EFFECT OF ASTA-Z 7575 (INN MAPHOSPHAMIDE) ON HUMAN LYMPHOKINE-ACTIVATED KILLER-CELL INDUCTION

Recent studies combining chemotherapeutic agents with various biologic al response modifiers for the treatment of cancer have shown promising results. Cyclophosphamide (Cy) is the most widely used alkylating age nt and a major constituent of combination chemotherapy regimens for ma ny neoplastic diseases. It has been reported that Cy is a cytotoxic dr ug, which becomes immunosuppressive at higher doses. A synthetic metab olite of Cy, ASTA-Z, has recently been produced. ASTA-Z is more active and stable by itself and does not need to be metabolically converted to an active compound. The combined effect of Cy and interleukin-2 (IL -2) on the induction of lymphokine-activated killer (LAK) cells is not known. Therefore, we decided to investigate the effect of ASTA-Z on t he induction and function of LAK. The coculture of peripheral blood mo nonuclear cells (PBMC) with various concentrations of ASTA-Z (0, 10(-6 ), 10(-5), 10(-4), and 10(-3) dilution) and IL-2 (50 U/ml) for 4 days produced significant suppression of cytotoxicity and lytic ability of the LAK cells against NK-sensitive (K562) and NK-resistant (M14) tumor cell lines. The lower doses of ASTA-7, did not affect the generation of LAK cells, its cytotoxicity and lytic ability of ASTA-Z against bot h NK-sensitive and NK-resistant tumor cell lines. Furthermore, the AST A-Z produced dose-dependent suppression of the proliferative response of LAK cells. The significant therapeutic benefit in the cancer patien t may be achieved by the low dose regimen of Cy and IL-2 because it ha s no deleterious effect on the induction and function of LAK cells.