Cytotoxic Drugs, Programmed Cell Death, and the Immune System: Defining New Roles in an Old Play

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Abstract
Since the first use of aminopterin to treat childhood leukemia by Sidney Farber almost 50 years ago, chemotherapy for leukemias and solid tumors has come a long way (1). With combinations of several drugs in the 1960s and early 1970s and the development of repetitive cycle protocols, long-term remission of some cancers has been achieved in a considerable number of patients. Dose-intensification strategies and more sophisticated protocols developed primarily in pediatric oncology in the early 1980s have now established that the majority of children and adolescents with leukemias and solid tumors (neuroblastoma and sarcomas) can be cured from these otherwise fatal diseases. In addition, adjuvant chemotherapy has become an important treatment option for tumors such as those of the colon or breast. However, the widespread use of chemotherapy also has shown that certain tumors are chemosensitive, whereas others are chemoresistant. Most malignant disorders in children and adolescents are chemosensitive, whereas most of the malignant tumors in later life are relatively chemoresistant. This situation has been explained by the “immature” state of tumors early in life, with fewer genetic mutations, in contrast to the “mature” tumors found with increasing age or by the different origin of the tissue involved (e.g., sarcomas versus carcinomas).