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Thesis (doctoral)--Ludwig-Maximilians Universität München, 2002.

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L’hypothèse prédominante de cette thèse est que les traitements utilisés pour le cancer du sein de stade précoce (chimiothérapie avec des anthracyclines et/ou avec l’anticorps monoclonal trastuzumab) peuvent amener à des toxicités cardiaques à long terme, et qu’une évaluation de ce risque cardiaque ainsi qu’un suivi à long terme sont importants. Pour évaluer la toxicité cardiaque secondaire à ces deux agents chez les patientes avec un cancer du sein de stade précoce, nous avons réalisé deux séries d’études cliniques, la première pour évaluer la toxicité cardiaque à long terme induite par les anthracyclines, et la deuxième pour explorer la toxicité cardiaque induite par le trastuzumab. 1) Le premier chapitre de cette thèse explore la toxicité cardiaque à long terme induite par la chimiothérapie administrée aux patientes avec cancer du sein de stade précoce et ganglions positifs. La population de notre étude a été recrutée au sein de la population d’une étude de phase III randomisée menée entre 1988 et 1996 en Belgique et comparant trois schémas de traitement de chimiothérapie adjuvante, soit deux différents protocoles de chimiothérapies à base d’anthracyclines (basse dose ou haute dose d’epirubicine) ainsi qu’un schéma de chimiothérapie sans anthracyclines (CMF classique). Nous avons identifié 82 patientes (30%) traitées avec chimiothérapie adjuvante dans cette étude qui n’avaient pas de signe de récidive en 2010 (survivantes à long terme). Une évaluation cardiaque approfondie de ces patientes a été effectuée, incluant une échographie cardiaque, une résonance magnétique nucléaire, des marqueurs cardiaques sériques (pro-BNP et troponine), ainsi qu’un test de marche de 6 minutes. Cette étude nous a permis de démontrer que la toxicité cardiaque à long terme liée aux anthracyclines reste faible, et que la résonance magnétique est potentiellement plus précise que l’échographie cardiaque pour mesurer la fonction du ventricule gauche. Ceci devra cependant être confirmé dans d’autres études. Au cours de notre démarche, nous avons été confrontés à la difficulté de motiver les patientes plusieurs années après le traitement pour étudier les potentiels effets à long terme de ce dernier. 2) Le deuxième chapitre de cette thèse explore la toxicité cardiaque induite par l’anticorps monoclonal trastuzumab (anti-HER2). En un premier temps, nous avons examiné la toxicité cardiaque immédiate et à long terme au sein de la population de l’étude HERA, un large essai clinique randomisé de phase III du Breast International Group évaluant le bénéfice du trastuzumab en traitement adjuvant du cancer du sein HER2-positif. Après un suivi moyen de 8 ans des 5,102 participantes de l’étude, nous avons pu démontrer que la toxicité cardiaque demeure faible à long terme, avec très peu de nouveaux évènements cardiaques diagnostiqués dans la phase de suivi. Nous avons aussi pu démontrer que la toxicité cardiaque du trastuzumab apparait surtout pendant la phase de traitement, et qu’une fois le trastuzumab arrêté, la majorité des patientes récupèrent de l’épisode de toxicité cardiaque avec normalisation de la fraction d’éjection ventriculaire gauche. En un deuxième temps, en effectuant une analyse combinée de la toxicité cardiaque dans trois essais cliniques randomisés, nous avons démontré que l’usage concomitant du trastuzumab avec une chimiothérapie néo-adjuvante à base d’anthracyclines augmente le risque d’une toxicité cardiaque chez les patientes ayant un cancer du sein de stade précoce. Conséquemment, ces schémas de traitements ne sont pas recommandés de routine.En conclusion, une bonne évaluation cardiologique et oncologique doit avoir lieu avant de démarrer une chimiothérapie à base d’anthracyclines chez les patientes ayant un cancer du sein de stade précoce. Actuellement, la recommandation est d’évaluer les facteurs de risque cardiaque avant le traitement, et de suivre la fraction d’éjection du ventricule gauche avant, pendant et environs 6 mois après la fin du traitement. L’usage de marqueurs cardiaques et/ou de tests d’imagerie modernes pour un diagnostic de toxicité cardiaque tardive reste un domaine d’investigation intéressant. Pour les patientes avec un cancer du sein HER2-positif de stade précoce, le risque de toxicité cardiaque induite par le trastuzumab demeure faible. Cependant, les facteurs de risque doivent être évalués pour chaque patiente avant le traitement. L‘usage concomitant de trastuzumab et anthracyclines n’est pas recommandé vu le risque augmenté de toxicité cardiaque. En cas de facteurs de risque cardiaque, un dialogue étroit entre l’oncologue et le cardiologue est recommandé avant de débuter un traitement adjuvant. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world and Taiwan. The major factors involved in the molecular pathogenesis for the development of HCC had been explored in recent years. An extensive array of growth factors and their receptors had been identified and may act as positive and negative modulators in different stages of hepatocarcinogenesis. Current therapeutic approaches for HCC include surgical resection (include liver transplantation), trans-arterial embolization (TAE), alcohol injection, etc. However, the effect is limited due to most of the HCC patients present with advanced stages of the disease. Therefore, this underscores the need for the development of novel therapeutic strategies. It is pivotal to set up an orthotopic hepatoma model for the development of novel intervention strategies for HCC. Under the guidance of ultrasound, we are able to create hepatoma in the liver lobe of Sprague-Dawley (SD) rats by injection of Novikoff (N1-S1) hepatoma cells. In addition, sonographic technique was employed for the monitoring of tumor growth in this animal model in the following subprojects. The continuous, non-invasive measurement of orthotopic hepatoma development will be a valuable tool for the evaluation of effects of drugs for treatment of HCC. In Chapter 1, the study employed a relatively non-invasive approach to establish an orthotopic HCC model in immune-competent rats. This was done by ultrasound-guided implantation of cancer cells and the model was used to evaluate the therapeutic efficacy of short-term and low-dose epirubicin chemotherapy. Ultrasound-guided implantation of Novikoff hepatoma cells led to the formation of orthotopic HCC in 60.4% of the SD rats. Moreover, tumor sizes measured by ultrasound significantly correlated with those measured by calipers after sacrificing the animals (P < 0.00001). The rate of tumor induction by ultrasound-guided implantation was comparable to that of laparotomy (55/91, 60.4% vs. 39/52, 75%) and no significant difference in sizes of tumor was noted between the two groups. Moreover, there was a significant correlation in tumor size measurement by ultrasound and computerized tomography. In tumor-bearing rats, short-term and low-dose epirubicin chemotherapy caused a significant reduction in tumor growth, and was found to be associated with enhanced apoptosis and attenuated proliferation as well as a decrease in microvessel density in tumors. In chapter 2, we investigated the chemopreventive effects of celecoxib in the growth of orthotopic rat HCC and the possible signal pathways involved. The status of COX-2 expression in rat Novikoff HCC was consistent with that in human HCC. Both Western blot and PCR tests had proved that N1-S1 was a HCC model presenting with low COX-2 enzymes in tumor cells. Then, low doses of celecoxib was shown to effectively inhibited the proliferation and increased the apoptosis of N1-S1 cells in vitro, which were also safe to the normal hepatocytes. Moreover, chemoprevention by celecoxib inhibiting the HCC tumor growth was shown in rat orthotropic HCC model. Tumor incidence was not affected by the celecoxib prevention, but, tumor weight was found significantly suppressed by the drug. Possible mechanisms of chemoprevention by celecoxib seen in the animal model were thought to be related to the anti-angiogenic, anti-proliferative and anti-hCSC characters of the drug. In chapter 3, we tried to test the combined inhibitory effects of low doses of celecoxib and epirubicin on the growth of HCC. Combined low doses of epirubicin and celecoxib was effective in inhibiting the hepatic cancer stem cells, tumor angiogenesis, tumor cell proliferation, as well as promoting cancer apoptosis. These are compatible with the effects of the individual drugs on HCC growth shown in the previous two chapters. In general, combination therapy expressed more effectiveness in tumor suppression and less bone marrow suppression than the individual drugs used alone. Taken together, ultrasound-guided implantation of Novikoff hepatoma cells is an effective means of establishing orthotopic HCC in SD rats, which is suitable and convenient for therapeutic trial of anti-HCC treatment. In the current study, we had proved the efficacies of low doses of two drugs, epirubicin and celecoxib, acting individually, as well as the combined effects of them in treating HCC in this model.

A recent clinical trial for locally advanced breast cancer patients treated with epirubicin and docetaxel prior to surgery reported significant dose-dependent reductions in tumour RNA integrity values which correlated with pathological complete response. The purpose of the present study was to assess whether similar chemotherapy-dependent alterations in RNA integrity could occur in vitro and to assess its relationship, if any, to apoptosis. Treatment of wildtype A2780 ovarian carcinoma cells with taxanes resulted in dose- and time-dependent RNA degradation, identified as several unique bands on electropherograms having mobilities lower than the 28S and 18S rRNAs. We refer to this chemotherapy-dependent generation of aberrant RNA bands on electropherograms as “RNA disruption”. RNA disruption was found to be temporally associated with the induction of apoptosis, as determined by the appearance of a sub G1 peak of DNA content, positive annexin-V staining, and both PARP-1 and caspase-3 cleavage. Treatment of cells with a caspase-3 inhibitor resulted in a significant reduction in rRNA disruption, suggesting the involvement of caspase-3 or related caspases in RNA disruption. In contrast, docetaxel-dependent rRNA disruption was absent when docetaxel was administered to docetaxel-resistant A2780DXL cells, indicating that changes in RNA integrity may possibly differentiate between responsive and non-responsive tumours in cancer patients.

Made available in DSpace on 2015-03-26T13:47:16Z (GMT). No. of bitstreams: 1 texto completo.pdf: 1204854 bytes, checksum: 3444b450baa838c9ffdcfffb1cfd08bd (MD5) Previous issue date: 2013-07-05 / Some drugs, such as doxorubicin, among other mechanisms act by triggering apoptosis, which not only affects the tumor but also normal cells in the body. Therefore, the study of the side effects of chemotherapy, seeking a less aggressive treatment for cancer patients, justifies this work. The objective was to investigate the hematological and gastrointestinal effects of doxorubicin and tamoxifen when used alone or in combination in male mice with or without the Ehrlich ascites tumor, with or without hormone therapy with estradiol cypionate. A total of 40 Balb / C male mice were divided into groups of 5 animals each, making 8 groups. At the end of 21 days, blood samples were collected for CBC (Complete Blood Count), aiming at evaluating parameters such as RBC count and hematocrit, hemoglobin, white blood cells count and platelets count. Samples of the stomach and intestines of the animals treated with hydrochloride doxorubicin, were also collected for histopathologic analysis, evaluating when present, the degree of damage to the epithelium and the degree of necrosis and apoptosis glands. The evaluation of the number of erythrocytes and the hematocrit value was significantly decreased (p <0.05) in groups I and VIII when compared to the other groups. Hemoglobin showed a significant decrease in group I in relation to groups II, III, IV and V. Counting the number of leukocytes showed a significant increase (p <0.05) when comparing groups I and VI with the other groups. The main histopathological changes evidenced in the stomach and small intestine were necrosis and apoptosis and loss of glands lining epithelium, and the group VII showed a slight decrease in the degree of lesions in group V. / Alguns medicamentos, como o cloridrato de doxorrubicina, atuam dentre outros mecanismos, desencadeando as vias da apoptose, que atingem não só o tumor, mas também as células normais do organismo. Por isso, o estudo dos efeitos colaterais dos quimioterápicos, buscando um tratamento menos agressivo para o paciente oncológico, justifica a realização deste trabalho. O objetivo foi verificar possíveis efeitos hematológicos e gastrointestinais das drogas doxorrubicina e tamoxifeno quando utilizadas em terapia ou em conjunto, em camundongos machos portadores ou não do tumor ascítico de Ehrlich, com e sem terapia hormonal com cipionato de estradiol. Foram utilizados 40 camundongos Balb/C machos, divididos em grupos de 5 animais cada, totalizando-se 8 grupos. Ao final de 21 dias, foi coletado sangue para a realização de hemograma, avaliando-se parâmetros como contagem de hemácias e hematócrito, dosagem de hemoglobina, contagem de leucócitos totais e contagem de plaquetas e amostras do estômago e intestino dos animais tratados com cloridrato de doxorrubicina, foram coletadas para análise histopatológica, avaliando-se quando presente, o grau das lesões no epitélio e o grau de necrose e apoptose das glândulas. A avaliação do número de hemácias e do valor do hematócrito apresentou diminuição significativa (p<0,05) nos grupos I e VIII quando comparado aos demais grupos. A dosagem de hemoglobina demonstrou diminuição significativa no grupo I em relação aos grupos II, III, IV e V. A contagem do numero de leucócitos demonstrou aumento significativo (p<0,05) quando se compararam os grupos I e VI com os demais grupos. As principais alterações histopatológicas evidenciadas no estomago e intestino delgado foram necrose e apoptose de glândulas e perda de epitélio de revestimento, sendo que o grupo VII demonstrou leve diminuição no grau das lesões em relação ao grupo V.

<p>Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect.</p><p>Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases.</p><p>Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases.</p><p>In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.</p>

Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect. Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases. Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases. In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.