Yes / Non-invasive methods to monitor tumour growth are an important goal in cancer drug development. Thermographic imaging systems offer potential in this area, since a change in temperature is known to be induced due to changes within the tumour microenvironment. This study demonstrates that this imaging modality can be applied to a broad range of tumour xenografts and also, for the first time, the methodology’s suitability to assess anti-cancer agent efficacy. Mice bearing subcutaneously implanted H460 lung cancer xenografts were treated with a novel vascular disrupting agent, ICT-2552, and the cytotoxin doxorubicin. The effects on tumour temperature were assessed using thermographic imaging over the first 6 hours post-administration and subsequently a further 7 days. For ICT-2552 a significant initial temperature drop was observed, whilst for both agents a significant temperature drop was seen compared to controls over the longer time period. Thus thermographic imaging can detect functional differences (manifesting as temperature reductions) in the tumour response to these anti-cancer agents compared to controls. Importantly, these effects can be detected in the first few hours following treatment and therefore the tumour is observable non-invasively. As discussed, this technique will have considerable 3Rs benefits in terms of reduction and refinement of animal use. / University of Bradford

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009. / Härtill 6 uppsatser.

Despite a rise in breast cancer incidence, mortality rates have fallen. This improvement in mortality is due to the success of anti-cancer treatments such as chemotherapy and radiotherapy. Such treatments, however, are known to be associated with a range of symptoms. A number of studies exploring patients’ chemotherapy-related symptom experiences have shown that patients consistently rate nausea and fatigue highly, not only in relation to severity, but also in relation to the associated distress they experience. The subjective and non-observable nature of both nausea and fatigue complicates their assessment. While a range of assessment tools exists to evaluate patients’ experiences of these two symptoms, there is currently no gold standard assessment tool for assessing either symptom. Moreover, while a range of pharmacological and non-pharmacological interventions have been developed for both symptoms, further evaluation is often needed to provide the level of evidence required to recommend their implementation in real life clinical environments. The SNA↔P (structured nursing assessment into practice) study arose in response to this clinical situation. The SNA↔P study was a longitudinal study that evaluated the impact of a complex evidence-based intervention, incorporating structured multidimensional symptom assessment and multiple symptom management techniques, on patients’ experiences of nausea and fatigue during a course of chemotherapy for breast cancer. Using complementary quantitative and qualitative research methods not only allowed in-depth understanding of patients’ experiences and patterns of nausea and fatigue during a course of chemotherapy, but also facilitated a rounded evaluation of the intervention, incorporating both statistical elements and those of personal significance. The use of these methods showed that the implementation of the SNA↔P intervention in routine clinical practice has significant potential for improving patients’ symptom experiences during a course of chemotherapy. In so doing, it also highlighted a number of areas in which clinical practice can be influenced, and research conducted, to further improve patients’ symptom experiences.

<p>Prostate cancer is the second leading cause of cancer-related death among American men. Prostate tumor cells exhibit significant tropism for the bone and once metastasis occurs, survival rates fall significantly. Current treatment options are not curative and focus on symptom management. Immunotherapies are rapidly emerging as a possible therapeutic option for a variety of cancers including prostate cancer, however, variable patient response remains a concern. Chemotherapies, like cabozantinib, can have immune-priming effects which sensitize tumors to immunotherapies. Additionally, lower doses of chemotherapy can be used in this context which can reduce patient side effects. It was hypothesized that a combination of chemotherapy (cabozantinib) and immunotherapy (Interleukin-27 (IL-27)) could treat bone-metastatic prostate cancer and also exert pro-osteogenic effects. IL-27 is a multi-functional cytokine, which promotes immune cell recruitment to tumors, while also promoting bone repair. To test this hypothesis, <i>in vivo</i> experiments were performed where syngeneic C57BL/6J mice were implanted intratibially with TRAMP-C2ras-Luc cells able to form tumors in bone. Immunotherapy was administered in the form of intramuscular gene therapy, delivering plasmid DNA encoding a reporter gene (Lucia), or a therapeutic gene (IL-27). Ultrasound was used to aid gene delivery. Various gene delivery methods were tested and optimized through <i>in vivo</i> studies, with microbubbles in combination with ultrasound (sonoporation) emerging as the best method. Following immunotherapy, the animals received either cabozantinib or a vehicle control by oral gavage. Bioluminescence imaging was used to monitor tumor size over time. Combinatorial therapy inhibited tumor growth and improved survival. Further, RNA sequencing and cytokine arrays were used to investigate the mechanisms involved. Microcomputed tomography and differentiation assays indicated that the combination therapy improved bone health by improving osteoblast differentiation and inhibiting osteoclast differentiation. Our conclusion is that a chemo-immunotherapy approach such as the one examined in this work has potential to emerge as a novel therapeutic strategy for treating bone-metastatic prostate cancer. This approach should enable a significant reduction in chemotherapy-associated toxicity, improving sensitivity to immunotherapy, and simultaneously improving bone quality.</p>

BACKGROUND:Neoadjuvant chemotherapy followed by cytoreduction surgery has been used where an accurate cytologic or pathologic diagnosis is usually required before the initiation of neoadjuvant chemotherapy. However, it is difficult to make definitive diagnosis of presence of cancer cells, particularly gynecologic versus non-gynecologic origin, from those ascites specimens due to the absence of specific biomarkers of gynecologic cancers. In the present study, we evaluated if, in addition to the routine morphologic diagnosis, the biomarker PAX8 could be useful in recognition of ovarian epithelial cancer cells prior to the neoadjuvant chemotherapy.METHODS:Two hundred and two cytology specimens including 120 pretreatment ovarian cancer samples, 60 benign controls, and 22 malignant non-gynecologic cases were studied. All cytology slides were morphologically reviewed in a blinded fashion without knowing corresponding pathology diagnosis, if present. A total of 168 cytology specimens with a cell block were stained with PAX8 and Calretinin. These included patients with potential for ovarian cancer neoadjuvant chemotherapy (n=96), metastatic cancers (n=22), and benign controls (n=50).RESULTS:Among the 96 ascitic samples prior to neoadjuvant chemotherapy, 76 (79%) showing morphologic features consistent with cancers of ovarian primary were all PAX+/Calretinin-. The remaining 20 (21%) cases were positive for adenocarcinoma, but morphologically unable to be further classified. Among the 22 metastatic cancers into the pelvis, one case with PAX8+/Calretinin- represented a renal cell carcinoma and the remaining 21 PAX8-/Calretinin- metastatic cancers were either breast metastasis (n=4) and the metastasis from gastrointestinal tract (n=17). Among the 50 benign control pelvic washing cases, 5 PAX8+/Calretinin-cases represented endosalpingiosis (n=4) and endometriosis (n=1), 25 PAX8-/Calretinin+cases showed reactive mesothelial cells, and the remaining 20 specimens with PAX8-/Calretinin- phenotype typically contained inflammatory or blood cells without noticeable diagnostic epithelia.CONCLUSIONS:PAX8 identifies all Mullerian derived benign or malignant epithelia. When combining with Calretinin, PAX8 is a sensitive marker to diagnose the carcinomas of ovarian origin, which will be ideal to be used for those patients with a possible advanced ovarian cancer prior to receiving neoadjuvant chemotherapy.

Chemotherapy treatment in premenopausal women has been linked to premature ovarian failure (POF), and hence infertility, through ovarian follicle loss. The exact mechanisms that lie behind this loss are unclear and so the action of two commonly used chemotherapeutic agents were compared here. Cisplatin is a DNA cross-linking agent commonly used in the treatment of ovarian, lung and bladder cancers, while the anthracycline doxorubicin is commonly used to treat leukaemia and breast cancer. Neonatal mouse ovaries were cultured in vitro and exposed to cisplatin or doxorubicin in order to determine their effects on primordial and early growing follicles. Both drugs caused a dose dependant follicle loss but targeted different cell types. Cisplatin caused a significant increase in follicles with unhealthy oocytes; furthermore primary stage follicles were the follicle class most affected (up to 98% classified as unhealthy compared with 13% in control, p<0.001). In contrast, doxorubicin caused a significant increase in follicles with unhealthy granulosa cells and affected all follicle stages present. When the mechanism of cell death was further investigated, apoptosis was the main pathway through which these drugs cause ovarian cell death. Doxorubicin in particular caused a significant increase in apoptosis of ovarian somatic cells including the granulosa cells and stroma. Imatinib mesylate, a tyrosine kinase inhibitor which is also used as a chemotherapeutic agent, has been implicated as a potential therapy to block the ovotoxic effects of cisplatin. Results here confirm this finding (29% of follicles classified as unhealthy in the cisplatin only group compared to 8% in the cisplatin and imatinib co-treatment group, p<0.001) and found further, that imatinib was unable to protect against doxorubicin-induced damage (28% of follicles classified as unhealthy in the doxorubicin treated group compared to 19% in the doxorubicin and imatinib cotreatment group). Imatinib treatment alone in newborn ovaries caused a significant increase in the number of follicles present at the end of culture compared to control (402±43 in the imatinib group compared to 188±34 in control, p<0.001), which is likely due to an effect on follicle formation. In conclusion, the work presented in this thesis demonstrates drug specific actions of cisplatin and doxorubicin on the mouse ovary. This suggests that any therapy designed to confer ovarian protection in the future may have to be tailored to be drug specific.

We consider modified versions of a cell population model for periodic chemotherapy treatment of tumors. These models contain both proliferating and quiescent cells, and treats the transitions between the two types of cells. Our models are defined by replacing the loss term function, μ(t, c), in Webb's model by a constant. This corresponds to having a constant infusion of the drug rather than having a periodic chemotherapy treatment. We compare our results with those of Webb who shows that shorter periods of treatment are advantageous.

This dissertation presents a collection of mathematical models for cellular response to the most common forms of anti-cancer therapy (radiation and chemotherapy) and the role of the cell cycle in this response. These models have application to improving cancer therapy through: optimization of dose and scheduling of agents already in clinical use; better predictive methods for selecting the most promising among new drug candidates or candidate combinations; and combination therapy with newer agents that target the cell cycle or cellular metabolism. The cellular pharmacodynamic models are based on the key concept of "cellular damage" that results from exposure to therapy and has distinct kinetics from cell kill. Damage is lethal only if it exceeds a cell's tolerance threshold at one or more checkpoints in the cell cycle (for apoptosis) or at any time point (for necrosis). This is the "peak damage" model. Each mechanism of cell kill, each agent in combination therapy, and each cycle in fractionated therapy increases the damage function (the "additive damage" model). The overall framework is termed the "peak additive damage model." This model framework is first tested on 128 independent in vitro dose-response data sets for radiation alone. It outperforms previously proposed models, including the widely-used linear-quadratic model. The peak additive damage model is then applied to radiochemotherapy. Its performance is superior to the previously proposed independent cell kill model when tested with 218 data sets for fixed-schedule exposure against. For varying-schedule exposures, cell heterogeneity and cycle asynchrony necessitate a cell-cycle-phase-structured model that divides the population into cohorts with different responses, still determined for each cohort by the peak additive damage model, that are then averaged. This model simultaneously predicts dose-response and cell cycle distribution data, and is tested with such data from the literature. Finally, a first step is taken towards allowing for microenvironmental input into cellular response, by developing a model for the cell cycle that is driven by metabolic inputs and external growth factors. Overall, the models presented here have great flexibility to be extended to complex schedules, any number of agents, and agents with metabolic or cell-cycle targets.

<p>Funding Agency:</p><p>Health Research Council in the South-East of Sweden</p>

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy