Interferon-Induced Growth Modulation: Low Dose Maintenance of the Antiproliferative Response

Abstract

Treatment of the Burkitt's lymphoma-derived Daudi cell line with human beta interferon (HuIFN-β) results in a dose-dependent antiproliferative response. We have defined three phases including: (1) initiation, (2) maintenance, and (3) termination of the antiproliferative state. Each phase is characterized by specific growth modulatory properties. Initiation of the antiproliferative state with a single interferon dose requires 200 International Reference Units (IRU) per ml, depending on such factors including cell density, serum content in the medium and the length of IFN exposure. Initiation of the IFN response occurred within a 4 h incubation period. Even following this short exposure, the vast majority of cells would be sequestered in the G₀/G₁ cell cycle compartment. As measured by cytofluorimetry there was a 16-20 h delay in the initiation of the antiproliferative response. The antiproliferative response, as measured by changes in the distribution of cells in the cell cycle, was maximal at 24 h after treatment. This delay was equal to the doubling time of the Daudi cell. The antiproliferative response initiated by 200 IRU/ml of IFN was reversible if the IFN was removed and not replenished. Cells showed renewed growth approximately 40 h after treatment. The antiproliferative state could be maintained by additional interferon, but, even after such treatment, the antiproliferative state decayed in a dose-dependent fashion. This decay was proportional to the decrease in the biological activity of the interferon molecule itself. Finally, we showed that the antiproliferative state could be maintained by using only 40 IRU/ml. These cells were maintained in the antiproliferative state for an extended period of time.