverse relationship of these diseases was replicated in the ADNI cohort, cancer history was associated with lower gray matter density, similar to findings from breast cancer studies, independent of AD diagnostic group. Finally, we reviewed microRNA studies, as microRNAs are important regulators of many cell signaling pathways and have been actively investigated in relation to both diseases. This review suggests several pathways that may be driving the inverse association and may contribute to cognitive dysfunction.