Some hormones and hormonal drugs were employed to treat cancer in the first half of the 20th century, but it was only with the introduction of alkylating agents, in particular, mustard agents, that chemotherapy as we know it was born.

Paul Ehrlich originated the term chemotherapy in 1914; Ehrlich dreamed of a “magic bullet” which would attack a disease and leave the healthy parts of the body unaffected.  For the next eight decades many antineoplastic drugs were developed, but they were closer to blunt tools than to the precisely targeted medicines Ehrlich wanted and they usually had severe side effects.  Only with the development of targeted antibodies and small molecule signal transduction inhibitors around the turn of the 21st Century would medicines approach the idea of a magic bullet.

The development of anti-cancer agents has been by trial and error, serendipity, and rational systematic searches.  Parallel to the development of new drugs has been research into the biology of cancer – “basic research” – why it forms, what causes it, the drivers of tumor growth, and how different types of cancer are different.

Scientists found early on that some cells were malignant and others normal, and a cancerous tumor was a mass with a large number of malignant cells.  They determined that malignant cells had different genetic code than normal cells, and that they multiplied rapidly, which is why tumors grew.  They did not respond to signals from other cells telling them to die.  Malignant cells are essentially immortal.  Further, they processed glucose differently and they used more of it than normal cells to fuel growth of the cancer.

The first alkylating agents were synthesized in 1854, but the dramatic effect on human tissue was not known until sulfur mustard was used as a weapon during World War I. Physicians caring for victims of this gruesome chemical weapon identified some of its widespread systemic effects. This was one of the serendipitous discoveries of anticancer agents.  Scientists noticed people who had been expose d to these materials had lower rates of cancer.   Between the two World Wars extensive research was undertaken by Gilman and colleagues on nitrogen mustard and similar compounds, specifically the ability of the alkylating agents to kill cancerous cells. In 1942 experiments with mustard gas to treat thyroid cancer and showed that it worked in mice and humans.  These were the first of the alkylating agents;  alkylation of DNA turned out to be one of the most important biochemical mechanisms in stopping cancer cells.  In the early 1960s mechlorethamine ushered in the modern age of chemotherapeutic cancer treatment as the first nitrogen mustard was introduced as an antineoplastic agent.

Also in the 1940s scientists began using antifolates to address selected cancers.  Antifolates are a type of antimetabolite; researchers later developed other compounds that work this way.

The 1960s saw a systematic survey of the natural world to find compounds that stop cancer growth.  Among the successes were Paclitaxel (derived from the Yew tree) and the vinca alkaloids (derived from Periwinkle).

The 1970s saw big increases in funding for cancer research, including drug discovery.  Cisplatin was the first of the platinum drugs (a type of alkylating agent) and was later so widely employed it earned the nickname “the penicillin of cancer”.  (Cisplatin was first synthesized in the 19th Century, but it wasn’t until the 1970s that its anticancer properties were recognized.) Anthracyclines (e.g. Dacarbazine), antibiotics (e.g. Bleomycin) and topoisomerase inhibitors first saw widespread use in the 70s and 80s.  Aromatase inhibitors for management of hormone-related cancers were introduced in the 80s.  In 1978 the first oncogene was discovered and was found to be a kinase.  This got scientists interested in pursuing methods to inhibit kinase expression.  In the laboratory naphthalene sulphonamides were found to be kinase inhibitors and although they were never used clinically, they provided the basis for further drugs, a line of inquiry that paid off in the 21st Century.

Except for hormone therapy all chemotherapy drugs developed up to 1990 were cytotoxic.  They were not targeted; they killed cells during their reproductive phase.  Healthy non-malignant cells that were reproducing were also affected, which gave the patient unpleasant side effects.  These side effects were sometimes so bad that they limited the size of the chemotherapy dose that could be administered.

In the 1990s, monoclonal antibodies hit the clinic.  Some say they are not chemo, but we disagree.  They were the first targeted therapies.  Some inhibited angiogenesis; some inhibited kinase enzymes; and some other targets.  In the 2000s small molecule kinase inhibitors (SMKI) were introduced.  These were often oral.  Both SMKI and MAbs had less severe side effects than conventional chemotherapy.

In 2001 tyrosine kinase inhibitor imatinib was approved by the FDA for the treatment of chronic myelocytic leukemia.  It proved very successful and soon became the go-to drug for that type of cancer.  CML is particularly well suited for targeted therapy in that a single molecular abnormality drives the disease.  Most cancers have multiple abnormalities.

Many SMKIs were introduced over the next two decades.  Today most of the new drugs gaining FDA approval for cancer treatment are targeted therapies: monoclonal antibodies, conjugates (MAbs plus attached toxin), and signal transduction inhibitors.  Over a quarter of new drugs approved by the FDA are for cancer.

Over two hundred medicines are now employed in cancer treatment; these agents can be classified according to their chemical structure, similarity to other compounds, derivation, and biochemical mechanism.  Therapies take advantage of the fact that malignant cells have different metabolic functions from normal cells.  Conventional chemotherapy agents function by inhibiting mitosis (cell reproduction) and inducing apoptosis (cell death).  Engineered anti-cancer agents such as monoclonal antibodies, cytokines, gene therapy vectors, signal transduction inhibitors, and peptide molecules have only been developed in the past 30 years.  No medicines work by affecting the underlying mutations that cause cancer.  Theranostics are agents that act to diagnose the disease and also to treat it.

Drugs currently approved by the FDA for cancer by year of approval: