Selective apoptosis of natural killer‐cell tumours by l‐asparaginase

Summary We examined the effectiveness of various anti‐tumour agents to natural killer (NK)‐cell tumour cell lines and samples, which are generally resistant to chemotherapy, using flow cytometric terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end‐labelling (TUNEL) assay. Although NK‐YS and NK‐92 were highly resistant to various anti‐tumour agents, l‐asparaginase induced apoptosis in these two NK‐cell lines. NK‐cell leukaemia/lymphoma and acute lymphoblastic leukaemia (ALL) samples were selectively sensitive to l‐asparaginase and to doxorubicin (DXR) respectively. Samples of chronic NK lymphocytosis, an NK‐cell disorder with an indolent clinical course, were resistant to both drugs. Our study clearly separated two major categories of NK‐cell disorders and ALL according to the sensitivity to DXR and l‐asparaginase. We examined asparagine synthetase levels by real‐time quantitative polymerase chain reaction (RQ‐PCR) and immunostaining in these samples. At least in nasal‐type NK‐cell lymphoma, there was a good correlation among asparagine synthetase expression, in vitro sensitivity and clinical response to l‐asparaginase. In aggressive NK‐cell leukaemia, although asparagine synthetase expression was high at both mRNA and protein levels, l‐asparaginase induced considerable apoptosis. Furthermore, samples of each disease entity occupied a distinct area in two‐dimensional plotting with asparagine synthetase mRNA level (RQ‐PCR) and in vitrol‐asparaginase sensitivity (TUNEL assay). We confirmed rather specific anti‐tumour activity of l‐asparaginase against NK‐cell tumours in vitro, which provides an experimental background to the clinical use of l‐asparaginase for NK‐cell tumours.