Synergy between chemotherapy and alpha particles: effects in cells directly hit and in bystander cells

Full text: Radioimmunotherapy with alpha-emitting nuclides offers the potential for selective targeting of micrometastatic sites. The short range of alpha particles and limited penetration of the labeled antibody into the tumor make it difficult to deliver a lethal dose to all tumor cells. In an effort to improve the extent and uniformity of tumor cell kill, experiments are underway to evaluate the ability of chemotherapy agents to produce synergistic effects in cells directly hit by alpha particles and in bystander cells. An alpha particle cell irradiation system comprised of planar americium-241 alpha particle sources together with custom-made cell culture dishes with replaceable mylar bottoms has been constructed and characterized. By changing the alpha particle source, the dose rate to cells on the mylar membrane can be varied from 0.0013 Gy/min to 13 Gy/min. The residual range of the alpha particles after exiting the mylar membrane is approximately 30 ∝/m. Preliminary results with alpha particle exposure in the presence or absence of low concentrations of either taxol or oxaliplatin show evidence of synergistic effects. A series of plastic grids have been designed and constructed that can be interposed between the alpha particle source and the cells to partially block the alpha particles. The ratio of open area to shielded area is kept constant at 50% but the diameter and total number of circular openings in the grid is varied, thus changing the proportion of bystander cells present close to the edge between the open and shielded zones. This approach creates a two-dimensional model system for micrometastatic tumors of various sizes where the shielded areas represent the deeper portions of a tumor beyond the range of surface-bound alpha particles. Experiments are underway to determine whether there are synergistic effects between the chemotherapy agents and the bystander cells