Zur Untersuchung des Potenzials von Kohlenstoffnanoröhren zum Wirkstofftransport wurden zwei verschiedene Typen mehrwandiger Kohlenstoffnanoröhren mit dem Zytostatikum Carboplatin (Diamminplatin(II)-cyclobutan-1,1-dicarboxylat) beladen. Unter Verwendung einer nasschemischen Methode sollten die Röhren vorwiegend mit dem Wirkstoff gefüllt werden. Verschiedene analytische Methoden, wie Atomabsorptionsspektroskopie, Röntgenpulverdiffraktometrie, Röntgenphotoelektronenspektroskopie und Transmissionselektronenmikroskopie, dienten der Charakterisierung der hergestellten CNT-Carboplatin-Assoziate. Die zytostatische Wirksamkeit wurde anhand von Zellstudien, durchgeführt an zwei verschiedenen Prostatakarzinozelllinien, bewertet. Anhand der Arbeit wurde demonstriert, das CNT ein prinzipielles Potenzial zum Wirkstofftransport besitzen.

Chemoresistance is one of the main causes of failure of anticancer chemotherapy. Vacuolar-type ATPase (V-ATPase) is an ATP-dependent proton pump involved in the regulation of the pH in cells, cell organelles and the intracellular space. A significant acidification of the extracellular space and intracellular compartments occurs in connection with the metabolism of tumour cells (glucose metabolism, hypoxia, insufficient blood perfusion of the cancer tissue). Basic drugs are transferred into acidic organelles based on the pH gradient, where they are then protonated and accumulated. This mechanism is called lysosomal sequestration and is one of the mechanisms how tumour cells resist to applied drugs, which then do not reach their target site in cancer cell. An increased expression of V-ATPases has been described in relation to chemoresistance and the progression of tumours. This dissertation is focused on observing the membrane subunit V0d from the complex of V-ATPase and the changes in resistance to ellipticine caused by the silencing of this subunit's gene in human neuroblastoma cell lines UKF-NB-4 (sensitive) and UKF-NB-4ELLI (resistant to ellipticine). The expression of the V0d protein was first examined on mRNA level using real-time polymerase chain reaction (RT-PCR). The silencing of selected...

Zur Untersuchung des Potenzials von Kohlenstoffnanoröhren zum Wirkstofftransport wurden zwei verschiedene Typen mehrwandiger Kohlenstoffnanoröhren mit dem Zytostatikum Carboplatin (Diamminplatin(II)-cyclobutan-1,1-dicarboxylat) beladen. Unter Verwendung einer nasschemischen Methode sollten die Röhren vorwiegend mit dem Wirkstoff gefüllt werden. Verschiedene analytische Methoden, wie Atomabsorptionsspektroskopie, Röntgenpulverdiffraktometrie, Röntgenphotoelektronenspektroskopie und Transmissionselektronenmikroskopie, dienten der Charakterisierung der hergestellten CNT-Carboplatin-Assoziate. Die zytostatische Wirksamkeit wurde anhand von Zellstudien, durchgeführt an zwei verschiedenen Prostatakarzinozelllinien, bewertet. Anhand der Arbeit wurde demonstriert, das CNT ein prinzipielles Potenzial zum Wirkstofftransport besitzen.

Bakgrund Cancer behandlad med cytostatika skapar både fysiska och psykiska biverkningar hos patienter som upplever förlorad kontroll orsakat av kroppsförändringar och psykiska effekter: isolering, förlorad kroppsuppfattning, depression och fatigue. Cytostatikan påverkar patientens sociala- och familjeroll där stöd från närstående och vården är essentiellt. Patienter upplever skuldkänslor gentemot sin familj till följd av den förändrade tillvaron cytostatikan medför. Syfte Syftet med denna studie var att utforska vilka psykiska upplevelser patienter fått under sin cytostatikabehandling för cancer. Metod En litteraturstudie genomfördes utifrån tio vetenskapliga studier med kvalitativ ansats. Studierna publicerades mellan år 2010 och år 2020, i databaserna PubMed, CINAHL och PsycInfo samt kvalitetsgranskades med en granskningsmall för kvalitativa studier. Resultat Patienterna upplevde negativa känslor under sin cytostatikabehandling: oro, skuldkänslor och nedstämdhet. Fysiska och psykiska biverkningar påverkade patienterna, där depression och fatigue upplevdes som påfrestande och begränsade patienternas sociala tillvaro. Kroppsliga förändringar ledde till psykiska konsekvenser: förlorad självständighet, ångest, maktlöshet och självmordstankar. Patienter upplevde isolering både i hemmet och på sjukhuset till följd av begränsningar cytostatikan medförde. Patienternas nära relation till vården och närstående under cytostatikabehandlingen skapade både positiva och negativa upplevelser. Slutsats Positiva psykiska upplevelser var någonting som patienterna upplevde från både sina närståendes stöd och sjukvårdens stöd samt närvaro, men även detta stöd medförde ibland negativa upplevelser. Sjukhusmiljön upplevdes som stressande men också som en källa för information och trygghet på grund av vårdpersonalens närvaro. Patienternas vanligaste psykiska upplevelser under cytostatikabehandlingen var negativa och uppstod från biverkningarna depression och fatigue. Fortsatt forskning behövs om hur depression och fatigue kan lindras för att underlätta patienternas psykiska upplevelser av dessa. / Background Cancer treated with chemotherapy creates both physical and psychological side effects for patients. Who experience loss of control caused by body changes and psychological effects: isolation, loss of body image, depression and fatigue. Chemotherapy changes the patients’ family and social role. Care from family and health care workers are essential but they can create feelings of guilt for the patient. Aim The aim of this study was to explore how patients psychologically experience chemotherapy treatment while undergoing treatment of cancer. Method The design of this study was a literature review that was conducted of ten scientific studies with a qualitative approach. The studies were published between the years 2010 and 2020, in the databases PubMed, CINAHL and PsycInfo and reviewed with the use of a qualitative review template. Results Patients experienced negative emotions during their chemotherapy treatment: anxiety, guilt and depression. Physical and psychological side effects affected how patients experienced the treatment, were depression and fatigue were perceived as stressful and limited their social life. Physical changes led to psychological consequences: loss of independence, anxiety, powerlessness and suicidal thoughts. Patients experienced isolation at home and in the hospital due to limitations caused by chemotherapy. The patients' close relationship with the healthcare workers and their families during the chemotherapy created both positive and negative experiences. Conclusion Patients received positive psychological experiences from the support of both their family and health professionals, however this support sometimes led to negative experiences. The hospital environment was perceived as stressful but could also be an opportunity for information and safety due to the presence of the health care workers. The patients' most common psychological experiences during chemotherapy were negative which developed from the side effects: depression and fatigue. More research is needed on how depression and fatigue can be soothed in order to accommodate patients' psychological experiences of these side effects.

Bakgrund Bröstcancer är den form av cancer som drabbar flest kvinnor världen över. Dagens behandling med bland annat cytostatika är väldigt tuff och leder till många biverkningar och symtom som påverkar kvinnors livskvalitet negativ och detta kan leda till lidande. Bara i Sverige får cirka 8000 kvinnor en bröstcancerdiagnos per år. Det som redan är känt är att många kvinnor drabbas. Det som inte finns lika mycket information om är hur dessa kvinnor mår och hur dom upplever sin behandling samt sjuksköterskans omvårdnad. Syfte Syftet med denna studie var att belysa bröstcancerdrabbade kvinnors erfarenheter av cytostatikabehandling som grund för sjuksköterskans professionella ansvar att bidra till lindrat lidande. Metod Metoden för detta arbete var en litteraturöversikt. Databaserna PubMed och CINAHL användes för att söka fram artiklar, vilket resulterade till 18 vetenskapliga artiklar som kvalitetsgranskats och sammanställts i en matris. En integrerad analysmetod användes för att analysera och presentera datainformationen i resultatet.   Resultat Resultatet ledde fram till fyra kategorier: Fysiska aspekter som kan leda till sjukdomslidande; Psykiska aspekter som kan leda till livslidande; Behov av stöd vid lidande som kan uppstå vid cytostatikabehandling och Brist på information vid cytostatikabehandling som kan leda till vårdlidande. Slutsats Kvinnors erfarenheter av cytostatikabehandling visade på ett påtagligt lidande och en försämrad livskvalitet. För att minska lidande och skapa en vård som håller en god kvalitet är det mycket viktigt att jobba vidare med information och kunskap inom bröstcancervård. Kvinnorna behöver mer stöd, information och vägledning från hälso- och sjukvården för att kunna minska sina besvär och få en bättre förutsättning för att kunna återgå till ett vanligt liv. Detta kan leda till att fler kvinnor kommer att få en mer tillfredsställande vård än vad de upplever i dagsläget. / Background Breast cancer is the form of cancer that affects most women worldwide. Today's treatment with, for example, cytostatic drugs is very tough and leads to many side effects and symptoms that affect women's quality of life negatively and this can lead to suffering. In Sweden alone, 8,000 women receive a breast cancer diagnosis per year. What is already known is that many women suffer, what is not as much information about is how these women feel and how they experience their treatment and the nursing. Aim The purpose of this study was to elucidate breast cancer-affected women's experiences of cytostatic therapy as a basis for the nurse's professional responsibility to contribute to alleviated suffering. Method The method for this essay was a literature review. The databases used to attain articles was PubMed and CINAHL. Arton scientific articles’ quality was assessed and was assembled in a matrix. An integrated analysis was used to analyse and present the data information in the results. Results The result led to four categories: Physical aspects that can lead to illness; Mental aspects that can lead to life-affliction; Need for support for suffering that may occur during cytostatic therapy and Lack of information in cytostatic therapy that can lead to suffering from care. Conclusions Women's experiences with cytostatic treatment showed a marked suffering and a deteriorating quality of life. In order to reduce suffering and to create a quality care service, it is very important to continue working with information and knowledge in breast cancer care. Women need more support, information and guidance from the health care system in order to reduce their inconvenience and to have a better condition in order to return to normal life. This can lead to more women receiving more satisfactory care than they currently experience.

Titel: Patienters upplevelser av diagnos och behandling vid akut myeloisk leukemi    Bakgrund: Akut myeloisk leukemi (AML) är den vanligaste formen av akut leukemi. Behandlingen och symtomen är påfrestande och långvariga, vilket inverkar på patienters livskvalitet. Genom god personcentrerad vård kan sjuksköterskan försöka tillgodose många av behoven som patienten kan få under vårdtiden.  Syfte: Att beskriva patienters upplevelser av att diagnostiseras med och genomgå behandling mot akut myeloisk leukemi. Metod: En litteraturöversikt med kvalitativ metod och induktiv ansats. Efter sökning i databaserna Cinahl, PubMed och PsyINFO samt artikelgranskning inkluderades tolv artiklar. Artiklarna analyserades genom Fribergs fem steg.  Resultat: Genom en sammanställning av artiklarna framkom det två olika teman (känslomässiga reaktioner och förändrad kroppsuppfattning) och sex olika subteman (att få ett obegripligt besked, känsla av att få svår och komplex information, känsla av isolering, förändrat utseende relaterat till symtom, fysiska symtom relaterat till behandling och känsla av att vara en börda). Slutsatser: I litteraturöversikten framkom det att beskedet om diagnosen var obegripligt. Patienterna upplevde att sjuksköterskan hade svårt att förmedla den komplexa informationen personcentrerat. Behandlingstiden orsakade att patienterna upplevde sig isolerade och att symtomen (illamående, trötthet och håravfall) påverkade patienternas vardagliga liv negativt. Sjuksköterskans stöd och undervisning relaterat till symtomhantering och omvårdnadsåtgärder till såväl patient och anhöriga är avgörande för att minska de negativa känslorna som framkom i resultatet.  Nyckelord: Cancer, cytostatikabehandling, personcentrerad vård, stamcellstransplantation

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The synthetic routes to three types of phosphate prodrugs of 6-hetaryl-7-deazapurine ribonucleosides based on palladium-catalyzed cross-coupling reactions have been developed. CycloSal- and phosphoramidate pronucleotides and octadecyl phosphates derived from 6- hetaryl-7-deazapurine ribonucleosides were screened for their in vitro cytostatic activity. It was shown that cytostatic activity of cycloSal phosphates was similar or slightly lower compared to the parent nucleosides. Significant drop of cytostatic activity was observed in phosphoramidate pronucleotides. Octadecyl phosphates were devoid of any cytostatic activity. 6-Hetaryl-7-deazapurine ribonucleosides with bulky groups in position 6 showed very strong and selective inhibition of adenosine kinase from Mycobacterium tuberculosis. 2'-Modified 6-hetaryl-7-deazapurine nucleosides: 2'-O-methylribonucleosides, arabinonucleosides and 2'- deoxy-2'-fluororibonucleosides, were prepared by multistep functional group transformations from a ribonucleoside. The synthesis of 2'-deoxy-2',2'-difluoro-erythro-pentofuranosyl nucleosides was based on a glycosylation of 6-chloro-7-deazapurine with a sugar synthon followed by palladium-catalyzed cross-coupling reaction and deprotection. Despite the low yields and laborious separation of the anomers,...

This thesis reports the syntheses and biological activities of benzo- and thieno-fused 7-deazapurine ribonucleosides, which were designed as extended analogues of potent cytostatic 6-hetaryl-7-deazapurine or 6-amino-7-hetaryl-7-deazapurine ribonucleosides. First of all, multigram syntheses of (di)chloro-9H-pyrimido[4,5-b]indoles from simple chloro- nitrobenzenes were developed. Pyrimidoindoles were successfully glycosylated and used for the synthesis of 4-hetaryl-6-chloro-, 4,6-bis(hetaryl)-, 4-amino-6-hetaryl-, 4-amino-5-hetaryl- and 4-susbtituted pyrimido[4,5-b]indole ribonucleosides. Hetaryl groups were introduced by Suzuki or Stille cross-coupling reaction. Standard catalysts and conditions were used for reaction in position 4. To observe some reactivity of unreactive chlorine in position 6, modification of standard protocol was necessary. Screening of several ligands had been done and Buchwald ligand X-Phos was found to be optimal. As chlorine in position 4 is activated for nucleophilic substitution, amino and dimethylamino derivatives were prepared by reaction with aqueous ammonia and dimethylamine, respectively. 4-Alkyl derivatives were synthesized by palladium-catalyzed alkylation with trialkylaluminium or by Negishi coupling in case of cyclopropyl derivative. Desired free nucleosides were...

O melanoma é responsável por menos de 5% dos cânceres de pele, porém, 95% das mortes ocorrem devido a ocorrência de metástases. O melanoma metastático é refratário às terapias convencionais e rapidamente adquire resistência às terapias como as oncogene-dirigidas, como o inibidor de BRAF, da via de MAPK. Estudos prévios de screening in silico do nosso grupo, onde se utilizou as bases de dados TCGA e GEO, identificaram o gene adenosina quinase (ADK) como sendo diferencialmente expresso entre o melanoma invasivo e os nevus. A 5-iodotubercidina (5-ITu) é um potente inibidor farmacológico da ADK que dentre os diversos efeitos relatados na literatura destaca-se pelo potencial genotóxico. Os danos no DNA são os principais ativadores de checkpoint do ciclo celular, que levam a parada do ciclo celular transitória ou permanente, além de induzir morte celular, levando a hipótese de que ADK possa ser potencial agente anti-melanoma. Este trabalho objetivou avaliar a expressão do gene ADK em melanomas humanos e quimiorresistentes ao inibidor de BRAF (iBRAF), avaliou os impactos de 5-ITu sobre a proliferação, progressão do ciclo celular e morte celular e por fim avaliamos sua capacidade de aumentar a sensibilidade das células. Foi realizado PCR em tempo real para avaliar os níveis de expressão de mRNA de ADK em linhagens de melanoma e na cultura primária de melanócitos; a fim de avaliar a citotoxicidade de 5-ITu foram realizados os ensaios de exclusão por azul de tripan e de apoptose - Anexina V e PI e em modelo de esferoide, usando live/dead; também foi avaliada a influência de 5-ITu sobre a capacidade clonogênica e seus efeitos sobre a proliferação celular, a partir dos ensaios de ciclo celular e avaliação de marcadores de proliferação por imunofluorescência; as linhagens foram submetidas a diferentes regimes de tratamento com 5-ITu e o iBRAF, a fim de avaliar a curva de crescimento e a sensibilidade ao iBRAF por MTT níveis de expressão de mRNA de ADK maiores nas linhagens tumorais em relação aos melanócitos. 5-ITu mostrou-se capaz de inibir a proliferação (IC50) das linhagens de melanoma em concentrações de 1,9 a 3,5 µM. 5-ITu não foi capaz de induzir inviabilidade celular, apesar de reduzir a quantidade de células viáveis em todas as condições de tratamento, também não foi capaz de induzir aumento significativo de células apoptóticas, nem mesmo necróticas. No entanto, o tratamento com 5-ITu reduziu a capacidade clonogênica de linhagens de melanoma e promoveu parada de ciclo celular nas fases G1 e G2/M, levou ao aumento da população subG1. O tratamento com 5-ITu promoveu a redução da expressão de marcadores de proliferação, como ki67, e a combinação de tratamentos 5-ITu e iBraf foi capaz de aumentar o tempo de dobramento das linhagens de melanoma, embora tenha se mostrado incapaz de sensibilizar as células de melanoma ao tratamento com iBRAF. Desse modo, pode-se concluir que 5-ITu induz o efeito citostático e se mostra um potente agente antiproliferativo para melanoma parental e resistente. / Melanoma accounts for less than 5% of skin cancers, but 95% of deaths occur due to metastases. Metastatic melanoma is refractory to conventional therapies and rapidly acquires resistance to therapies such as oncogene-directed, such as the BRAF inhibitor, of the MAPK pathway. Previous studies of screening in silico of our group, using the databases TCGA and GEO, identified the adenosine kinase gene (ADK) as differentially expressed between invasive melanoma and nevus. 5-iodotubercidin (5-ITu) is a potent pharmacological inhibitor of ADK that among the several effects reported in the literature stands out for the genotoxic potential. DNA damage is the main activator of the cell cycle checkpoint, which leads to transient or permanent cell cycle arrest, in addition to inducing cell death, leading to the hypothesis that ADK may be a potential anti-melanoma agent. This work aimed to evaluate the expression of the ADK gene in human melanomas and chemoresistants to the BRAF inhibitor (iBRAF), evaluated the impacts of 5-ITu on proliferation, cell cycle progression and cell death and finally we evaluated its ability to increase the sensitivity of cells. Real-time PCR was performed to assess the levels of ADK mRNA expression in melanoma lines and primary melanocyte culture; in order to evaluate the cytotoxicity of 5-ITu, the trypan blue and apoptosis - Annexin V and PI exclusion and blue spheroid models were performed using live / dead; the influence of 5-ITu on the clonogenic capacity and its effects on cell proliferation, from the cell cycle assays and the evaluation of proliferation markers by immunofluorescence; the cell lines were submitted to different treatment regimens with 5-ITu and iBRAF in order to evaluate the growth curve and the sensitivity to iBRAF by MTT levels of mRNA expression of ADK higher in the tumor lines in relation to the melanocytes. 5-ITu was able to inhibit the proliferation (IC 50) of melanoma lines at concentrations of 1.9 to 3.5 181;M. 5-ITu was not able to induce cell non-viability, although it reduced the amount of viable cells in all treatment conditions, nor was it able to induce a significant increase in apoptotic or even necrotic cells. However, treatment with 5-ITu reduced the clonogenic capacity of melanoma cells and promoted cell cycle arrest in the G1 and G2 / M phases, leading to an increase in the subG1 population. Treatment with 5-ITu promotes the reduction of expression of proliferation markers, such as ki67, and the combination of 5-ITu and iBRAF treatments was able to increase the doubling time of melanoma cells, although it has been shown to be unable to sensitize melanoma cells to treatment with iBRAF. Thus, it can be concluded that 5-ITu induces the cytostatic effect and shows a potent antiproliferative agent for parental and resistant melanoma.