M. Sc. Cathrine Elisabeth Olsen from Pål Kristian Selbo's project group at the Department of Radiation Biology will give her trial lecture on Thursday November 2nd at 13:15 on the following subject: "Methods for local delivery and activation of cancer drugs." Place: Auditorium U35, Helga Engs Hus, Sem Sælands vei 7
She will defend her PhD thesis - entitled "Mechanisms of Resistance to TPCS2a-Photodynamic Therapy: Implication for Photochemical Internalization" at 10:15 Friday November 3rd. Place: Auditorium 2, Helga Engs Hus, Sem Sælandsvei 7.
Photochemical internalization (PCI) is a clinically studied drug-delivery technique based on photodynamic therapy (PDT) for release of endocytically sequestered cancer drugs. The work of this thesis investigates the susceptibility and mechanisms behind development of in vitro PDT-resistance, and how PCI may be utilized in resistant cancers using the photosensitizer TPCS2a in combination with targeted and non-targeted drugs. The work shows that PDT-resistance may develop through repeated treatment, but also by other chemotherapeutics through cross-resistance. Mechanisms regulating growth, survival and protection against reactive oxygen species (ROS) were found as major drivers of PDTresistance, but differed among different cancer cell lines. Sustained treatment with chemotherapeutics also revealed induction of PDT-hypersensitivity, altogether showing that PDT sensitivity may depend on sensitivity to other therapies as well as being cell line dependent. The effect of PCI was not compromised by resistance to PDT or chemotherapeutics. Instead, resistance-induced alterations were utilized by targeted PCI, e.g. the use of ligand-and antibody based toxins and immunotoxins, such as EGF-, CD105- and CD133-saporin. Another more clinically relevant toxin (gelonin) was, by recombinant technology, fused to an antibody fragment of anti-CD133. Although receptor binding of this immunotoxin was retained, no more toxicity was induced in CD133-expressing cells compared to that of nonexpressing cells, warranting further optimization of such constructs. Another important finding was that mechanisms of ROS protection could reactivate and hence increase the effect of the chemotherapeutic bleomycin in combination with PCI. Other results also showed that PDT could act as an inhibitor of autophagy, a catabolic process regulating the balance of cell death and survival. Overall, PCI appeared to be a robust drug-delivery technique in PDT- and chemotherapyresistant cancers, utilizing several mechanisms for efficient cancer cell toxicity.