Since increasing evidence indicates that combination modality of
cancer treatment is preferable, and a series of 5-halo-6- phenylpyrimidinones 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 B 16
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 (10(6) 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 (greater than 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 B 16
melanoma when animals received the combination
therapy. The significance of these findings, in terms of theoretical consideration as well as
drug development, is discussed.