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Chemoimmunotherapy of B16 Melanoma and P388 Leukemia with Cyclophosphamide and Pyrimidinones¹

The Upjohn Company Kalamazoo, Michigan 49001

Since increasing evidence indicates that combination modality of cancer treatment is preferable, and a series of 5-halo-6-phenyl pyrimidinones has been found to induce interferon production and to stimulate a variety of immune responses, several were tested alone or in combination with cyclophosphamide (CY) against B16 melanoma and P388 leukemia. Thus far, 2-amino-5-bromo-6-(3-fluorophenyl)-4(3H)pyrimidinone (ABMFPP) and its sister compound 2-amino-5-bromo-6-(2-fluorophenyl)-4(3H)pyrimidinone (ABOFPP) were found to be superior to other pyrimidinones including 2-amino-5-bromo-6-(6-phenyl)-4-pyrimidinone which is currently under clinical investigation. Neither ABMFPP nor ABOFPP alone had any significant activity against P388 leukemia. However, a marked synergistic effect was observed when a single i.p. injection of CY at 24 hr after tumor inoculation (10⁶ cells/mouse) was followed by multiple i.p. injections of either ABMFPP or ABOFPP. For instance, the increase of life span was about 180% when animals received both CY (150 mg/kg) and ABMFPP (125 mg/kg/injection) as compared to 100% increased life span when animals received CY alone, and 0% increased life span when animals received ABMFPP alone. Also, 80% of the animals were long-term survivors (>30 days) when animals received the combination therapy as compared to 20% survivors when animals received CY alone. The synergistic effect exhibited by ABMFPP or ABOFPP correlated positively to the initial reduction of tumor burden by CY. The optimal gap between CY and pyrimidinone administration was one day. The best therapeutic response was observed when pyrimidinone was given every 4 days for a total of 7 injections; however, other schedules and dosing frequencies also gave significant responses. The synergistic effect was also observed with B16 melanoma when animals received the combination therapy. The significance of these findings, in terms of theoretical consideration as well as drug development, is discussed.

¹ A portion of this investigation was reported at the 74th Annual Meeting of the American Association for Cancer Research (12).

² To whom requests for reprints should be addressed.

Received 9/30/83. Accepted 4/ 2/84.