Urokinase antisense oligodeoxynucleotides as a novel therapeutic agent for malignant glioma: in vitro and in vivo studies of uptake, effects and toxicity.
Antisense therapy might offer an improved treatment for patients with malignant glioma. We studied the uptake and effects of urokinase antisense oligodeoxynucleotides on rat and human glioma cells in vitro and the uptake and toxicity of these nucleotides in rat carcinomatosis and brain tumor models. Cultured glioma cells readily incorporated fluorescein isothiocyanate-conjugated oligonucleotides, as demonstrated by immunofluorescence microscopy and flow cytometry. Effects on urokinase expression as assessed by immunofluorescence microscopy varied according to cell line. Northern blot analysis showed decreases in urokinase expression with oligodeoxynucleotide treatment. Uptake into tumor cells was also demonstrated in vivo, with no detectable toxicity at concentrations exceeding expected therapeutic levels. These data are encouraging for the further study of antisense oligodeoxynucleotides as a new therapeutic modality for malignant glioma.
Engelhard
H
H
Department of Surgery, Northwestern University Medical School, Chicago, Illinois 60611, USA. hhe@merle.acns.nwu.edu
Narang
C
C
Homer
R
R
Duncan
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005909:Glioblastoma; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D014568:Urokinase-Type Plasminogen Activator