Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas.
OBJECTIVE
Preclinical animal experiments support the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor (IGF-IR/AS ODN) as an effective potential antitumor agent. We performed a human pilot safety and feasibility study using an IGF-IR/AS ODN strategy in patients with malignant astrocytoma.


METHODS
Autologous glioma cells collected at surgery were treated ex vivo with an IGF-IR/AS ODN, encapsulated in diffusion chambers, reimplanted in the rectus sheath within 24 hours of craniotomy, and retrieved after a 24-hour in situ incubation. Serial posttreatment assessments included clinical examination, laboratory studies, and magnetic resonance imaging scans.


RESULTS
Other than deep venous thrombosis noted in some patients, no other treatment-related side effects were observed. IGF-IR/AS ODN-treated cells, when retrieved and assessed, were < or = 2% intact by trypan blue exclusion, and none of the intact cells were viable in culture thereafter. Parallel Western blots disclosed IGF-IR downregulation to < or = 10% after ex vivo antisense treatment. At follow-up, clinical and radiographic improvements were observed in eight of 12 patients, including three cases of distal recurrence with unexpected spontaneous or postsurgical regression at either the primary or the distant intracranial site.


CONCLUSIONS
Ex vivo IGF-IR/AS ODN treatment of autologous glioma cells induces apoptosis and a host response in vivo without unusual side effects. Subsequent transient and sustained radiographic and clinical improvements warrant further clinical investigations.
Andrews
D W
DW
Kimmel Cancer Center, Departments of Neurosurgery, Radiology, Pathology, Internal Medicine, Radiation Oncology, and Neurology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA. david.w.andrews@mail.tju.edu
Resnicoff
M
M
Flanders
A E
AE
Kenyon
L
L
Curtis
M
M
Merli
G
G
Baserga
R
R
Iliakis
G
G
Aiken
R D
RD
D000328:Adult; D017209:Apoptosis; D001254:Astrocytoma / Q000628:therapy*; D001932:Brain Neoplasms / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use*; D010865:Pilot Projects; D017451:Receptors, Somatomedin / Q000235:genetics / Q000502:physiology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D020246:Venous Thrombosis / Q000209:etiology
D020319:Oligodeoxyribonucleotides, Antisense; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I