Improving the therapeutic index in breast cancer treatment: the Richard and Hinda Rosenthal Foundation Award lecture.

Improving the relationship between desired and undesired effects of therapy, the therapeutic index, is a major goal of cancer therapy. Clinical research pertinent to breast cancer treatment attempting to manipulate this therapeutic index is not restricted to studies in patients. Described herein is research in humans, mouse, machine, marrow, and molecule, concerned with either increasing care or decreasing treatment complications. Molecular studies use 125I-tamoxifen as a specific cytotoxic agent for cells which contain estrogen receptors able to bind the agent and transport it into the nucleus where the limited range radiations are cytotoxic. Murine bone marrow stem cells are heterogeneous as regards their self-renewal potential. Chemotherapeutic agents used in the adjuvant treatment of breast cancer have different effects on these cells. L-Phenylalanine mustard is toxic to the most primitive stem cells and produces a permanent stem cell self-renewal deficit when given to mice in an "adjuvant" setting. Cyclophosphamide and 5-fluorouracil act primarily on later stem cells and do not produce such proliferative limitations. Eliminating breast cancer while preserving normal structure and function is the goal of combining radiation therapy and tumor excision. Results with this technique are comparable to those following mastectomy without loss of the breast or chest musculature.