ABINOFURANOSYLCYTOSINE-5'-ALKYLPHOSPHONOPHOSPHATES AND DIPHOSPHATES -NEW ORALLY-ACTIVE DERIVATIVES OF ARA-C

ara-Cytidine-5'-alkylphosphonophosphates and the corresponding -diphos phates were found to be cytostatically active in vitro against the hum an mammary epithelial cell line H184 A1N4 and the human mammary tumor cell line MaTu. Our results indicate that the replacement of the dipho sphate by the phosphonophosphate group has no influence on antiprolife rative activity in this case. The compounds were more active than the corresponding cytidine phospholipid conjugates and related compounds l acking a cytostatically active nucleoside, the ara-C prodrug Cytoros, and were slightly less active than an;C. The cytostatic effect was pre vented by 2'-deoxycytidine indicating their action as prodrugs of ara- C. In contrast to ara-C, they increase [Ca2+](1) in H184 A1N4 cells, p ointing to a different mechanism of action in addition to their prodru g effect. In combination with phospholipid analogs, synergistic effect s could be observed. Further studies within the disease-oriented in vi tro Anticancer Screening Program of the National Cancer Institute show selectivity for certain cancer cell lines. The hexadecyl derivatives revealed a significant antitumor activity in vivo against the murine l ymphatic leukemia P 388 cells being equally potent or even superior to ara-C. In contrast to ara-C, they were found to be orally active. Sid e effects measured as leukopenia and body weight reduction were less p ronounced than with the parent drug.