J1 (L-melphalanyl-L-p-fluorophenylalanyl ethyl ester) is a dipeptide derivative of the alkylating agent melphalan with increased cytotoxicity. In this thesis the preclinical pharmacology of J1 has been characterized. Our results show that J1 rapidly enters the cells, where melphalan is released by hydrolysis. The maximum concentration (Cmax) of melphalan was detected 15 min after exposure to J1 in human cancer cell lines. In comparison, melphalan exposure resulted in a 10-fold lower Cmax that was shifted to later time points. J1 induced more DNA damage and apoptosis than melphalan. The cytotoxic activity and release of melphalan from J1 were inhibited by preincubating cells with the aminopeptidase inhibitor bestatin. In accordance with these results, we showed that J1 is a substrate for aminopeptidase N (APN), which may result in increased tumor selectivity. J1 effectively inhibited cell growth in a set of neuroblastoma cell lines. Athymic mice carrying neuroblastoma xenografts were treated either with equimolar doses of melphalan or J1. J1 inhibited the tumor growth more effectively than melphalan and the untreated control, and was associated with higher caspase-3 activation, fewer proliferating tumor cells and decreased mean vascular density. J1 and melphalan showed similar activity profiles when tested in 176 primary tumor cell cultures from patients, but J1 exhibited 50- to 100-fold higher potency. The difference was greater in some diagnoses (e.g. breast cancer, NHL and AML), and was exceptionally large in some breast cancer samples with aggressive phenotypes. A combination screening of J1 and standard chemotherapeutics yielded mostly additive interactions, except for etoposide which induced synergy in all tested cell lines. In conclusion, the melphalan prodrug J1 is effectively transported into the cells, where aminopeptidases (for example APN) catalyze the formation of melphalan. J1 shows promising preclinical potential in the diagnoses neuroblastoma and breast cancer.

Background: Chemotherapy has side effects that may interfere with food intake. Children suffering from a malignant disease are subjected to treatment with chemotherapy. They may therefore become at risk of undernutrition during the period of treatment. This in turn may increase the risk of infections, delayed therapy and influence the outcome of treatment. Few studies have investigated how children undergoing chemotherapy for cancer perceive food and eating. Attempts to improve food intake and the nutritional status require an understand-ing of how eating patterns are altered during chemotherapy in children. Study design: Dietary information and anthropometric data were collected after the initiation of chemotherapy in 14 children, consecutively admitted to the Paediatric Haematology and Oncology Unit at Umeå University Hospital. This initial study resulted in the establishment of more flexible mealtime routines on the ward. A follow-up study was conducted with another group of 11 children. Interviews were performed with a third group of 21 consecutively ad-mitted children, their parents and attending nurses. The focus was on the children’s own per-ception of and their parents’ and nurses’ attitudes to their food intake during hospitalisation. Recognition thresholds for the basic tastes were determined with 10 of the oldest of these children and 10 healthy controls. Results: Before introduction of new mealtime routines, the average daily oral energy intake during hospitalisation was 58% of the Swedish Nutrition Recommendations, SNR. The chil-dren had a significant weight loss up to three months after onset of chemotherapy. After the introduction of new mealtime routines, the average daily oral intake on hospital days was 61% of SNR and thus still lower than recommended despite efforts to serve palatable food on the ward. When enteral and parenteral nutrition was included, the energy intake came close to that recommended for healthy children, 91% of SNR. Both children and parents perceived that altered taste was an important cause of the children’s eating problems. The children also viewed food aversions, nausea and vomiting and pain as important causes, while the parents perceived nausea, food aversions and altered smell as significant factors. The nurses on the other hand, viewed nausea, the ward environment, and food rejection as a way of gaining some influence over the situation as important factors. The patients had significantly higher thresholds for bitter taste and significantly more patients made mistakes in taste recognition compared with controls. Conclusion and clinical implication: There seem to be changes both in the sense of taste as well as in the perception of food in children undergoing chemotherapy for malignant disease. Thus, single solutions such as providing a variety of “tasty food” in the hospital setting in order to improve food intake does not suffice for many paediatric cancer patients. The indi-vidual’s food preferences and aversions should be considered and combinations of oral, en-teral and parenteral nutrition support should be provided.

Illamående och kräkning är förekommande biverkningar hos patienter med cancer som behandlas med cytostatika och är därmed tillstånd som sjuksköterskan kommer i kontakt med. Om patientens illamående och kräkning inte förebyggs kan det leda till konsekvenser som att patienten blir dehydrerad, tappar aptiten, blir undernärd och försvårar skadad vävnad att återhämta sig från cytostatikabehandling. Trots att de flesta patienter får antiemetika lyckas inte deras illamående och kräkning förebyggas. Syftet var att belysa komplementära behandlingsmetoder vid cytostatikarelaterat illamående och kräkning. Studien är utförd som en litteraturstudie och baserad på 14 vetenskapliga studier. Resultatet visar att komplementära behandlingsmetoder har ett visst vetenskapligt stöd och är ett bra komplement till antiemetika. Akupressur är den behandlingsmetod som är effektivast för att förebygga cytostatikarelaterat illamående och kräkning. Även akustimulation, elektroakupunktur och avslappning minskar patienternas illamående och kräkning. Mer forskning behövs för att ge mer styrka åt de olika komplementära behandlingsmetoder, eftersom sjuksköterskans arbete måste utföras utifrån vetenskap och beprövad erfarenhet. Genom att sjuksköterskan får ökad kunskap om hur cytostatikarelaterat illamående och kräkning förebyggs kan patientens lidande minska.

Because of the failure so far to find effective treatment for patients with advanced stages of melanoma, increasing efforts have been made to find prognostic factors identifying patients in the risk zone for development of metastasis. This thesis investigates the prognostic powers of a few selected serological and immunohistochemical biomarkers. In the first and second study, patients operated on for localized malignant melanoma were investigated regarding the prognostic impact of angiogenic serological markers and circulating levels of S100. We concluded that the S100 assays, especially S100BB, are potential biomarkers in patients with malignant melanoma, correlated to both survival and disease free survival. However, no such conclusion could be drawn from the first study, where we found no correlation to survival and investigated angiogenic markers. In the third and fourth study four new potential immunohistochemical biomarkers where investigated in collaboration with the Swedish Human Protein Atlas Program, and those where TRP-1, galectin-1, DLG5 and syntaxin-7. We found that TRP-1 correlated inversely with tumor stage and galectin-1 correlated to Ki-67. DLG5 showed a significant inverse correlation to Ki67 and the expression of STX7 was inversely correlated to tumor stage, suggesting that decreased expression is associated with more aggressive tumors. None of the investigated markers in study III and IV correlated with disease free survival or overall survival. In the fifth and last study, we examined the expression of SOX10, a transcription factor, in different melanocytic lesions. Also, a proliferation assay was carried out in a human melanoma cell line. The results reveal the presence of SOX10 in different melanocytic lesions, with a weak inverse correlation to survival and a significant inverse correlation to T-stage. A significant decrease in proliferation rate for SOX10 silenced cells was found and our data also suggests an increased migratory response in SOX10 silenced cells.

Ovarian cancer remains the deadliest gynecologic malignancy. Current treatment has low efficacy in the long term, leading to low 5-year survival rates of 20-40%. Treatment-free periods between cycles of chemotherapy are accepted in standard treatment. These periods lead to accelerated tumor cell proliferation, angiogenesis and drug resistance development. Studies presented herein show advantages of continuous carboplatin dosing schedule over conventional intermittent regimen, both administered intraperitoneally. Continuous carboplatin therapy blocked acceleration of cell proliferation observed during treatment-free period of intermittent therapy. Moreover, continuous carboplatin led to 57% inhibition of SKOV3 tumors grown intraperitoneally in SCID mice, a significant advantage over the 33% tumor suppression observed with intermittent carboplatin. Immunohistochemical analysis revealed continuous carboplatin led to greater tumor cell death while suppressing tumor cell proliferation and angiogenesis when compared to intermittent administration. These results show that the suppression of tumor growth with carboplatin can be enhanced by the elimination of treatment free periods.

Folate is an essential cofactor in one-carbon transfer reactions including nucleotide biosynthesis, thereby playing an important role in DNA replication and repair. In cancer cells, folate depletion interrupts DNA synthesis, thereby causing cancer cell death. This has been the basis for chemotherapy using antifolates and 5-fluorouracil (5FU). We determined the effect of folate deficiency on the sensitivity of colon cancer cells to 5FU in a well established in vitro model of folate deficiency. Folate deficient cells had lower intracellular folate concentrations, had functional evidence of intracellular folate depletion, proliferated less, and had increased chemosensitivity to 5FU with and without Leucovorin. These data suggest that folate deficiency significantly enhances the sensitivity of colon cancer cells to 5FU based chemotherapy via changes in intracellular folate. Dietary or other strategies to deplete intracellular folate concentrations in colon cancer cells to enhance chemosensitivity to 5FU are worthy of further investigation.

Ovarian cancer remains the deadliest gynecologic malignancy. Current treatment has low efficacy in the long term, leading to low 5-year survival rates of 20-40%. Treatment-free periods between cycles of chemotherapy are accepted in standard treatment. These periods lead to accelerated tumor cell proliferation, angiogenesis and drug resistance development. Studies presented herein show advantages of continuous carboplatin dosing schedule over conventional intermittent regimen, both administered intraperitoneally. Continuous carboplatin therapy blocked acceleration of cell proliferation observed during treatment-free period of intermittent therapy. Moreover, continuous carboplatin led to 57% inhibition of SKOV3 tumors grown intraperitoneally in SCID mice, a significant advantage over the 33% tumor suppression observed with intermittent carboplatin. Immunohistochemical analysis revealed continuous carboplatin led to greater tumor cell death while suppressing tumor cell proliferation and angiogenesis when compared to intermittent administration. These results show that the suppression of tumor growth with carboplatin can be enhanced by the elimination of treatment free periods.

Folate is an essential cofactor in one-carbon transfer reactions including nucleotide biosynthesis, thereby playing an important role in DNA replication and repair. In cancer cells, folate depletion interrupts DNA synthesis, thereby causing cancer cell death. This has been the basis for chemotherapy using antifolates and 5-fluorouracil (5FU). We determined the effect of folate deficiency on the sensitivity of colon cancer cells to 5FU in a well established in vitro model of folate deficiency. Folate deficient cells had lower intracellular folate concentrations, had functional evidence of intracellular folate depletion, proliferated less, and had increased chemosensitivity to 5FU with and without Leucovorin. These data suggest that folate deficiency significantly enhances the sensitivity of colon cancer cells to 5FU based chemotherapy via changes in intracellular folate. Dietary or other strategies to deplete intracellular folate concentrations in colon cancer cells to enhance chemosensitivity to 5FU are worthy of further investigation.

Aim: The aim of this study was to determine whether or not there is evidence for the usage of ginger as an antiemetic in patients experiencing chemotherapy related nausea, based on available scientific literature. Methods: The original articles were found by using search engines PubMed and CINAHL. The selected articles were then analyzed based on their content, quality and results. Based on the results from the content analysis the articles were placed in four different themes. Results: In the first theme two of the articles found that ginger had significant effect on chemotherapy related nausea, when used in combination with regular antiemetic treatment. Two other articles said that it does not. In the second theme four studies found that different forms of ginger lessens nausea, in contrast two other articles found that it does not have any increased effect on said nausea. In the third theme one article found that ginger has significant effect in quelling nausea whilst another article says that it does not show any difference in effect to 5HT3-receptorantagonist metoclopramide. The fourth theme contains one article that find that ginger in combination with high protein diet have antiemetic effect. Conclusions: The conclusion of this literary overview is that there is good evidence that using ginger as an antiemetic in combination with 5HT3-receptor antagonist in patients experiencing chemotherapy related nausea, mainly when given cisplatin.

No description available.