A BRIEF HISTORY OF CANCER CHEMOTHERAPY

Clinical cancer chemotherapy in the 20th century has been dominated by the development of genotoxic drugs, initiated by the discovery of the anticancer properties of nitrogen mustard and the folic acid analog, aminopterin, in the 1940s. The development of inbred strains of mice in the early part of the 20th century led to the use of transplantable tumors for the screening of very large numbers of compounds, both natural and synthetic, for experimental antitumor activity. Such screening led to the identification of clinically useful drugs at a rate of approximately one in every 2 years. The huge expansion in the basic knowledge of cancer has facilitated the development of two new anticancer strategies. First is the inhibition of specific cellular growth pathways and second is the inhibition of growth of cancer as a tissue. One of the most important principles to emerge is that loss of growth control of cancer cells is mechanistically associated with an increased tendency to undergo programmed cell death, or apoptosis. Thus, cancer growth is a balance between cell birth and cell death, which is maintained not only by the genetic status of the cancer cell, but also by the interactions with host cells and extracellular matrix components in the tumor environment. The identification of estrogen as a factor for stimulating the growth led to anti-estrogens as therapeutic agents and, more recently, to antagonists of growth factor receptor-mediated pathways. The early use of bacterial toxins in cancer treatment has led to strategies based on host–tumor interactions, such as anti-angiogenic and immune approaches.