Systemic cancer therapy: evolution over the last 60 years.

The 1940s marked the beginning of an era of important discoveries that contributed to modern concepts underlying the current practice of cancer chemotherapy, such as the log kill hypothesis reported by Skipper, the Norton-Simon hypothesis, and the Goldie-Coldman hypothesis. The early success of nitrogen mustards and antifolates in the treatment of hematologic malignancies paved the way for drug discovery platforms, which resulted in the generation of more drugs that nonetheless predominantly are genotoxic. The turn of the new millennium marked a new phase in the evolution of cancer chemotherapy. Scientific progress in the preceding 60 years elucidated the important ideas behind tumor microenvironment and 'targeted' therapy that had their inception in the late 19th century. Breakthroughs in molecular biology have paved the way for the development of novel agents that modulate the dysregulated molecular pathways implicated in carcinogenesis. The key approaches and evidence pertinent to the clinical development of these novel agents are presented in this review.