Bruce C. Baguley

Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand

Summary

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 analogue 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 every 2 years. New targets for cytotoxicity were identified in this program, including tubulin and DNA topoisomerases I and II. The huge expansion in our basic knowledge of cancer has facilitated the development of two new anticancer strategies: the inhibition of specific cellular growth pathways and 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. The balance is maintained not only by the genetic status of the cancer cell but by 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 antiestrogens 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 antiangiogenic and immune approaches. Current research has underlined the enormous complexity not only of growth and death control systems within the tumor cell but of interactions of tumor cells with vascular endothelial, immune, and other cells in cancer tissue. The challenge of future development of low-molecular-weight anticancer drugs is to apply knowledge gained in basic studies to develop new strategies.

1. Introduction

It is difficult to assign a date to the beginning of the treatment of cancer with drugs because herbal and other preparations have been used for cancer treatment since antiquity. However, the 1890s, a decade that represents an extraordinarily creative period in painting, music, literature, and technology, encompassed discoveries that were to set the scene for developments in cancer treatment in the 20th century. The discovery of penetrating radiation, or x-rays, by Roentgen in Germany in 1895 was complemented 3 years later by the discovery of radium by Marie and Pierre Curie. The discovery of ionizing radiation led not only to radiotherapy as form of cancer treatment but eventually to the development of anticancer drugs that mimicked the effect of radiation by damaging DNA. The discovery by George Beatson, working in Scotland in 1896, that the growth of a breast cancer could be halted by removal of the ovaries indicated that the growth of cancer cells in the body could be influenced by external factors. This provided the basis for cancer treatment strategies that changed the regulation of cancer cell growth. The demonstration by William Coley in 1898 that the administration to cancer patients of a bacterial extract, sterilized by passage through a porcelain filter, caused regressions in lymphoma and sarcoma indicated that activation of the body’s defense systems might provide a strategy for cancer treatment. Each of these three advances lent weight to the bold assumption, made by Paul Ehrlich and others in the early part of the 20th century, that low-molecular-weight drugs might be used in the management of cancer as well as infectious diseases. This chapter considers each of these three approaches in turn.

2. Genotoxic (Cytotoxic) Therapy

The first practical anticancer drugs were discovered accidentally. One such discovery was an outcome of war, stemming from the finding that sulfur mustard gas, used as a toxic vesicant in the First World War, caused myelosuppression. Although gas warfare was not employed in the Second World War, a considerable stock of mustard gas canisters was maintained in the Mediterranean area. An accident in the Italian port of Bari, involving leakage of one of these canisters, rekindled interest in the myelosuppressive effect of nitrogen mustard, leading to clinical trials in lymphoma patients (Karnofsky et al., 1948; Kohn, 1996).

The identification of vitamins as small low-molecular-weight enzyme cofactors was an important biochemical achievement in the early part of the 20th century. The structural elucidation and crystallization of folic acid in 1946 led, as with other isolated vitamins, to studies on its effect on the course of a number of diseases. Unexpectedly, administration to leukemia patients of folic acid and its glutamylated derivatives resulted in an increase in tumor growth. While the use of low-folate diets in the management of leukemia was investigated, the development of the folic acid analogue aminopterin provided a significant advance in the management of childhood acute leukemia (Farber et al., 1948; Bertino, 1979).

The link between these two disparate types of drugs and their biological activity was found to be related to their damaging effect on DNA. Although Friedrich Miescher had characterized DNA as a substance in 1862, the informational complexity and significance to life of DNA was not appreciated until the 1940s. The elucidation in 1953 by James Watson and Francis Crick of the double-helical structure of DNA had a singular impact on strategies of anticancer drug development. The cancer chemotherapeutic agent nitrogen mustard was found to react chemically with DNA (Kohn et al., 1966). Studies on aminopterin indicated that it interrupted DNA biosynthesis and in so doing caused DNA damage. The next two decades brought a massive development of new drugs that affected the integrity of the cell’s genetic material, with approximately one new drug entering widespread clinical use every 2 years. Many of these drugs, which revolutionized the treatment of many types of cancer, are shown in Figure 1.