Conditional expression of human TNF-alpha: a system for inducible cytotoxicity.
Tumour necrosis factor-alpha (TNF-alpha) is currently being used in clinical trials for cancer treatment, but toxic side effects, due to systemic administration and high doses, are observed. Inducible expression of TNF may permit selective killing of tumour cells in gene therapy protocols without need for prolonged and/or high-level TNF expression. A conditional TNF expression vector has been constructed in which the coding sequences of human TNF have been placed under the transcriptional control of the glucocorticoid-regulated murine mammary tumour virus long terminal repeat (MMTV-LTR). Negligible levels of TNF expression, associated with no phenotypic alterations, are observed in cells transfected with MMTV-TNF vectors in the absence of glucocorticoid. Expression levels could be stimulated by the addition of the synthetic glucocorticoid dexamethasone. Increasing expression levels of TNF were associated with enhanced cytotoxicity. Our results suggest the potential use of inducible TNF systems for the treatment of tumours in gene therapy protocols.
Sparmann
G
G
Max-Delbrück Centre for Molecular Medicine, Berlin, Germany.
Walther
W
W
Günzburg
W H
WH
Uckert
W
W
Salmons
B
B
D000818:Animals; D000970:Antineoplastic Agents; D002415:Cats; D002460:Cell Line; D005354:Fibrosarcoma; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D005909:Glioblastoma; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007668:Kidney; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D012091:Repetitive Sequences, Nucleic Acid; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000235:genetics*
D000970:Antineoplastic Agents; D005938:Glucocorticoids; D014409:Tumor Necrosis Factor-alpha