<p>Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. </p><p>HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G>C)) was identified and the 434GG genotype correlated to NS histology and high ESR.</p><p>The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. </p><p>Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome.</p><p>In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.</p>

Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G&gt;C)) was identified and the 434GG genotype correlated to NS histology and high ESR. The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome. In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.

L'adenocarcinoma ductal de pàncrees és un càncer molt agressiu que actualment representa la quarta causa de mort per càncer als països occidentals. Les teràpies clàssiques, basades en la resecció quirúrgica, la radioteràpia i el tractament amb quimioteràpics com la gemcitabina, no són efectives en la gran majoria del pacients. En aquests darrers anys s'està estudiant l'aplicació de la teràpia gènica com a teràpia alternativa o adjuvant per al tractament d'aquesta neoplàsia. Una aproximació important és la que es basa en la transferència del gen de la timidina quinasa del virus Herpes simplex tipus 1 (TK) i l'administració de la pro-droga ganciclovir (GCV). Un dels atractius que presenta aquest sistema TK/GCV és que disposa d'un mecanisme amplificador de la mort cel·lular, que va més enllà d'eliminar la cèl·lula tumoral modificada genèticament amb el gen TK i que es coneix com l'efecte adjacent. S'ha proposat, que aquest efecte podria ser degut al trànsit dels metabòlits tòxics del GCV a través dels canals intercel·lulars que formen les unions gap.En aquesta tesi hem realitzat una caracterització de l'expressió de les molécules constitutives de les unions gap, les connexines, en l'adenocarcinoma de pàncrees; i hem estudiat el seu paper en l'eficàcia de dues estratègies terapèutiques basades en l'administració de compostos anàlegs de nucleòsids: el sistema suïcida TK/GCV i el quimioteràpic gemcitabina. S'ha estudiat també la possible contribució de l'E-cadherina, element clau de les unions adherents epitelials, en l'efecte citotòxic d'aquestes teràpies i amb especial èmfasi en el sistema TK/GCV.

Text in Afrikaans / Selfmoord is 'n kontroversiele aangeleentheid wat beide omstanders en agterblywendes met onsekerheid vervul. 'n Belangrike rede hiervoor is dat dit 'n onnatuurlike afsterwe is wat teen baie mense se norme en waardes indruis. ldiografiese navorsing is onderneem om die belewenisse van agterblywende gesinslede te ondersoek aangesien hulle die eintlike slagoffers van 'n selfmoord is wat met 'n komplekse realiteit gelaat word. Die doel van die navorsing was om riglyne daar te stel vir die hantering en ondersteuning van hierdie mense. Vanuit 'n in-diepte literatuurstudie, het dit geblyk dat die grootste probleme waarmee agterblywendes gekonfronteer word, wentel random problematiese emosies, veroordeling deur omstanders en belewings van persoonlike onvermoe om te midde van intense rousmart selfaktualisering optimaal te volvoer. 'n Vraelys wat aspekte (socs dit uit die literatuurstudie geblyk het) inkorporeer, is opgestel en aan agterblywendes gegee om te beantwoord. Van die belangrikste elemente wat na vore gekom het, is dat intense verhoudingskomplikasies na 'n selfmoord figureer, dat agterblywendes 'n behoefte het om rouverwerking teen hul eie tempo te doen, dat agterblywendes verkies dat omstanders nie voortdurend die gebeure sal ontleed en soek na oorsake in die teenwoordigheid van agterblywendes nie en dat elke agterblywende persoon se roubelewing persoonlik en uniek is. 'n Hoofstuk is gewy aan 'n wye verskeidenheid terapeutiese tegnieke wat geimplementeer kan word tydens hulpverlening aan agterblywendes. Die studie beskryf ook 'n gevallestudie en die verloop van sestien individuele terapeutiese sessies. In die terapeutiese insette is daar hoofsaaklik gebruik gemaak van hipnoterapie as 'n vorm van ontspanningsterapie waartydens daar gelokus word op problematiese emosies en persepsies wat voortgesette kwalitatiewe selfaktualisering belemmer. In die studie word Opvoedkundige Sielkundige riglyne vir hulpverlening aan agterblywendes, wat benut kan word deur hulpverleners (soos sielkundiges, onderwysers en ander ondersteuningsisteme). verskaf. Die studie bevestig dat die agterblywendes as die werklike slagoffers na 'n selfmoord agtergelaat word, maar dat sinvolle intervensie hierdie persone in staat kan stel om ten spyte van die gebeure weer optimaal te selfaktualiseer. / Suicide is a controversial topic. It causes both bystanders and survivors to feel insecure. An important reason for this is that it is an unnatural death which directly opposes the norms and values of the majority of people. ldiografic research has been undertaken to closely examine the experiences of suicide survivors as they are the real victims who are left to cope with a complex reality after a suicide. The objective of this study was to provide guidelines to effectively manage and render assistance to survivors. From an in depth review of available literature it appeared that troubled emotions, being denounced by bystanders and the inability to proceed with continued qualitative self-actualization are some of the most important problems survivors have to cope with. A questionnaire, incorporating significant aspects reported in literature, was compiled and given to survivors to complete. From their responses certain facets seemed to be problematic. Among the more problematic aspects were complicated interpersonal relations, the basic need to grieve at their own pace, the preference that bystanders avoid analysing the suicide and possible contributing factors (especially in the presence of survivors) and the recognition that each survivor's grief is personal and unique. A chapter has been devoted to a wide range of therapeutic techniques that can be implemented to facilitate the support given to survivors. The study also describes a case study as well as the progression of sixteen individual therapy sessions. Therapeutic intervention was mainly based on hypnotherapy as a form of relaxation therapy during which the focus is placed on problematic emotions and perceptions which prevent continued qualitative self-actualization. Educational Psychological guidelines along which assistance can be rendered by psychologists, teachers as well as other support services are given. This study not only confirms that the survivors are the actual victims of a suicide, but also that it is possible to assist these people to achieve optimal self-actualization through meaningful intervention. / Psychology of Education / D. Ed. (Sielkundige Opvoedkunde)

In sign-language interpreting and conference interpreting it is common for interpreters to work in pairs and well-established norms exist for how that cooperation is carried out. Working in pairs is becoming more common in Swedish courts for spoken language interpreting. Yet how court interpreters collaborate in these situations is not well described. This study, based on 29 hours of audio-files, examines how interpreters working in English and Swedish cooperate during consecutive interpreting when defendants are questioned in Swedish courts. Using Goffman’s terms, the interpreters can be said to be either ratified or bystander at any given point. Five types of cooperation were identified. Two show prompted support - the ratified interpreter either explicitly asks for support or her communicative behaviour makes the bystander conclude that support is needed, two show how the bystander interpreter self-selects to provide support. The fifth covers situations when a bystander interpreter is using non-renditions to explicitly coordinate the interaction. The study can confirm that interpreters are more noticeable in the courtroom than the traditional view of a good interpreter allows. It also shows how a team of two interpreters together can solve communicative problems related to the interpreter’s parallel tasks of translating and coordinating. / Inom teckenspråkstolkning och konferenstolkning är det vanligt att två eller fler tolkar arbetar tillsammans. Det finns väletablerade normer för hur samarbetet ska genomföras. Svenska domstolar anlitar ibland två tolkar till uppdrag i talade språk, men det saknas forskning om hur domstolstolkar samarbetar. Föreliggande studie, baserad på 29 timmar inspelat material undersöker på vilket sätt tolkar med engelska som arbetsspråk samarbetar vid konsekutivtolkning av förhör med tilltalade i svenska domstolar. Med Goffmans terminologi kan tolkarna sägas vara antingen ratified eller bystander vid varje given tidpunkt. Studien identifierar fem typer av samarbeten. Två av dem innefattar efterfrågat stöd där tolken som är ratified antingen ber om stöd eller agerar kommunikativt på ett sätt som får tolken som är bystander att dra slutsatsen att stöd behövs. Två andra kategorier beskriver situationer där tolken som är bystander tar initiativ att erbjuda en rättelse eller ett tillägg. Den femte kategorin täcker situationer där en tolk som är bystander använder sig av icke-återgivningar för att explicit samordna interaktionen. Studien bekräftar att tolkar tar mer plats i en rättssal än vad den gängse uppfattningen är, men också att samarbetande tolkar för det mesta smidigt löser kommunikativa problem relaterade till tolkens två parallella praktiker, att översätta och samordna.

Title: The men we don’t see, and the women we can’t hear: A qualitative interview study about prostitution and human trafficking in hotel environment. This qualitative interview study aims to put a light on hotel staff’s experiences of how prostitution and human trafficking exist within their workplaces. We examine this on the basis of the Swedish policy ‘Hotellkurage’ as a crime prevention method in the hotel environment in Northern Sweden. The policy is built on the idea of civil courage and aims to include both hotel staff and hotel guests. Thematic analysis was used to collect data and code it to themes describing similarities, differences and patterns in the data. The theoretical framework for this thesis is based on the routine activity theory, the bystander effect, the emotional labor theory, and the halo effect within stereotypes. By interviewing six informants with different work positions we discovered that it seems to be hard for the hotel staff to intervene based on their gut feeling in situations involving violence. We also found that there is an underlying expectation on hotel staff to have knowledge about handling situations of prostitution and/or human trafficking, and cope with their personal emotions through out emotional labor. The role conflict of being service-minded and intervene in situations involving prostitution or human trafficking are severe. The organizational conditions, response from the management and the cooperation with local police seem to be crucial in order to use methods based on civil courage in hotel staff’s working environment. Hotel staff should be more educated and encouraged to act upon their gut feeling in situations involving prostitution and human trafficking. Finally, the study finds that stereotypes of perpetrators in prostitution and human trafficking usually don’t add up to the stereotypical view of a perpetrator due to their often common apperance. Also, the victims of prostitution and human trafficking are viewed in a stereotypical way, which leads to a higher risk of other vulnerable social groups not to be discovered in the hotel environment.

De nombreuses études ont montré que l'exposition de cultures cellulaires à des particules α conduit à des changements biologiques importants autant dans les cellules irradiées que dans les cellules bystander non-irradiées. L'étude des réponses biologiques non-ciblées dans des cultures cellulaires exposées à de faibles fluences d’ions lourds permet d’estimer les risques pour la santé du rayonnement spatial et de la radiothérapie. Nous avons caractérisé les mécanismes sous-jacents de l'induction d'effets stressants dans des cultures confluentes de fibroblastes normaux humains exposés à de faibles fluences d’ions fer de 1000 MeV/u (transfert d'énergie linéique (TEL) ~151 keV/µm), d’ions silicium de 600 MeV/u (TEL ~50 keV/µm) ou d’ions carbone de 290 MeV/u (TEL ~13 keV/µm). Nous avons comparé ces résultats avec ceux obtenus dans des cultures cellulaires exposées, en parallèle, à de faibles fluences de particules α de 0,92 MeV/u (TEL ~109 keV/µm). L'induction de dommages à l'ADN, les changements dans l'expression des gènes, la carbonylation des protéines et la peroxydation lipidique durant les 24 h suivant l'exposition de cultures confluentes à de faibles doses (0,2 cGy et plus) d’ions fer ou d'ions silicium ont très largement contribué à la propagation d’effets stressants des cellules irradiées aux cellules bystander non-irradiées. Pour une dose moyenne de 0,2 cGy, seules ~1 et 3 % des cellules seraient irradiées dans le noyau par un ion, respectivement, fer ou silicium. Les immunoblots ont révélés des augmentations significatives des niveaux de phospho-TP53 (sérine 15), p21Waf1 (CDKN1A), HDM2, phospho-ERK1/2, de carbonylation des protéines et de peroxydation lipidique dans les 24 h suivant l’exposition. L'ampleur de ces réponses suggère la participation de cellules non ciblées dans les effets observés. De plus, lorsque les populations cellulaires irradiées ont été ré-ensemencées dans un milieu de culture frais peu après l'irradiation, les niveaux de ces marqueurs ont aussi augmentés durant 24 h. Ensemble, ces résultats montrent un effet rapidement propagé et persistant. Des analyses in situ réalisées dans des cultures cellulaires confluentes ont montré que la formation de foyers de la protéine 53BP1, marqueur de dommages à l'ADN, touchait un nombre de cellules plus important que celui auguré par la fraction de cellules traversées dans le noyau par un ion fer ou silicium. Cet effet est exprimé dès 15 min suivant l'exposition, atteint son maximum 1 h après l’exposition puis diminue jusqu’à 24 h. Une tendance similaire s'est produite après exposition à une dose moyenne absorbée de 0,2 cGy de particules α de 3,7 MeV, mais non après 0,2 cGy d’ions carbone de 290 MeV/u.Des analyses utilisant des puits de cultures intégrant une fine épaisseur de CR-39, détecteur solide de traces nucléaires, et permettant ainsi l’identification des cellules irradiées aux ions fer ou silicium, confirment la participation de cellules bystander dans la réponse au stress. Des études mécanistiques ont, de plus, indiqué que les jonctions gap permettant la communication intercellulaire, certaines voies de la réparation de l’ADN, ainsi que le métabolisme oxydatif participent à la propagation des effets non ciblés induit par des radiations de haut TEL. Nous avons également examiné la contribution possible des particules secondaires produites le long des traces d’ions primaires dans les réponses biologiques. Les simulations réalisées avec le code de transport de particules FLUKA ont révélé que la dose due aux produits de fragmentation, autres que les électrons, est inférieure à 1 % de la dose absorbée dans les cultures cellulaires exposées à des ions lourds. De plus, la dose radiale des ions lourds secondaires est limitée à ~10-20 µm autour de l’ion primaire. Ainsi, ces derniers sont peu susceptibles de contribuer de manière significative à la réponse biologique observée dans des cellules non ciblées par des ions lourds primaires / Widespread evidence indicates that exposure of cell cultures to α particles results in significant biological changes in both the irradiated and non-irradiated bystander cells in the population. The induction of non-targeted biological responses in cell cultures exposed to low fluences of high charge (Z) and high energy (E) particles is relevant to estimates of the health risks of space radiation and to radiotherapy. Here, we investigated the mechanisms underlying the induction of stressful effects in confluent normal human fibroblast cultures exposed to low fluences of 1000 MeV/u iron ions (linear energy transfer (LET) ~151 keV/µm), 600 MeV/u silicon ions (LET ~50 keV/µm) or 290 MeV/u carbon ions (LET ~13 keV/µm). We compared the results with those obtained in cell cultures exposed, in parallel, to low fluences of 0.92 MeV/u α particles (LET ~109 keV/µm).Induction of DNA damage, changes in gene expression, protein carbonylation and lipid peroxidation during 24 h after exposure of confluent cultures to mean doses as low as 0.2 cGy of iron or silicon ions strongly supported the propagation of stressful effects from irradiated to bystander cells. At a mean dose of 0.2 cGy, only ~1 and 3 % of the cells would be targeted through the nucleus by an iron or silicon ion, respectively. Within 24 h post-irradiation, immunoblot analyses revealed significant increases in the levels of phospho-TP53 (serine 15), p21Waf1 (also known as CDKN1A), HDM2, phospho-ERK1/2, protein carbonylation and lipid peroxidation. The magnitude of the responses suggested participation of non-targeted cells in the response. Furthermore, when the irradiated cell populations were subcultured in fresh medium shortly after irradiation, greater than expected increases in the levels of these markers were also observed during 24 h. Together, the results imply a rapidly propagated and persistent bystander effect. In situ analyses in confluent cultures showed 53BP1 foci formation, a marker of DNA damage, in more cells than expected based on the fraction of cells traversed through the nucleus by an iron or silicon ion. The effect was expressed as early as 15 min after exposure, peaked at 1 h and decreased by 24 h. A similar tendency occurred after exposure to a mean absorbed dose of 0.2 cGy of 3.7 MeV α particles, but not after 0.2 cGy of 290 MeV/u carbon ions.Analyses in dishes that incorporate a CR-39 solid state nuclear track detector bottom identified the cells irradiated with iron or silicon ions and further supported the participation of bystander cells in the stress response. Mechanistic studies indicated that gap junction intercellular communication, DNA repair, and oxidative metabolism participate in the propagation of the induced effects.We also considered the possible contribution of secondary particles produced along the primary particle tracks to the biological responses. Simulations with the FLUKA multi-particle transport code revealed that fragmentation products, other than electrons, in cells cultures exposed to HZE particles comprise <1 % of the absorbed dose. Further, the radial spread of dose due to secondary heavy ion fragments is confined to approximately 10-20 µm Thus, the latter are unlikely to significantly contribute to the stressful effects in cells not targeted by primary HZE particles.

Background: It has been proved that bystander cardiopulmonary resuscitation (CPR) saves lives; however, which training method in CPR is most instructive and whether survival is affected by the training level of the bystander have not yet been fully described. Aim: To identify the factors that may affect 7th grade students’ acquisition of CPR skills during CPR training and their willingness to act, and to describe 30-day survival from outof- hospital cardiac arrest (OHCA) after bystander CPR and the actions performed by laymen versus off-duty medically educated personnel. Methods: Studies I–III investigate a CPR training intervention given to students in 7th grade during 2013–2014. The classes were randomized to the main intervention: the mobile phone application (app) or DVD-based training. Some of the classes were randomized to one or several additional interventions: a practical test with feedback, reflection, a web course, a visit from elite athletes and automated external defibrillator (AED) training. The students’ practical skills, willingness to act and knowledge of stroke symptoms, symptoms of acute myocardial infarction (AMI) and lifestyle factors were assessed directly after training and at 6 months using the Laerdal PC SkillReporting system (and entered into a modified version of the Cardiff test scoring sheet) and a questionnaire. The Cardiff test resulted in a total score of 12–48 points, and the questionnaire resulted in a total score of 0–7 points for stroke symptoms, 0–9 points for symptoms of AMI and 0– 6 points on lifestyle factors. Study IV is based on retrospective data from the national quality register, the Swedish registry of cardiopulmonary resuscitation, 2010-2014. Results: A total of 1339 students were included in the CPR training intervention. The DVD-based group was superior to the app-based group in CPR skills, with a total score of 35 (SD 4.o) vs 33 (SD 4.2) points directly after training (p&lt;0.001) and 33 (SD 4.0) vs 31 (SD 4.2) points at six months (p&lt;0.001). Of the additional interventions, the practical test with feedback had the greatest influence regarding practical skills: at six months the intervention group scored 32 (SD 3.9) points and the control group (CPR only) scored 30 (SD 4.0) points (p&lt;0.001). Reflection, the web course, visits from elite athletes and AED training did not further increase the students’ acquisition of practical CPR skills. The students who completed the web course Help-Brain-Heart received a higher total score for theoretical knowledge in comparison with the control group, directly after training: stroke 3.8 (SD 1.8) vs 2.7 (SD 2.0) points (p&lt;0.001); AMI 4.0 (SD 2.0) vs 2.5 (SD 2.0) points (p&lt;0.001); lifestyle factors 5.4 (SD 1.2) vs 4.5 (SD 2.0) points p&lt;0.001. Most of the students (77% at 6 months), regardless of the intervention applied, expressed that they would perform both chest compressions and ventilations in a cardiac arrest (CA) situation involving a relative. If a stranger had CA, a significantly lower proportion of students (32%; p&lt;0.001) would perform both compressions and ventilations. In this case, however, many would perform compressions only. In most cases of bystander-witnessed OHCA, CPR was performed by laymen. Off-duty health care personnel bystanders initiated CPR within 1 minute vs 2 minutes for laymen (p&lt;0.0001). Thirty-day survival was 14.7% among patients who received CPR from laymen and 17.2% (p=0.02) among patients who received bystander CPR from off-duty health care personnel. Conclusions: The DVD-based method was superior to the app-based method in terms of teaching practical CPR skills to 7th grade students. Of the additional interventions, a practical test with feedback was the most efficient intervention to increase learning outcome. The additional interventions, reflection, web course, visit from elite athletes and AED did not increase CPR skills further. However, the web course Help-Brain-Heart improved the students’ acquisition of theoretical knowledge regarding stroke, AMI and lifestyle factors. For OHCA, off-duty health care personnel bystanders initiated CPR earlier and 30-day survival was higher compared with laymen bystanders.

At low doses, relevant to nuclear incidents and accidental releases of radioactivity, the detriment of radiation extends beyond direct effects. This thesis investigates genomic instability, a subclass of non-targeted effects where damage and lethality is transmitted vertically and expressed in the progeny of cells many generations after initial radiation exposure. Through a series of experiments using clonogenic assay of human and fish cell culture, studies described in this thesis describe lethal mutations, hyper radiosensitivity and increased radioresistance – processes involving repair mechanisms that dictate survival in cells exposed to low doses. Further study investigates the difference in the relative biological effect of alpha particle radiation compared to what is expected at high doses. Results demonstrate increased radioresistance in a human cell line while also revealing increased lethality in a fish cell line confirming the need for consideration of dose-dependence as well as variance in behaviors of different cell lines and species. It is hoped the conclusions of this thesis will inspire the creation of protocols with greater attention to the indirect consequences of exposure to radiation at doses relevant to nuclear incidents and accidents. / Thesis / Master of Science (MSc)

No / PURPOSE: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents. EXPERIMENTAL DESIGN: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts. RESULTS: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue. CONCLUSION: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1.