In vitro and in vivo effects of 2′-deoxycoformycin (Pentostatin) on tumour cells from human γδ+ T-cell malignancies

Hepatosplenic gamma delta(+) T-cell lymphoma represents a rare neoplasm of post-thymic phenotype, characterized by an aggressive clinical course and a poor response to conventional chemotherapy. In the present study we have examined the cytotoxic effects of the purine analogue 2'-deoxycoformycin (dCF) on cultured mononuclear cells and purified gamma delta(+) tumour cells from bone marrow or peripheral blood of four patients with hepatosplenic gamma delta(+) T-cell lymphoma. At a concentration of 10 mu M, dCF in the presence of 2'-deoxyadenosine (dAdo), displayed an early and selective cytotoxic effect on gamma delta(+) tumour T cells. After 48 h of in vitro exposure to dCF, the absolute number of viable CD3(+)/gamma delta(+) tumour T cells was reduced by more than 90% in all samples with respect to control cultures, with absolute counts of viable CD3(+)/alpha beta(+) lymphocytes being reduced only by 6-40% of the initial cell input. Analysis of cultures after 5 d of exposure to dCF plus dAdo revealed the persistence of normal CD3(+)/alpha beta(+) T cells, which accounted, however, for only 20-25% of the initial cell input. Accordingly, the combination of dCF (10-100 mu M) plus dAdo was able to induce a dose-dependent inhibition of clonogenic growth and [H-3]-thymidine incorporation in purified CD3(+)/CD4(-)/CD8(-) gamma delta(+) tumour cells. We also report that one patient with hepatosplenic gamma delta(+) T-cell lymphoma in terminal leukaemic phase showed a striking haematological response to single-agent dCF given as fourth-line treatment. In particular, the selective clearance of gamma delta(+) tumour T cells in peripheral blood and bone marrow was observed starting after the second course of treatment. Our results suggest that dCF may represent a potentially active drug for the management of this aggressive form of T-cell lymphoma.