Am. J. Respir. Cell Mol. Biol., Vol 11, No. 3, 09 1994, 270-278.
Suppression of in vivo tumorigenicity of human lung cancer cells by retrovirus-mediated transfer of the human tumor necrosis factor-alpha cDNA
SK Han, SL Brody and RG Crystal
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
The clinical use of tumor necrosis factor-alpha (TNF) is constrained by
tumor cell resistance and systemic toxicity. Based on observations with
murine tumors, we hypothesized that induction of local TNF production by
the tumor may suppress growth of human cancer cells. To evaluate this, a
human TNF cDNA was transferred to human lung cancer cell lines in vitro
using a retrovirus vector to produce TNF cDNA-modified cell lines secreting
TNF. In vitro cell growth was similar for parental and modified cells. All
cells were resistant to TNF. The in vivo tumorigenicity of parental and
modified cells was compared in nude mice. Animals injected subcutaneously
with parental cells uniformly developed tumors. Tumor growth was markedly
less for all modified cells, and this suppression of tumor development was
reversed by anti- TNF antibody administration. Animals injected with a
mixture of 50% modified and 50% parental cells or parental cell tumors
injected with modified cells had decreased tumor growth, demonstrating that
modified cells could suppress tumorigenicity. These data suggest that TNF
can induce antitumor defenses to suppress in vivo human tumor cell growth
and provide a rationale for transferring the human TNF cDNA directly to
malignant cells for the therapy of human lung cancer.
