https://gupea.ub.gu.se/handle/2077/57961
Advanced renal cell
carcinoma - The role of orellanine and associated therapeutic
challenges
Najar, Deman Hadi
Koska sienimyrkky orellaniini selektiivisesti aiheuttaa munuaissoluissa apoptoosin, nekroosin ja solutoimintojen ja solukasvun palauttumattomasti, siitä voi olla munuaissyövän viimevaiheissa hoidollista apua munuaissyöpäsoluillekin toksisena molekyylinä - tosin anuriatilanne on hoidettava dialyysein. Tässä tarkoituksessa on tehty asiaa kartoittava väitöstyö, jossa vahvistettiin orellaniin myrkkyvaikutusten rajoittuminen nefronien munuaistubulusten epiteelisoluihin ja munuaissolukarsinomaan - orellaniinia kertyi munuaiskorteksiin ja virtsarakkoon, virtsateiden alueelle, eikä merkittäviä vaikutuksia muihin testattuihin solulinjoihin ollut havaittavissa.
Orellanine is a fungal nephrotoxin selectively toxic to the human
tubular epithelial cells (HTEC) of the kidney nephrons leading to kidney
failure. Patients treated with renal replacement therapy after
orellanine poisoning show no signs of damage to other organs in the
body.
Aims: Our main aim in this thesis is to develop chronic peritoneal
dialysis (PD) in anuric rodents, to better understand the
pharmacokinetic properties of orellanine and to evaluate orellanine as
an experimental treatment
against metastasized clear cell renal cell carcinoma (ccRCC).
Methods: The first paper is an in vivo study of chronic automated PD in
anuric rats. Orellanine was used to induce uremia. Blood, dialysis
fluid, and tissue samples were examined for electrolyte profiles,
inflammatory status, and morphology. The second paper is an in vivo
study in which rats were given intravenous injections of
labeled/unlabeled orellanine. The distribution of orellanine was imaged,
and orellanine plasma concentrations were measured over different time
points. The third paper had two parts: an in vitro part examining the
effect of orellanine on HTEC, epithelial cells, ccRCC cells, and other
cancer cell lines, and an in vivo part with a xenograft rat model
testing the effect of orellanine on metastasized ccRCC tumors.
Results: The levels of urea and creatinine in orellanine-treated rats
indicated severe uremia. The automated PD system developed in our lab
provided adequate dialysis. The rats gained weight and had normal
homeostasis. Orellanine was cleared renally and was mainly distributed
to the renal cortex and the urinary bladder. Orellanine induced
necrosis, apoptosis, and disruption of cellular functions and growth on
HTEC and ccRCC cells while having no significant effect on other tested
cell lines at the same doses. Finally, orellanine induced significant
apoptosis and necrosis in the xenografted tumors in vivo.
Conclusions: Orellanine selectively causes renal failure, which is
irreversible at high doses. We describe the first successful treatment
of rats with severe uremia that, despite anuria, were kept healthy over a
period of at least 21 days. The system can be used to improve PD and to
study various aspects of uremia. The pharmacokinetic properties of
orellanine were investigated and it was shown that orellanine is
distributed mainly to the urinary system. Orellanine induced significant
apoptosis and necrosis in metastasized xenografted tumors in vivo and
showed no signs of affecting other organs. Therefore, we suggest that
its therapeutic effects should be further examined as a treatment option
for late stage ccRCC patient
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