bropirimine and Melanoma

2-Amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) was given to 59 patients in a Phase I study. The agent was selected because it is an interferon inducer and an immunotherapeutic agent in animal tumor models. The study was conducted in two phases. In the first phase, the drug was administered as a single oral dose of 25-2,000 mg/m2. In the second part, the highest tolerated dose reached during part one was used as the initial dose in a multiple-dose scheme of treatment. Patients were treated weekly. The dose was escalated each week, starting with a dose of 2 g/m2 and escalating to 3, 4, and 5 g/m2. No cardiac, hematologic, hepatic, or renal toxicity was observed. The most common toxicity was nausea and vomiting, which occurred in 18% of the patients; others were headache (8%), abdominal pain (8%), and diarrhea (6%). No consistent induction of interferon and no major modification of host defense parameters occurred. One patient with malignant melanoma showed evidence of tumor regression. Pharmacologic studies demonstrated a significant decrease in the bioavailability of the drug as it was administered in this study. Further studies of ABPP with a preparation that has good availability are indicated to determine the potential antitumor activity of this agent or this class of agents in humans.

Topics: Adult; Aged; Cytosine; Drug Evaluation; Humans; Interferon Inducers; Interferons; Male; Melanoma; Middle Aged; Neoplasms

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

Topics: Animals; Cytosine; Female; Immunity; Interferon Inducers; Interferons; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Pyrimidines; Pyrimidinones; Virus Diseases