Aspects of immuno- and suicide gene therapies for cancer - A combination with radiation therapy.

摘要

Gene therapies may serve as adjuvant treatments against tumors. We studied potential immuno-gene and gene-directed enzyme pro-drug (GDEPT) therapy systems in rat models; and examined the presence of transferrin receptor in human pancreatic tumors. Systemic Flt3-ligand (FL) treatment leads to expansion of dendritic cells with antitumoral effect in animal models. We hypothesized, that intratumoral FL gene transfer would have effect on the antitumoral immune response and tumor growth in experimental DSL6A rat pancreatic cancers. The unknown rat FL cDNA was sequenced, and cloned into a plasmid. Transfection of s.c. growing tumors was augmented by cationic liposomes - 10% transfection rate was achieved. While control tumors grew continuously, 6 times repeated injections of FL-coding plasmids resulted in shrinkage of tumors in half of the treated animals; total regression and tumor size stabilization could also be achieved in some cases. Most treated tumors regained proliferative activity after cessation of treatment. The therapy was accompanied by considerable increase in the expression of CD80 on splenic dendritic cells in some treated animals and increase in splenic NK cell number in therapy responders. The effect of therapy was limited; combinational strategies aiming to activate dendritic cells may be helpful.;We present the first experimental attempt to enhance the radiosensitizing effect of the widely used chemotherapeutic agent gemcitabine by means of GDEPT. Both the cytotoxic and radiosensitizing effect of gemcitabine could be significantly improved by adenovirus mediated overexpression of the dCK enzyme in murine C6 and human U373 glioma cell lines. dCK overexpression in pre-transduced C6 gliomas significantly improved the survival rate of tumor bearing rats in response to chemoradiotherapy by enhancing the radiosensitizing effect of gemcitabine. After further in vivo studies in a therapeutic setting (local transfection), the dCK/gemcitabine GDEPT system might be a candidate of adjuvant gene-therapeutical protocols against tumors, where gemcitabine and radiation is already in clinical use - such as pancreatic cancer and gliomas.;We found that malignant human ductal and neuroendocrine pancreatic tumor cells express considerable amount of transferrin receptor in most cases (90%), while healthy pancreatic tissue and benign tumors do not show expression by immunohistochemistry. This observation may have implication in the diagnosis and (vector-) targeting of these malignancies.