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Malignant gliomas are the most common primary brain tumors in adults. Patients with these highly malignant tumors have an extremely poor prognosis. The situation with a highly proliferative tumor in a non-proliferating tissue should favor cytostatic treatment but so far the role of conventional chemotherapy has been adjunctive. The concentrations of three sex steroids, estradiol, progesterone and testosterone, were analyzed by radioimmunoassay after celite chromatography in brain tumor samples. Some malignant gliomas had high tissue concentrations of estradiol. Low progesterone levels may suggest steroid consumption. Estramustine (EM), a conjugate of estradiol-17ß and nornitrogen mustard had a dose-dependent antiproliferative effect on several human malignant glioma cell lines. At equimolar concentrations the inhibitory effects of the EM complex were clearly more pronounced than those of estradiol and nornitrogen mustard given alone or in combination. A specific binding protein (EMBP) is important for the cytotoxic action of EM. Using a mouse monoclonal antibody and an indirect antibodyperoxidase technique, EMBP was demonstrated in human glioma cells. Significant amounts of EMBP were also detected in human brain tumor tissue by radioimmunoassay. The mean concentrations (ng/mg protein) in 16 astrocytomas (2.6) and 7 meningiomas (5.1) were higher (p&lt;0.001) than in 18 samples of normal brain (0.5). The presence of the specific binding protein may suggest a selective binding and effect of EM in human brain tumor tissue. Human glioma cells displayed significant uptake, retention and metabolism of estramustine phosphate (EMP). After incubation with ^H-EMP a progressive uptake of radioactivity was recorded during 24 hours. Metabolism of parent EMP into estramustine and estromustine, which is a well known part of the metabolic pathway in man, was also demonstrated. A dose- dependent increase in DNA strand breaks was recorded at EMP- concentrations ranging 10-40 yg/ml. The uptake of ®^Rb, used as a tracer for potassium to study ion transport and membrane permeability, was reduced after incubation with EMP. Scanning electron microscopy gave further evidence for membrane damage. According to flow cytometric analyses exponentially growing glioma cells were accumulated in the G2/M stage and the fraction of Gi/Gq was reduced. EM seems to attack malignant cells in a multifocal fashion on several vital functions including the microtubule, the nucleus, and the cell membrane. The intact EM complex may be important for effects related to microtubule function which add to the cytotoxic potential of its constituents. These experimental findings justify further investigations on the role of sex hormones in brain tumor growth and development and of hormone-linked cytostatics in clinical treatment. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1990, härtill 6 uppsatser.</p> / digitalisering@umu

Anthracene was attached to light activated, ruthenium-based DNA disruptors to probe their distribution in cancer cells. The objective of this research is to understand the photophysical properties (Chapter 2), photoreactivity toward DNA and proteins (Chapter 3), and localization within cancer cells (Chapter 4) of ruthenium complexes that demonstrate promise as photodynamic therapy (PDT) agents. [(AnthbpyMe)(bpy)Ru(dpp)]2+ (1) and [(AnthbpyMe)2Ru(dpp)]2+ (2) absorb visible light with metal-to-ligand charge transfer (MLCT) transitions at 459 nm (16,000 M-1 cm-1 ) and 461 nm (21,000 M-1 cm-1 ), respectively. These species exhibit 3 MLCT emissions at λem = 661 nm and λem = 663 nm for 1 and 2, respectively, while the anthracene show emissions at 450 – 560 nm. The anthracene unit(s) quench the 3 MLCT to give quantum yields (lifetime) of Φem = 0.0059 [398(1) ns] and Φem = 0.0011 [414(1) ns] for 1 and 2, respectively. Voltammetry shows an irreversible anthracene oxidation at 1.23 – 1.28 V, RuIII/II oxidation at 1.53 – 1.55 V, and quasi-reversible reduction couples attributed to dpp0/-1 at 0.98 V. DNA gel shift assays demonstrate that complexes 1 and 2 modify DNA in the presence and absence of 3 O2 upon light activation to convert supercoiled DNA to a mixture of open circular (OC) DNA and a species that exhibit sa distinctly different migration rate than either OC and linear DNA. Binding constants, Kb, for complexes 1 and 2, toward DNA are 3.50 × 105 (3.50 × 104 ) and 4.50 × 103 (4.50 × 102 ) respectively. SDS-PAGE assays show that the complexes 1 and 2 modify bovine serum albumin (BSA) through an 3 O2-dependent mechanism upon light iii activation. The localization and PDT potency of the anthracene-Ru-dpp complexes are tested against F98 cells, which are rat glioma cells that simulate the infiltrative patterns of growth in cancer. Confocal microscopy demonstrates that complexes 1 and 2 internalize and localize primarily along the cell membrane and associate with dot-like vesicles within the cytoplasm. Complexes 1 and 2 show IC50 values of 107 µM and 85 µM, respectively, after 15 min of drug exposure and 1 h of PDT-treatment (λPDT = 455 nm). / Ph. D.

Die vorliegende Arbeit ist eine retrospektive Kohortenstudie, welche alle Patienten einschloß, die im Zeitraum von 07/1988 bis 06/1997 aufgrund eines anaplastischen Astrozytoms oder eines Glioblastoma multiforme im damaligen Rudolf-Virchow-Klinikum in Berlin eine Strahlentherapie des Kopfes erhielten. Von den 111 Patienten erlitten im Beobachtungszeitraum 85 ein radiologisches Rezidiv. Die mediane Überlebenszeit betrug 9 Monate. 69 der Rezidive waren Zentralrezidive, 7 Randrezidive und 9 Fernrezidive. Auch die Rand- und Fernrezidive rezidivierten zusätzlich am Ort der Primärläsion. Es konnte gezeigt werden dass ein Sicherheitsabstand von 2-3 cm ausreicht um 90% der Rezidive vollständig zu erfassen und dass die lokale Kontrolle weiterhin das Hauptproblem bei der Behandlung dieser malignen Gliome ist. / This retrospective study reviews the data of 111 patients treated from 07/1988 to 06/1997 at the Rudolf-Virchow-Klinikum in Berlin. Both patients with anaplastic astrocytoma and glioblastoma multiforme were included. 85 patients showed radiological recurrence of tumour. Median survival was 9 months. 69 recurrences were central, 7 near and 9 distant recurrences. Near and distant recurrences were always multifocal, i. e. they recurred also at central locations. It was shown that a safety margin of 2-3 cm is sufficient to completely cover 90% of recurrent tumour. Local failure is still the primary difficulty in treating these malignant glioma.

Les gliomes malins de l’enfant (GME), de pronostic sombre, se distinguent des gliomes malins de l’adulte (GMA) sur le plan biologique mais aussi clinique, avec des taux de réponse au témozolomide (chimiothérapie alkylante de référence chez l’adulte) moindres. L’efficacité du temozolomide est réduite par l’action de l’enzyme de réparation de l’ADN, l’O6-methylguanine-DNA-methyltransferase (MGMT), dont l’expression est fréquemment inhibée par méthylation du promoteur de son gène dans les GMA. En première partie, la mise au point d’une nouvelle technique de PCR spécifique de méthylation a montré une fréquence plus faible dans les GME (15%) vs les GMA (45%, p<0,001). En deuxième partie, l’hypoxie intra-tumorale et la dérégulation en amont de l’axe mTOR-HIF-1α, connus pour être impliqués dans la chimio-résistance, ont été étudiés dans les GME et ciblés par l’association rapamycin-irinotecan dans une étude in vitro, pour laquelle des lignées dérivées de GME ont été développées. / Pediatric malignant glioma (PMGs), are associated with a very dismal prognosis. They are distinct from their adult counterparts (AMGs), biologically but also clinically, with a lower response to temozolomide (the current reference alkylating chemotherapy) compared to AMGs. Temozolomide efficacy is reduced by the activity of the DNA repair enzyme, O6-methylguanine-DNA-methyltransferase (MGMT), whose expression is frequently silenced by promoter methylation. First, the development of a new methylation-specific PCR showed a lower frequency of MGMT methylation in PMGs (15%) vs AMGs (45%, p<0,001). Secondly, intra-tumor hypoxia and the upstream deregulation of mTOR-HIF-1α axis, well-known to be involved in chemo-resistance and the up-regulation of MGMT expression, were studied in a PMG cohort. The targeting of this axis was then studied in vitro using a therapy combining rapamycin and irinotecan. For this, pediatric patient-derived malignant glioma cell lines were developed.

Glioblastoma (GBM) is the most common and deadliest of the malignant primary brain tumors in humans, with a reported 5-year survival rate of only 6.8% despite years of extensive research. Failure to improve local tumor control rates and overall patient outcome is attributed to GBM's inherent therapeutic resistance. Marked heterogeneity, extensive local invasion within the brain parenchyma, and profound immunosuppression within the tumor microenvironment (TME) are some of the unique features that drive GBM therapeutic resistance. Furthermore, tumor cells are sequestered behind the blood-brain barrier (BBB), limiting delivery of effective therapeutics and immune cell infiltration into the local tumor. Electroporation-based therapies, such as irreversible electroporation (IRE) and second generation, high-frequency IRE (H-FIRE) represent attractive alternative approaches to standard GBM therapy given their ability to induce transient BBB disruption (BBBD), achieve non-thermal tumor cell ablation and stimulate local and systemic anti-tumor immune responses without significant morbidity. The following work explores the use of H-FIRE to overcome GBM-induced therapeutic resistance and improve treatment success. Chapter 1 opens with an overview of GBM and known barriers to treatment success. Here, we emphasize the utility of spontaneous canine gliomas as an ideal translational model for investigations into novel treatment approaches. Chapter 2 introduces novel ablation methods (i.e. IRE/H-FIRE) capable of targeting treatment-resistant cancer stem cells. The focus of Chapter 3 is to highlight IRE applications in a variety of spontaneous tumor types. In Chapter 4, we investigate the feasibility and local immunologic response of percutaneous H-FIRE for treatment of primary liver tumors using a spontaneous canine hepatocellular carcinoma (HCC) model. In chapter 5, we characterize the mechanisms of H-FIRE-mediated BBBD in an in vivo healthy rodent model. In Chapter 6, we characterize the local and systemic immune responses to intracranial H-FIRE in rodent and canine glioma models to enhance the translational value of our work. Collectively, our work demonstrates the potential for H-FIRE to overcome therapeutic resistance in GBM, thereby supporting its use as a novel, alternative treatment approach to standard therapy. / Doctor of Philosophy / Glioblastoma (GBM) is the most common and deadliest form of primary brain cancer in humans, with only 6.8% of people surviving 5-years after their diagnosis. GBM is characterized by a number of unique features that make it resistant to standard treatments, such as surgery, radiation and chemotherapy. Examples include: (1) extensive invasion of tumor cells into the brain, making complete removal via surgery very difficult; (2) tumor cells are protected by a structure called the blood-brain barrier (BBB), which restricts the entry of most drugs (i.e. chemotherapy) and many immune cells, into the brain, thereby preventing them from reaching tumor cells; (3) tumor cells produce substances that block the immune system from being able to detect the tumor itself, which allows it to continue to grow undetected. High-frequency irreversible electroporation (H-FIRE) represents a new approach for the treatment of GBM. H-FIRE uses electric pulses to temporarily or permanently injure cell membranes without the use of heat, which allows for very precise treatment. The following work explores the ways in which H-FIRE can interfere with specific GBM features that drive its resistance to treatment. Here, we demonstrate that H-FIRE is capable of temporarily disrupting the BBB and characterize the mechanisms by which this occurs. This allows for drugs and immune cells within the blood to enter the brain and access the tumor cells, particularly those extending beyond the visible tumor mass and invading the brain. We also illustrate the potential for H-FIRE treatment within the brain to stimulate local and systemic immune responses by causing the release of proteins from injured cells. Similar to a vaccine, these proteins are recognized by the immune system, which becomes primed to help fight off cancer cells within the body. The end result is an anti-tumor immune response. Collectively, this work supports the use of H-FIRE as an alternative treatment approach to standard therapy for GBM given its potential to overcome certain causes of treatment resistance.

Patients and methods: Malignant supratentorial glioma (anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma and glioblastoma incl. gliosarcoma), age 16-70y, KPS 50-100. Postoperative randomization to chemotherapy with either BCNU (B) (80 mg/m2 x 3 every 6 weeks) alone or additional VM 26 (V) (50 mg/m2 x 3 every 6 weeks) starting concomitant with radiotherapy. Central histopathological review was required. Primary endpoints were survival time (ST) and progression free survival (PFS) . In addition confirmative analysis of prognostic factors and their interaction with therapy was performed. Results: Eligible: 501 of 522 randomized pts: 82% WHO grade IV gliomas, 18% grade III gliomas. 57% male, mean KPS 74, mean age 50.9 years. The high incidence of lung toxicity – with a cumulative risk of 19% during the first year - was alarming. Survival was not significantly different ( median 50.3 (B) versus 52.4 (V) (weeks), but an increase in long term survivors was observed (18 months: 29% B, 34% V, 5 years 5% B, 12% V) and PFS showed a significant difference with a median of 31.4 (B) versus 34.3 (V) weeks. Qualitative interaction between KPS and therapy (p < 0.01) was demonstrated: pts with a KPS ≥ 70 benefited from additional VM26, those with reduced KPS < 70 did better with BCNU-monotherapy. Conclusion: Adding VM26 to BCNU is effective in the chemotherapy of malignant gliomas. Because of the demonstrated interaction with therapy performance status, not tumor grade is the crucial factor to determine application and aggressiveness of chemotherapy. With risk adapted therapy a significant proportion of patients even with glioblastoma survive for years in good general condition. BCNU should be replaced by an equipotent alkylans to avoid the unacceptable high rate of lung toxicity.

Insulin-like growth factor binding proteins (IGFBPs) modulate the bioavailability of IGFs in circulation. IGFBPs 1-6 bind IGFs with high affinity and can either potentiate or inhibit IGF signaling in a context dependent manner. IGFBP2 is a 36 kDa protein and the second most abundant IGFBP in serum. Numerous studies in the recent past have implied a pro-tumorigenic role of IGFBP2. Elevated expression of IGFBP2 has been observed in multiple malignancies, including glioblastoma multiforme (GBM), ovarian, pancreatic, gastric, prostate, colon, breast, thyroid cancer and leukemia. In addition, increased expression of IGFBP2 in both tissues and serum of patients has been correlated with poor prognosis in prostate, glioblastoma and colon cancers. Pro-tumorigenic actions of IGFBP2 have been supported by in vitro studies, where IGFBP2 increases the tumorigenic potential of adrenocortical tumor cells, epidermoid carcinoma cells, glioma cells and ovarian cancer cells. Further, using xenograft animal models, the role of IGFBP2 in the progression of glioma has been established. In breast cancer, IGFBP2 was found to be over expressed in ductal carcinoma in situ and invasive breast cancer samples. IGFBP2 over expression has been shown to confer drug resistance and an increased expression has been reported to correlate with lymph node metastasis in T1 breast carcinomas. These reports implicate IGFBP2 in breast cancer biology. However, its role in breast cancer progression is not well defined. With this background, the following objectives were set for the current study: Functional characterization of IGFBP2 with respect to its possible role in breast cancer progression. Elucidation of the molecular mechanisms of IGFBP2 actions. Towards this, immunohistochemistry was performed on 132 invasive ductal carcinoma (IDC) grade III tumors using IGFBP2 specific antibody. It was observed that IGFBP2 expression was significantly higher in tumors in comparison to normal tissues that showed no detectable staining for IGFBP2. It was also observed that expression of IGFBP2 significantly correlated with the expression of ER. To understand the functional significance of IGFBP2 over expression in breast cancer, IGFBP2 was characterized with respect to proliferation, survival and tumor forming ability (in vitro and in vivo) in BT474 breast cancer cells. The knockdown of IGFBP2 expression resulted in suppression of colony formation (nearly 70%) in these breast cancer cells, which could be partially reversed upon exogenous addition of IGFBP2 protein. Proliferation assays using stable clones with knockdown of IGFBP2 in BT474 cells showed a significant decrease in proliferation as compared to vector transfected cells in the presence of serum. Culturing of IGFBP2 knockdown breast cancer cells in serum free medium resulted in their growth arrest in G0/G1 phase of cell cycle as compared to control cells, which progressed through the cell cycle. Prolonged culturing of IGFBP2 knockdown cells in serum free condition (up to 72 h) resulted in the increase of cells in sub G1 phase of the cell cycle. Prolonged depletion of growth factors (serum free conditions) could result in apoptosis of these G1 arrested IGFBP2 knockdown cells. When serum starved IGFBP2 knockdown cells were treated with IGFBP2 protein, the cells arrested in G0/G1 phase were able to progress through the cell cycle and concomitant decrease in sub G1 fraction was observed. Knockdown of IGFBP2 resulted in significantly decreased number and visibly smaller colonies in anchorage independent conditions in vitro. Consistent with this observation, in vivo tumor xenograft formation with IGFBP2 knockdown cells also showed significant reduction in tumor weight as compared to vector generated tumors. These results imply that IGFBP2 has potent growth promoting effects on breast cancer and acts as a mitogen/survival factor for breast cancer cells. To elucidate the molecular mechanisms underlying the pro-tumorigenic effects of IGFBP2, the transcriptome profile following IGFBP2 perturbation in breast cancer cells was determined. IGFBP2 knockdown resulted in significant changes in the expression of genes associated with cellular proliferation and tumorigenicity. The down regulated genes were found to be associated with several events, notably cell cycle, p53 and Wnt signaling, as revealed by Gene Set Enrichment Analysis (GSEA). To further validate these results in breast cancer tissues, whole genome expression analysis was performed in 19 breast tumor samples which were categorized as IGFBP2 positive or negative based on immunohistochemical staining pattern. In comparison to IGFBP2 negative tumors, IGFBP2 positive tumors showed increased expression of genes belonging to MAPK, focal adhesion and Wnt signaling pathway. In order to identify the genes commonly regulated by IGFBP2 in cell lines and tumors, the gene expression profiles of IGFBP2 positive versus IGFBP2 negative tumors and IGFBP2 knockdown breast cancer cells were compared. 347 genes were found to be common among IGFBP2 regulated genes in tumors and cell line. The most significant networks representing the web of interactions among these genes were found to be associated with cellular growth and proliferation, cellular movement and nucleic acid metabolism, indicating an association of IGFBP2 expression phenotype to the distinct changes in expression of genes associated with the regulation of cellular growth and migration. Silencing of IGFBP2 in BT474 cells resulted in a reduced IGF signaling as evidenced by the reduced phosphorylation of IGF1R and concomitantly that of ERK. This effect could be reversed upon addition of the IGFBP2 protein, implying that IGFBP2 potentiates IGF signaling in breast cancer cells. Besides IGF ligand and their receptors, regulation of proliferation associated genes like CENPF, TOP2A, CCND1 and FOXM1 by IGFBP2 was observed, thus providing a molecular basis for the pro-proliferative effects of IGFBP2 on breast cancer cells. Addition of IGFBP2 to immortal breast cells resulted in reduced IGF1R signaling and reduced pERK and pAKT signaling. Additionally, the genes involved in cellular proliferation were down regulated upon IGFBP2 treatment in immortal cells. IGFBP2 knockdown clones had reduced expression of FOXM1, a key regulator of cell cycle for G1/S and G2/M transition, and M phase progression. The regulation of CENPF and CCND1 genes was established following over expression of FOXM1 in IGFBP2 knockdown cells. One of the important and novel finding of this study is the regulation of Wnt signaling pathway genes such as CCND1, MMP7, FGF18, MYCBP, FN1 and survivin by IGFBP2. In support of this, β-catenin protein was found to be regulated by IGFBP2 in breast cancer and GBM cells, as evidenced by knockdown and over expression studies. Furthermore, regulation of β-catenin by IGFBP2 was found to involve integrin-FAK and IGF1R signaling. Another important finding of this study is the correlation of IGFBP2 over expression with elevated β-catenin levels in breast tumors. When expression of both IGFBP2 and β-catenin was correlated with the lymph node status of breast cancers, a significant association of IGFBP2 and β-catenin staining with increased lymph node metastasis was observed in comparison with tumors that did not show staining for either protein. Altogether, in this study employing genomic, cellular and molecular approaches, a pro- tumorigenic role for IGFBP2 in breast cancer has been established. Furthermore, this study provides novel insights into the molecular mechanisms employed by IGFBP2 involving IGF1R, FAK and Wnt signaling pathways during breast cancer progression.

Patients and methods: Malignant supratentorial glioma (anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma and glioblastoma incl. gliosarcoma), age 16-70y, KPS 50-100. Postoperative randomization to chemotherapy with either BCNU (B) (80 mg/m2 x 3 every 6 weeks) alone or additional VM 26 (V) (50 mg/m2 x 3 every 6 weeks) starting concomitant with radiotherapy. Central histopathological review was required. Primary endpoints were survival time (ST) and progression free survival (PFS) . In addition confirmative analysis of prognostic factors and their interaction with therapy was performed. Results: Eligible: 501 of 522 randomized pts: 82% WHO grade IV gliomas, 18% grade III gliomas. 57% male, mean KPS 74, mean age 50.9 years. The high incidence of lung toxicity – with a cumulative risk of 19% during the first year - was alarming. Survival was not significantly different ( median 50.3 (B) versus 52.4 (V) (weeks), but an increase in long term survivors was observed (18 months: 29% B, 34% V, 5 years 5% B, 12% V) and PFS showed a significant difference with a median of 31.4 (B) versus 34.3 (V) weeks. Qualitative interaction between KPS and therapy (p < 0.01) was demonstrated: pts with a KPS ≥ 70 benefited from additional VM26, those with reduced KPS < 70 did better with BCNU-monotherapy. Conclusion: Adding VM26 to BCNU is effective in the chemotherapy of malignant gliomas. Because of the demonstrated interaction with therapy performance status, not tumor grade is the crucial factor to determine application and aggressiveness of chemotherapy. With risk adapted therapy a significant proportion of patients even with glioblastoma survive for years in good general condition. BCNU should be replaced by an equipotent alkylans to avoid the unacceptable high rate of lung toxicity.

Cette thèse a été conçu pour explorer les modèles dynamiques de régression, d’évaluer les inférences statistiques pour l’analyse des données de survie et de fiabilité. Ces modèles de régression dynamiques que nous avons considérés, y compris le modèle des hasards proportionnels paramétriques et celui de la vie accélérée avec les variables qui peut-être dépendent du temps. Nous avons discuté des problèmes suivants dans cette thèse.Nous avons présenté tout d’abord une statistique de test du chi-deux généraliséeY2nquiest adaptative pour les données de survie et fiabilité en présence de trois cas, complètes,censurées à droite et censurées à droite avec les covariables. Nous avons présenté en détailla forme pratique deY2nstatistique en analyse des données de survie. Ensuite, nous avons considéré deux modèles paramétriques très flexibles, d’évaluer les significations statistiques pour ces modèles proposées en utilisantY2nstatistique. Ces modèles incluent du modèle de vie accélérés (AFT) et celui de hasards proportionnels (PH) basés sur la distribution de Hypertabastic. Ces deux modèles sont proposés pour étudier la distribution de l’analyse de la duré de survie en comparaison avec d’autre modèles paramétriques. Nous avons validé ces modèles paramétriques en utilisantY2n. Les études de simulation ont été conçus.Dans le dernier chapitre, nous avons proposé les applications de ces modèles paramétriques à trois données de bio-médicale. Le premier a été fait les données étendues des temps de rémission des patients de leucémie aiguë qui ont été proposées par Freireich et al. sur la comparaison de deux groupes de traitement avec des informations supplémentaires sur les log du blanc du nombre de globules. Elle a montré que le modèle Hypertabastic AFT est un modèle précis pour ces données. Le second a été fait sur l’étude de tumeur cérébrale avec les patients de gliome malin, ont été proposées par Sauerbrei & Schumacher. Elle a montré que le meilleur modèle est Hypertabastic PH à l’ajout de cinq variables de signification. La troisième demande a été faite sur les données de Semenova & Bitukov, à concernant les patients de myélome multiple. Nous n’avons pas proposé un modèle exactement pour ces données. En raison de cela était les intersections de temps de survie.Par conséquent, nous vous conseillons d’utiliser un autre modèle dynamique que le modèle de la Simple Cross-Effect à installer ces données. / This thesis was designed to explore the dynamic regression models, assessing the sta-tistical inference for the survival and reliability data analysis. These dynamic regressionmodels that we have been considered including the parametric proportional hazards andaccelerated failure time models contain the possibly time-dependent covariates. We dis-cussed the following problems in this thesis.At first, we presented a generalized chi-squared test statisticsY2nthat is a convenient tofit the survival and reliability data analysis in presence of three cases: complete, censoredand censored with covariates. We described in detail the theory and the mechanism to usedofY2ntest statistic in the survival and reliability data analysis. Next, we considered theflexible parametric models, evaluating the statistical significance of them by usingY2nandlog-likelihood test statistics. These parametric models include the accelerated failure time(AFT) and a proportional hazards (PH) models based on the Hypertabastic distribution.These two models are proposed to investigate the distribution of the survival and reliabilitydata in comparison with some other parametric models. The simulation studies were de-signed, to demonstrate the asymptotically normally distributed of the maximum likelihood estimators of Hypertabastic’s parameter, to validate of the asymptotically property of Y2n test statistic for Hypertabastic distribution when the right censoring probability equal 0% and 20%.n the last chapter, we applied those two parametric models above to three scenes ofthe real-life data. The first one was done the data set given by Freireich et al. on thecomparison of two treatment groups with additional information about log white blood cellcount, to test the ability of a therapy to prolong the remission times of the acute leukemiapatients. It showed that Hypertabastic AFT model is an accurate model for this dataset.The second one was done on the brain tumour study with malignant glioma patients, givenby Sauerbrei & Schumacher. It showed that the best model is Hypertabastic PH onadding five significance covariates. The third application was done on the data set given by Semenova & Bitukov on the survival times of the multiple myeloma patients. We did not propose an exactly model for this dataset. Because of that was an existing oneintersection of survival times. We, therefore, suggest fitting other dynamic model as SimpleCross-Effect model for this dataset.