Abstract
We have studied the cytotoxic effects of recombinant tumour necrosis factor and recombinant gamma interferon on primary cultures of leukaemia cells. The agents were added alone or in a combination to cells from 17 patients. Eleven had acute myeloblastic leukaemia (6 at presentation, 5 at relapse), 4 had acute lymphoblastic leukaemia, one had hairy cell leukaemia, and 2 had chronic myeloid leukaemia--one of whom was in myeloid blast transformation. Cells from patients with lymphoid malignancies or from the patient with chronic phase CML were not affected by either agent in any dose combination. In contrast, reduction of viability of myeloid blasts was weakly accelerated by TNF and gamma-interferon individually. Combination of the agents invariably produced enhanced killing and additive or synergistic effects were seen when 20-500 IU ml-1 of each cytokine was present. This sensitivity was also shown by blast cells from 5 patients with relapsed AML. We therefore suggest that trials of such combination therapy may be indicated in drug resistant or relapsed AML.
Highlights
Two cytokines, tumour necrosis factor (TNF) and yinterferon (y-IFN), have been frequently suggested as therapeutic agents for the treatment of malignant disease
We have investigated the susceptibility of acute leukaemia blast cells to TNF and y-IFN alone or in combination
We show that lymphoid leukaemias are generally unaffected by these cytokines, but that myeloid blast cells, including those obtained from patients in relapse, may be highly susceptible to the combination of TNF and yIFN, while showing little response to either agent alone
Summary
Tumour necrosis factor (TNF) and yinterferon (y-IFN), have been frequently suggested as therapeutic agents for the treatment of malignant disease. TNF was first characterised as a product from activated macrophages that induced regression of some transplanted tumours in rodents (Carswell et al, 1975; Ruff et al, 1980) while having little or no effect on primary cell cultures or normal cell lines. It is clear that in addition to its cytotoxic effects on malignant cells, TNF regulates the growth of many normal cells including haemopoietic precursors - by producing reversible suppression of some specific cellular proteins at the level of transcription (Beutler et al, 1985a, b) and by increasing production of others (Kohase et al, 1986). TNF effectively destroys some tumour derived lines, others are almost entirely insensitive, and it has been postulated that lack of susceptibility may correlate with low level or absent expression of specific TNF receptors (Tsujimoto et al, 1986; Ruggiero et al, 1986)
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