In vitro and in vivo effects of 2'-deoxycoformycin (Pentostatin) on tumour cells from human gammadelta+ T-cell malignancies.
Hepatosplenic gammadelta+ 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 gammadelta+ tumour cells from bone marrow or peripheral blood of four patients with hepatosplenic gammadelta+ T-cell lymphoma. At a concentration of 10 microM, dCF, in the presence of 2'-deoxyadenosine (dAdo), displayed an early and selective cytotoxic effect on gammadelta+ tumour T cells. After 48 h of in vitro exposure to dCF, the absolute number of viable CD3+/gammadelta+ tumour T cells was reduced by more than 90% in all samples with respect to control cultures, with absolute counts of viable CD3+/alphabeta+ 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+/alphabeta+ T cells, which accounted, however, for only 20-25% of the initial cell input. Accordingly, the combination of dCF (10-100 microM) plus dAdo was able to induce a dose-dependent inhibition of clonogenic growth and [3H]-thymidine incorporation in purified CD3+/CD4-/CD8- gammadelta+ tumour cells. We also report that one patient with hepatosplenic gammadelta+ 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 gammadelta+ 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.
Developmental Oncology/Haematology and Leukaemia Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
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Aldinucci
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Poletto
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Zagonel
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Rupolo
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Degan
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Nanni
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Gattei
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Pinto
D058892:Adenosine Deaminase Inhibitors; D000328:Adult; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015649:Pentostatin / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013160:Splenic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015649:Pentostatin