2-amino-5-bromo-6-(3-fluorophenyl)-4(3h)pyrimidinone and bropirimine

At least three marked differences were noted in the results compared from two parallel experiments using identical protocols with virus-free mice and mouse hepatitis virus (MHV) infected mice inoculated with P388 leukemia. First, the therapeutic effect of cyclophosphamide (CY), a cytotoxic antitumor drug, was apparently augmented in MHV-infected mice. A 162% increase of life span (ILS) was obtained in MHV-infected mice compared to a 100% ILS in uninfected mice. Second, the experimental error in terms of the range of animal survival time was much larger with MHV-infected mice than with uninfected mice. In MHV-infected mice, the therapeutic effect of the combination treatment with CY and pyrimidinone was not statistically different from that of the treatment with CY alone. In uninfected mice, the effects of the combination therapy at all doses of pyrimidinone were statistically more effective than that of CY treatment alone.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Cytosine; Drug Therapy, Combination; Female; Hepatitis, Viral, Animal; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Murine hepatitis virus; Pyrimidinones

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.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Combined Modality Therapy; Cyclophosphamide; Cytosine; Drug Synergism; Immunotherapy; Leukemia P388; Leukemia, Experimental; Melanoma; Mice; Mice, Inbred Strains