Le protocole TICE (Taxol, Ifosfamide, Carboplatine et Etoposide) représente le traitement standard du cancer germinal réfractaire en première ligne ou en rechute de mauvais pronostic. Une étude de phase II a été réalisée consistant en une adaptation de posologie du carboplatine (utilisé à haute dose) basée sur un suivi thérapeutique pharmacologique (TDM) de ses concentrations ultrafiltrables (UF) alors que les pratiques habituelles se limitent à des doses calculées à partir d'une valeur cible de l'aire sous la courbe (AUC) des concentrations UF et la clairance UF prédite du patient. Les analyses pharmacocinétiques effectuées dans le cadre de cette thèse ont permis de démontrer la faisabilité du TDM ainsi que sa performance dans la maîtrise de l'AUC du carboplatine utilisé dans le protocole TICE. Cependant, la réalisation de cette pratique est limitée, dans certains hôpitaux, par les contraintes matérielles et humaines liées à l'obtention des concentrations UF par l'ultrafiltration des prélèvements plasmatiques. Une méthodologie a donc été développée et validée pour permettre la réalisation du TDM à partir des concentrations plasmatiques totales. Par ailleurs, l'étude pharmacocinétique réalisée pour l'étoposide, médicament associé au carboplatine dans la phase d'intensification de ce protocole, indique que le calcul actuel de la dose en fonction de la surface corporelle s'accompagne d'une variabilité interindividuelle limitée de l'exposition et qu'il n'y a pas lieu de pratiquer un TDM pour ce médicament. Enfin, l'implication de différents facteurs génétiques correspondant, d'une part, à la toxicité auditive du carboplatine et, d'autre part, à la pharmacologie de l'étoposide a été aussi évaluée. En conclusion, ces travaux permettront d'améliorer la prise en charge des patients traités par ce protocole à haute dose de carboplatine et étoposide et, au-delà de cette indication thérapeutique, notre connaissance de ces deux médicaments cytotoxiques importants. / The TI-CE protocol ((Taxol, Ifosfamide, Carboplatin and Etoposide) is the standard treatment of germ cell tumor refractory to first-line chemotherapy or relapsed germ cell tumor having unfavorable prognostic features. A phase II study was conducted and consisted in adapting the dose of (high dose) carboplatin using therapeutic drug monitoring (TDM) of unbound concentrations instead of the usual method of dose individualization based on a target area under the curve (AUC) of unbound concentrations and predicted unbound clearance. Pharmacokinetic analyses carried out in the context of this thesis have demonstrated the feasibility of conducting the TDM as well as its performance in terms of controlling the variability of AUC of carboplatin in the TI-CE protocol. However, the use of this practice is limited, in some hospitals, by material and human constraints related to the ultrafiltration of plasma samples to obtain unbound concentrations. A method was developed and validated to enable the use of total plasma concentrations for the TDM instead of unbound concentrations. Furthermore, the pharmacokinetic study of etoposide, used in combination with carboplatin during the dose intensification phase of the protocol, showed that the usual dose calculation method based on body surface area is associated with a low interindividual variability of exposure and that TDM is, therefore, not necessary for this drug. Finally, the role of different genetic factors in the ototoxicity of carboplatin and in the pharmacology of etoposide was also assessed. In conclusion, these analyses help to improve the level of care of patients treated with this protocol of high dose carboplatin and etoposide as well as our current knowledge of these two important cytotoxic drugs.

Chemotherapy is the first line of treatment used in cancer. Chemotherapy drugs such as cisplatin, carboplatin and oxaliplatin are used in treatment. Cisplatin enters the cell through copper transporter CTR1 by passive diffusion and bind to DNA and proteins. Cisplatin is found to inhibit several enzymes targeting cysteine, histidine and methionine residues, which are expected to be responsible for its anticancer activity. A better understanding of how the size and shape and leaving ligands of platinum complexes affect cysteine protease, papain enzyme are studied. This could give new ways to optimize anticancer activity. The activity of papain enzyme was measured on UV-Visible spectroscopy. The inhibition profile of papain with different platinum (II) complexes, and with different combinations was studied.

Ο σκοπός της παρούσας μελέτης ήταν να εξετάσει τον ρόλο της ταξόλης (paclitaxel) και της καρβοπλατίνης σε σχέση με τις παραμέτρους του ανοσοποιητικού συστήματος σε ασθενείς πάσχοντες από μη μικροκυτταρικό καρκίνο του πνεύμονα και από καρκίνο των ωοθηκών· πριν, κατά τη διάρκεια και μετά από χημειοθεραπεία και η επίδραση που είχε ο ανωτέρω συνδυασμός φαρμάκων στην συνολική επιβίωση των ασθενών. Υλικό και Μέθοδος: Εξετάσθηκαν 24 ασθενείς με μη-μικροκυτταρικό καρκίνο του πνεύμονα και 20 με καρκίνο των ωοθηκών (όλοι μεταστατικοί), όπου χωρίστηκαν σε δύο ομάδες με κριτήριο την επιβίωση και που εν συνεχεία τους χορηγήθηκε συνδυασμός καρβοπλατίνης και ταξόλης για έξι θεραπευτικούς κύκλους. Ομάδα Α. Ασθενείς με καλή επιβίωση (>12 μήνες για μη-μικροκυτταρικό καρκίνο του πνεύμονα, >30 μήνες για καρκίνο των ωοθηκών) Ομάδα Β. Ασθενείς με «φτωχή» επιβίωση (<12 μήνες για μη-μικροκυτταρικό καρκίνο του πνεύμονα, <18 μήνες για καρκίνο των ωοθηκών) Την ίδια χρονική περίοδο εξετάσθηκαν οι λεμφοκυτταρικοί υποπληθυσμοί (CD3, CD4, CD8, CD56, CD34) καθώς και οι κυτταροκίνες ιντερλευκίνη-3 (IL-3) και ιντερφερόνη-γ (IFN-γ), σε σχέση με την ποιότητα ζωής και το προσδόκιμο επιβίωσης κατά την διάρκεια της χημειοθεραπευτικής αγωγής. Η στατιστική ανάλυση των αποτελεσμάτων έγινε με την μέθοδο ANOVA. Αποτελέσματα: Από την εξαγωγή των αποτελεσμάτων παρατηρήθηκε μία στατιστικώς σημαντική διαφορά ανάμεσα στις τιμές των λεμφοκυτταρικών 207 υποπληθυσμών CD4 και CD4/CD8 μετά από χημειοθεραπεία μεταξύ των δύο ομάδων ασθενών Α και Β (p=0,001 και p=0,006). Αυτό σημαίνει ότι η περαιτέρω αύξηση του αριθμού των βοηθητικών Τ-λεμφοκυττάρων (T-helper) μετά από χημειοθεραπεία συμβάλλει θετικά στο προσδόκιμο επιβίωσης. Επιπροσθέτως, στατιστικώς ενδιαφέρων σε σημείο που να μπορούμε να μιλήσουμε και για προγνωστικό παράγοντα, ήταν η διαφορά ανάμεσα στις τιμές της ιντερφερόνης-γ μεταξύ των ομάδων Α και Β πριν και μετά τη χημειοθεραπεία (p=0,039 και p=0,027, αντιστοίχως). Οι ασθενείς με υψηλές τιμές ιντερλευκίνης-3 παρουσίαζαν επίσης χαμηλή τοξικότητα. Συμπεράσματα: Στην παρούσα μελέτη η προσπάθεια μας επικεντρώθηκε στο να καταδείξουμε την επίδραση που ασκείται, από την χρήση του συνδυασμού καρβοπλατίνης-ταξόλης, στους λεμφοκυτταρικούς υποπληθυσμούς και στις κυτταροκίνες καθώς και την επιρροή που ασκούν και τα δύο αυτά στοιχεία του ανοσοποιητικού συστήματος στο προσδόκιμο επιβίωσης και στην εν γένει ποιότητα ζωής. / The aim of the present study was to exam the role of Paclitaxel (Taxane) and Carboplatin in the parameters of the immune system in patients with non-smallcell lung cancer and in patients with ovarian cancer before, during and after chemotherapy treatment, and the effect of this combination in the overall survival of the patients. Methods: 24 patients with non-small-cell lung cancer (NSCLC) and 20 patients with ovarian cancer (all in stage IIIb-IV) were treated with a combination of paclitaxel and carboplatin for six treatment cicles and they were separated into two groups in terms of survival. GROUP (A). Long survival (>12 months for NSCLC, >30 months for ovarian Ca) GROUP (B). Long survival (<12 months for NSCLC, <18 months for ovarian Ca) At the same time we combined the relevant parameters (CD3, CD4, CD8, CD56, CD34, IL-3, IFN-γ) with the quality of life during treatment with chemotherapy. The results were analyzed using ANOVA system. Results: We observed a significant statistical difference between the values of CD4 and CD4/CD8 after chemotherapy between group A and group B (p=0,001 and p=0,006). This means that the further increase of T-helper cells after chemotherapy has a better prognosis concerning survival. In addiction, statistically interesting, which we may call a prognostic factor, was the difference in values of IFN-γ between individuals of groups and B before and after chemotherapy (p=0,039 and p=0,027, respectively). Patients with high IL-3 had little chance of toxicity. Conclusions: In the current study we tried to demonstrate the effects from the use of the combination of carboplatin-paclitaxel in the whole population of Tcells/ cytokines and the reaction of them in the quality of life.

Fundação de Amparo a Pesquisa do Estado de Minas Gerais / Platinum compounds, such as cisplatin, oxaloplatin and carboplatin, have been used as chemotherapeutic agents for the treatment of various types of cancer. Several other complexes of this metallic ion are also under clinical evaluation. However, the utilization of platinum compounds as antitumor agents is associated with many severe effects and cellular resistance has also been observed. Therefore, many research groups have been working to synthesize new platinum complexes that are more efficient and show fewer undesired effects associated with their use in medicine. Thus in this work, six new complexes of platinum and palladium were isolated with 4- nitrobenzoic hydrazide(4-NH), acid 2-furoic hydrazide(FH) and 2,4- dinitrophenylhydrazine(2,4-DNPH). These complexes were characterized by spectroscopic techniques and the results have shown that the ligands are coordinated to platinum or palladium by the basic nitrogen of NH2 group and have the general formula [M(L)2X2].nH2O where M= Pt2+ or Pd2+, X = Cl- or I- and n = 0 or 1. Infrared Analyses were made in the region of 400 - 4000 cm-1, except the complex with the ligand 2,4 - dinitrophenylhydrazine which began in the range of 200 cm-1. In addition, UV spectroscopy was performed on-visible range of 200-800 nm. The thermal stability of the complexes containing acid 2-furoic hydrazide and 2, 4-dinitrophenylhydrazine was analyzed in the temperature range 25 900 ºC. The antitumor activity of the synthesized compounds has been studied. The compound [Pt(4-NH)2I2], was found to display cytotoxicity (IC50 = 0.96 &#956;mol/L) against K562 tumoral cell line and, when compared to cisplatin, it was five times more active. / Alguns compostos de platina(II), como por exemplo, a cisplatina, a oxaloplatina e a carboplatina, têm sido utilizados como agentes quimioterápicos no tratamento de alguns tipos de câncer, sendo que vários outros complexos deste íon metálico encontram-se em fase de testes clínicos. Entretanto, estes fármacos apresentam diversos efeitos colaterais severos e, além disso, tem sido observado o aparecimento de resistência celular. Nesse sentido, vários grupos de pesquisa têm buscado a síntese de novos complexos de platina que sejam mais eficazes e que apresentem uma diminuição dos efeitos indesejáveis associados à utilização destes na medicina. Assim, neste trabalho seis novos complexos de platina(II) e paládio(II) foram isolados com os ligantes 4-nitrobenzóico hidrazida(4-NH), ácido 2-furóico hidrazida(FH) e 2,4 dinitrofenilhidrazina(2,4-DNPH). Esses complexos foram caracterizados por técnicas espectroscópicas e, os resultados mostram que os ligantes estão coordenados ao íon platina ou paládio via nitrogênio (NH2) e possuem a fórmula geral [M(L)2X2].nH2O, em que M= Pt2+ ou Pd2+, X = Cl- ou I- e n = 0 ou 1. As analises de infravermelho foram feitas na região de 400- 4000 cm-1, salvo os complexos com o ligante 2,4- dinitrofenilhidrazina que começaram na faixa de 200 cm-1. Além disso, a espectroscopia na região do UV-visível foi feita na faixa de 200-800 nm. A estabilidade térmica dos complexos contendo os ligantes ácido 2-furóico hidrazida e 2,4- dinitrofenilhidrazina foi avaliada no intervalo de temperatura compreendido entre 25- 900°C. A atividade antitumoral dos compostos sintetizados foi estudada contra a linhagem celular tumoral K562. O composto [Pt(4-NH)2I2] exibe uma ótima atividade antiproliferativa (IC50 = 0,96 &#956;mol/L) e, se comparado à cisplatina, é cerca de cinco vezes mais ativo. / Mestre em Química

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12803号 / 論医博第2075号 / 新制||医||1001(附属図書館) / 80847 / (主査)教授 伊達 洋至, 教授 武藤 学, 教授 川上 浩司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and urgently requires new therapies. Oncolytic viruses (OV) are a strong contender. OVs interact with immune components of the TME, which can be altered due to specific genetic mutations. The present study evaluates the impact of specific tumour mutations on the response to carboplatin, the current standard of care, and VSV∆M51, a promising OV candidate. After a study of genetically diverse models, constitutive KRas activation enhanced VSV∆M51 replication in-vitro and sensitivity in syngeneic in-vivo models. VSV∆M51 prolonged survival in syngeneic tumour- bearing mice with KRas, Trp53 and Pten mutations, including one tumour model that did not respond to carboplatin. Response to VSV∆M51 in-vivo was associated with activation of CD4+ and CD8+ T lymphocytes in the peritoneal TME. In summary, VSV∆M51-based immunotherapy has shown promise in diverse murine models of EOC bearing clinically relevant mutations.

No description available.

In this study, we have explored the combination of a novel Purine Nucleoside Phosphorylase mediated Gene-Directed Enzyme Prodrug Therapy (PNP-GDEPT) with chemotherapeutics, Taxotere and/or Carboplatin to target prostate and ovarian cancer (PC & OC). PNP converts the prodrug (Fludarabine-phosphate) to a toxic purine, 2-fluoroadenine (2FA) that inhibits RNA/DNA synthesis. Taxotere is active against late stage PC whilst carboplatin is first line therapy for OC. Neither modality is adequately effective. We expect that a combination will target heterogeneity via cytotoxicity to diverse cancer cell populations leading to effective synergies, which may improve efficacy and quality of life. For PC, Synergy between Ad-PNP-GDEPT and Taxotere were assessed in vitro and in vivo. Cell killing effects of combination led to significant synergistic killing of human PC-3 & murine RM1 PC cells accompanied by enhanced apoptosis. A lower individual dose (by up to 8 fold) led to enhanced efficacy. In vivo, the combination regimen given at the suboptimal doses led to reduction in local tumour (PC-3 & RM1) growth in nude and in C57BL/6 mice, respectively. A significant reduction in lung RM1 colony numbers indicated enhanced systemic efficacy. Combination treated mice also displayed significantly improved survival (25 days vs 15 days for control mice). Importantly, the condition of combination treated mice (e.g. weight loss) was better than those given individual treatments. The possible involvement of the immune system in this enhanced effect is under investigation. For OC, three-way synergy between Ad-PNP-GDEPT, Taxotere and carboplatin was effectively demonstrated in SKOV-3 and OVCAR-3 cells. This was significantly greater than bimodal or individual treatments. A 10-50 fold dose reduction of individual treatments was effective when combined, accompanied by enhanced apoptosis. Western-blotting analyses revealed a shift in the expression of anti-apoptotic and proapoptotic proteins upon treatment with various combinations. This is the first demonstration of synergy between these modalities.

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2014-12-11T16:01:41Z No. of bitstreams: 2 Tese -Cesar Augusto Sam Tiago Vilanova Costa - 2013.pdf: 2101811 bytes, checksum: 1cf67584701df4c2df1009b299703f7b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Jaqueline Silva (jtas29@gmail.com) on 2014-12-11T19:00:48Z (GMT) No. of bitstreams: 2 Tese -Cesar Augusto Sam Tiago Vilanova Costa - 2013.pdf: 2101811 bytes, checksum: 1cf67584701df4c2df1009b299703f7b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-12-11T19:00:48Z (GMT). No. of bitstreams: 2 Tese -Cesar Augusto Sam Tiago Vilanova Costa - 2013.pdf: 2101811 bytes, checksum: 1cf67584701df4c2df1009b299703f7b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-02-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Não consta resumo em outro idioma. / Foi com a descoberta da atividade antimitótica da cisplatina por Rosenberg na década se 1960 e 70, em seu célebre estudo com bactérias Escherichia coli, que surgiu o interesse em sintetizar e entender as bases moleculares responsáveis pelo mecanismo de ação biológica dos compostos metálicos, visto que a própria cisplatina foi inicialmente sintetizada por Peyrone nos idos de 1840. Os primeiros estudos envolvendo o uso de complexos metálicos de rutênio como agentes antitumorais foram realizados por Tochter no final dos anos 1980 (Dale et al., 1992). Àquela época, foi inferido que todos os compostos de rutênio apresentavam como mecanismo de ação, a sua ligação com o DNA, formando adutos e desencadeando processos celulares de natureza deletéria que, por fim, levariam a morte celular. É interessante lembrar que esse é o mesmo mecanismo de ação dos compostos de platina mais aceitos nos dias atuais. Sadler e Dyson (2003) estudando compostos de rutênio que continham cloro em sua estrutura, como o cloreto de cis-(dicloro)tetraaminorutênio(III) [cis-[RuCl2(NH3)4]Cl], observaram que estes compostos apresentavam mecanismos de ação biológica muito parecidos com os apresentados pela cisplatina [Pt(NH3)2Cl2], onde a hidrólise da ligação Ru–Cl pode ser fortemente influenciada pela natureza dos coligantes presentes na estrutura do rutenato, como grupamentos amino ou até mesmo pela presença de átomos de carbono. A alta concentração de cloretos no sangue permite a esses compostos metálicos, levados por proteínas séricas, chegar até as células e atravessar sua membrana celular e nuclear. Uma vez no interior do núcleo, a ligação Ru–Cl é hidrolisada, devido a queda abrupta da concentração de cloretos (que é cerca de 25 vezes menor), levando o composto a se ligar ao DNA, mais especificamente à posição N7 da base nitrogenada guanina. Por outro lado, compostos que não possuem cloro em sua estrutura, parecem apresentar mecanismos de ação diferentes ao padrão "ligação ao DNA". Sabe-se que compostos que apresentam carboxilatos em sua molécula, como a carboplatina, oxaliplatina e o próprio ditionato de cis-tetraammino(oxalato)rutênio(III) [Cis-[Ru(C2O2)(NH3)4]2(S2O6)], uma vez no interior das células, são hidrolisados muito mais lentamente do que os compostos ricos em cloretos, o que leva a um acúmulo desses compostos no citoplasma, diminuindo sua migração até o núcleo e, assim reduzindo a sua capacidade de se ligar ao DNA. Mas se o DNA não é o alvo desses compostos, então, quem poderia ser? Essa pergunta está sendo respondida com recentes estudos, que revelaram a interação desses compostos, ricos em carboxilatos, com uma miríade de proteínas e enzimas, que vão desde catepsinas, chegando até mesmo à Pgp (Melchart & Sadler, 2008). Estudos realizados por Dyson e colaboradores (2007), utilizando alguns inibidores da proteína Pgp, como fenoxazinas e antracenos, coordenados com compostos de rutênio, observaram que estes novos complexos não somente inibiram a ação da enzima, como também induziram morte celular, demonstrando uma multifuncionalidade. Seguindo essa linha de pensamento, acreditamos que a capacidade do composto ditionato de cistetraammino(oxalato)rutênio(III) em induzir apoptose nas células tumorais, assim como os baixos níveis de expressão de Pgp apresentados pelas células tratadas, corroboram os resultados previamente observados por outros grupos, utilizando compostos de rutênio similares. A resistência a fármacos mediada por Pgp é o mecanismo de MDR mais estudado atualmente. Apesar do desenvolvimento de novos agentes antitumorais, a MDR mediada pela Pgp protege as células de possíveis agentes citotóxicos, limitando a eficácia dos tratamentos quimioterápicos em pacientes com câncer. Atualmente, a extensa maioria dos inibidores da Pgp disponíveis estão associados a vários inconvenientes, que limitam o seu uso no reestabelecimento da eficácia da quimioterapia antineoplásica, após o aparecimento do fenótipo MDR. A procura de inibidores de Pgp alternativos, com um processo sintético exequível e efeitos secundários reduzidos, continua a ser um desafio para os químicos, farmacêuticos e pesquisadores. É nesse contexto que estão sendo desenvolvidos e estudados novos agentes antitumorais que possam agir como inibidores de Pgp, apresentando um efeito dual, ou até mesmo multifuncional, no tratamento clínico das neoplasias malignas. Muito tem se discutido que a próxima geração de fármacos antitumorais poderá ser formada por substâncias que se ligam a mais do que um único alvo terapêutico, o que poderia acelerar tratamento contra a doença, reduzindo o número e a concentração de fármacos que deveriam ser administrados, como os coquetéis atualmente utilizados, e até mesmo aumentando a adesão ao tratamento por parte do paciente. No presente trabalho, estudamos dois complexos de rutênio, o cloreto e o ditionato de rutênio(III), que se apresentam como promissores no possível desenvolvimento de um novo fármaco antitumoral. Essa promessa transparece no fato de ambos serem de síntese química relativamente simples (processo sintético exequível) e, principalmente, por apresentarem efeito biológico de interesse em células tumorais, como citotoxicidade e indução de morte celular, especialmente por apoptose. Pelo que foi observado nos resultados de nossa pesquisa, os complexos aqui estudados, podem constituir um modelo para o estudo de novos agentes anticancerígenos com concomitante capacidade de não induzir MDR. Esta característica se mostrou muito evidente sobre a linhagem leucêmica K-562, onde os níveis de expressão de MDR1, após o tratamento com os rutenatos, foram muito inferiores aos apresentados pelas células tumorais tratadas com o fármaco controle Cisplatina. Ainda, é importante pontuar que o composto ditionato de cistetraammino(oxalato)rutênio(III) apresentou efeito citotóxico em ambas as linhagens tumorais K-562 e A549, sem contudo induzir altos níveis de expressão de Pgp (MDR1), apresentados pelos fármacos platinados. Assim, estudos mais aprofundados sobre a estrutura e funcionamento biológico desses complexos de rutênio, representam um ponto de partida interessante para o desenvolvimento de fármacos multifuncionais e de efeito desejável, auxiliando na delineação de estudos clínicos dirigidos a grupos selecionados de pacientes que reúnam características genotípicas e fenotípicas preditivas de máxima resposta terapêutica com mínima toxicidade. Posteriormente, estes estudos podem levar às realizações de testes diagnósticos e farmacológicos mais eficazes que poderão ser estabelecidos como rotina voltada para uma melhor definição de tratamentos. Isso traria um maior sucesso no teste de novos medicamentos e reduziria os custos e riscos, minimizando o tempo gasto para aprovação de um novo medicamento e a sua disponibilização para a sociedade.

Ovarian cancer is serious and one of the most common gynecologic cancers. Carboplatin is the therapeutic agent of the first choice in the ovarian cancer therapy. However, after the primary therapeutic response to carboplatin, the relapse of the disease may occur with developed resistance to carboplatin. Chemoresistance and insufficient therapy response are considered to be the reason of the high mortality rate of ovarian cancer. The DNA damage response pathways play an important role in the therapeutic response and chemoresistance development. Restoration of homologous recombination function in cancers is the key mechanism of resistance development to platinum agents. Based on this knowledge, we formed our hypothesis, that the inhibition of homologous recombination could increase the sensibility to carboplatin. The main goal of this thesis was to define the role of double-strand breaks repair in response to chemotherapy of ovarian cancer. Protein MRE11 is part of the MRN complex, that participates in double-strand breaks repair. Using mirin as a pharmaceutic inhibitor of MRE11 we were aiming to determine the impact of homologous recombination on the effect of carboplatin and its role in resistant development to carboplatin. In the practical part of the thesis, we described the association between...