History of cancer chemotherapy
Encyclopedia
The era of cancer chemotherapy
began in the 1940s
with the first use of nitrogen mustard
s and folic acid
antagonist drugs. Cancer
drug development has exploded since then into a multi-billion dollar industry. The targeted therapy
revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.
, a chemical warfare agent, as an effective treatment for cancer. Two pharmacologists, Louis S. Goodman and Alfred Gilman
, were recruited by the United States Department of Defense
to investigate potential therapeutic applications of chemical warfare
agents. A year into the start of their research a German air raid in Bari, Italy
led to the exposure of more than one thousand people to the SS John Harvey
's secret cargo composed of mustard gas bombs. Dr. Stewart Francis Alexander, a Lieutenant Colonel who was an expert in chemical warfare, was subsequently deployed to investigate the aftermath. Autopsies
of the victims suggested that profound lymphoid
and myeloid
suppression had occurred after exposure. In his report Dr. Alexander theorized that since mustard gas all but ceased the division of certain types of Somatic cells
whose nature it was to divide fast, it could also potentially be put to use in helping to suppress the division of certain types of cancerous cells.
Using this information, Goodman and Gilman reasoned that this agent could be used to treat lymphoma
, since lymphoma is a tumor of lymphoid cells. They first set up an animal model - they established lymphomas in mice
and demonstrated they could treat them with mustard agents. Next, in collaboration with a thoracic surgeon, Gustav Linskog, they injected a related agent, mustine (the prototype nitrogen mustard
anticancer chemotherapeutic), into a patient with non-Hodgkin's lymphoma. They observed a dramatic reduction in the patient's tumour masses. Although this effect lasted only a few weeks, and then had to return for another set of treatment, this was the first step to the realization that cancer could be treated by pharmacological agents.
Shortly after World War II, a second approach to drug therapy of cancer began. Sidney Farber
, a pathologist at Harvard Medical School
, studied the effects of folic acid
on leukemia patients. Folic acid, a vitamin
crucial for DNA metabolism (he did not know the significance of DNA
at that time), had been discovered by Lucy Wills
, when she was working in India, in 1937. It seemed to stimulate the proliferation of acute lymphoblastic leukemia
(ALL) cells when administered to children with this cancer. In one of the first examples of rational drug design (rather than accidental discovery), in collaboration with Harriett Kilte and Yellapragada Subbarao
of Lederle Laboratories, Farber used folate analogues. These analogues — first aminopterin
and then amethopterin (now methotrexate) were antagonistic to folic acid, and blocked the function of folate-requiring enzymes. When administered to children with ALL in 1948, these agents became the first drugs to induce remission in children with ALL. Remissions were brief, but the principle was clear — antifolates could suppress proliferation of malignant cells, and could thereby re-establish normal bone-marrow function. It is worth noting that Farber met resistance to conducting his studies at a time when the commonly held medical belief was that leukemia was incurable, and that the children should be allowed to die in peace. Afterwards, Farber's 1948 report in the New England Journal of Medicine
was met with incredulity and ridicule. Remarkably, a decade later at the National Cancer Institute
, Roy Hertz and Min Chiu Li discovered that the same methotrexate
treatment alone could cure choriocarcinoma
(1958), a germ-cell malignancy that originates in trophoblastic cells of the placenta. This was the first solid tumour to be cured by chemotherapy.
in New York
, with Farber's help, started his own methotrexate study and found the same effects. He then decided to try to develop anti-metabolites in the same way as Farber, by making small changes in a metabolite needed by a cell to divide. With the help of George Hitchings and Gertrude Elion, two pharmaceutical chemists who were working at the Burroughs Wellcome Co. in Tuckahoe
, many purine
analogues were tested, culminating in the discovery of 6-mercaptopurine (6-MP), which was subsequently shown to be a highly active antileukemic drug.
The Eli Lilly
natural products group found that alkaloid
s of the Madagascar periwinkle (Vinca rosea), originally discovered in a screen for anti-diabetic drug
s, blocked proliferation of tumour cells. The antitumour effect of the vinca alkaloids (e.g. vincristine
) was later shown to be due to their ability to inhibit microtubule
polymerization, and therefore cell division.
The United States Congress
created a National Cancer Chemotherapy Service Center (NCCSC) at the NCI in 1955 in response to early successes. This was the first federal programme to promote drug discovery for cancer – unlike now, most pharmaceutical companies were not yet interested in developing anticancer drugs. The NCCSC developed the methodologies and crucial tools (like cell lines and animal model
s) for chemotherapeutic development.
hypothesized that cancer chemotherapy should follow the strategy of antibiotic therapy for tuberculosis with combinations of drugs, each with a different mechanism of action. Cancer cells could conceivably mutate to become resistant to a single agent, but by using different drugs concurrently it would be more difficult for the tumor to develop resistance to the combination. Holland, Freireich, and Frei simultaneously administered methotrexate
(an antifolate), vincristine
(a Vinca alkaloid), 6-mercaptopurine
(6-MP) and prednisone
— together referred to as the POMP regimen — and induced long-term remissions in children with acute lymphoblastic leukaemia (ALL). With incremental refinements of original regimens, using randomized clinical studies by St. Jude Children's Research Hospital
, the Medical Research Council
in the UK (UKALL protocols) and German Berlin
-Frankfurt
-Münster
clinical trials group (ALL-BFM protocols), ALL in children has become a largely curable disease.
This approach was extended to the lymphomas in 1963 by Vincent T. DeVita
and George Canellos
at the NCI, who ultimately proved in the late 1960s that nitrogen mustard, vincristine, procarbazine and prednisone — known as the MOPP regimen — could cure patients with Hodgkin's and non-Hodgkin's lymphoma. Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously.
Adjuvant
As predicted by studies in animal models, drugs were most effective when used in patients with tumours of smaller volume. Another important strategy developed from this - if the tumour burden could be reduced first by surgery, then chemotherapy may be able to clear away any remaining malignant cells, even if it would not have been potent enough to destroy the tumor in its entirety. This approach was termed "adjuvant therapy".
Emil Frei
first demonstrated this effect - high doses of methotrexate prevented recurrence of osteosarcoma
following surgical removal of the primary tumour. 5-fluorouracil, an inhibitor of DNA synthesis, was later shown to improve survival when used as an adjuvant to surgery in treating patients with colon cancer. Similarly, the landmark trials of Bernard Fisher
, chair of the National Surgical Adjuvant Breast and Bowel Project, and of Gianni Bonadonna, working in the Istituto Nazionale Tumori di Milano, Italy
, proved that adjuvant chemotherapy
after complete surgical resection of breast tumours significantly extended survival — particularly in more advanced cancer.
(Taxol) was a novel antimitotic agent that promoted microtubule
assembly. This agent proved difficult to synthesize and could only be obtained from the bark of the Pacific Yew tree
, which forced the NCI into the costly business of harvesting substantial quantities of yew trees from public lands. After 4 years of clinical testing in solid tumours, it was found in 1987 (23 years after its initial discovery) to be effective in ovarian cancer
therapy. Notably, this agent, although developed by the NCI in partnership with Bristol-Myers Squibb
, was exclusively marketed by BMS (who had utilized the synthetic methodology developed by Robert Holton at Florida State University) who went on to make over a billion dollars profit from Taxol.
, derived from a Chinese ornamental tree, inhibits topoisomerase
I, an enzyme that allows DNA unwinding. Despite showing promise in preclinical studies, the agent had little antitumour activity in early clinical trials, and dosing was limited by kidney toxicity
: its lactone ring is unstable at neutral pH, so while in the acidic environment of the kidneys it becomes active, damaging the renal tubules. In 1996 a more stable analogue, irinotecan
, won Food and Drug Administration
(FDA) approval for the treatment of colon cancer. Later, this agent would also be used to treat lung and ovarian cancers.
, a platinum
-based compound, was discovered by a Michigan State University
researcher, Barnett Rosenberg
, working under an NCI contract. This was yet another serendipitous
discovery: Rosenberg had initially wanted to explore the possible effects of an electric field on the growth of bacteria. He observed that the bacteria unexpectedly ceased to divide when placed in an electric field. Excited, he spent months of testing to try to explain this phenomenon. He was disappointed to find that the cause was an experimental artifact
– the inhibition of bacterial division was pinpointed to an electrolysis
product of the platinum electrode
rather than the electrical field. This accidental discovery, however, soon initiated a series of investigations and studies into the effects of platinum compounds on cell division, culminating in the synthesis of cisplatin. This drug was pivotal in the cure of testicular cancer
. Subsequently, Eve Wiltshaw and others at the Institute of Cancer Research
in the United Kingdom
extended the clinical usefulness of the platinum compounds with their development of carboplatin
, a cisplatin derivative with broad antitumour activity and comparatively less nephrotoxicity.
at the Southern Research Institute
, synthesized nitrosoureas, an alkylating agent which cross-links DNA. Fludarabine
phosphate, a purine analogue which has become a mainstay in treatment of patients with chronic lymphocytic leukaemia, was another similar development by Montgomery.
s and epipodophyllotoxin
s — both of which inhibited the action of topoisomerase II, an enzyme
crucial for DNA
synthesis.
s. Patients receiving these agents experienced severe side-effects that limited the doses which could be administered, and hence limited the beneficial effects. Clinical investigators realized that the ability to manage these toxicities was crucial to the success of cancer chemotherapy.
Several examples are noteworthy. Many chemotherapeutic agents cause profound suppression of the bone marrow. This is reversible, but takes time to recover. Support with platelet
and red-cell transfusions as well as broad-spectrum antibiotic
s in case of infection during this period is crucial to allow the patient to recover.
Several practical factors are also worth mentioning. Most of these agents caused very severe nausea (termed chemotherapy-induced nausea and vomiting
(CINV) in the literature) which, while not directly causing patient deaths, was unbearable at higher doses. The development of new drugs to prevent nausea (the prototype of which was ondansetron
) was of great practical use, as was the design of indwelling intravenous catheters (e.g. Hickman line
s and PICC lines
) which allowed safe administration of chemotherapy as well as supportive therapy.
One important contribution during this period was the discovery of a means that allowed the administration of previously lethal doses of chemotherapy. The patient's bone marrow
was first harvested, the chemotherapy
administered, and the harvested marrow then returned to patient a few days later. This approach, termed autologous bone marrow transplantation, was initially thought to be of benefit to a wide group of patients, including those with advanced breast cancer
. However, rigorous studies have failed to confirm this benefit, and autologous transplantation is no longer widely used for solid tumors. The proven curative benefits of high doses of chemotherapy afforded by autologous bone marrow rescue are limited to both Hodgkin's and selected non-Hodgkin's lymphoma patients who have failed therapy with conventional combination chemotherapy. Autologous transplantation continues to be used as a component of therapy for a number of other hematologic malignancies
.
The hormonal contribution to several categories of breast cancer subtypes was recognized during this time, leading to the development of pharmacological modulators (e.g. of oestrogen
) such as tamoxifen
.
Although clinical oncologists appeared to have hit a wall at this point in terms of results, under the surface something extraordinary was happening: namely, elucidation of the mechanisms underlying cancer. Understanding of the machinery of the cell and advances in techniques to probe perturbations in its function allowed researchers to understand the genetic nature of cancer. It is important to realize that prior to this point, chemotherapeutic agents had been discovered essentially by chance, or by inhibiting the metabolic pathways crucial to cell division, but none were particularly specific to the cancer cell.
Targeted therapy
Molecular and genetic approaches to understanding cell biology uncovered entirely new signalling networks that regulate cellular activities such as proliferation and survival. Many of these networks were found to be radically altered in cancer cells, and these alterations had a genetic basis caused by a chance somatic mutation.
. The genetic abnormality causing chronic myelogenous leukemia
(CML) has been known for a long time to be a chromosomal translocation
creating an abnormal fusion protein, kinase BCR-ABL, which signals aberrantly, leading to uncontrolled proliferation of the leukemia cells. Imatinib precisely inhibits this kinase. Unlike so many other anti-cancer agents, this pharmaceutical was no accident. Brian Druker
, working in Oregon Health Science University, had extensively researched the abnormal enzyme kinase in CML. He reasoned that precisely inhibiting this kinase with a drug would control the disease and have little effect on normal cells. Druker collaborated with Novartis
chemist Nick Lydon, who developed several candidate inhibitors. From these, imatinib
was found to have the most promise in laboratory experiments. First Druker and then other groups worldwide demonstrated that when this small molecule is used to treat patients with chronic-phase CML, 90% achieve complete haematological remission. It is hoped that molecular targeting of similar defects in other cancers will have the same effect.
is the increasing use of monoclonal antibodies in cancer therapy. Although monoclonal antibodies (immune proteins which can be selected to precisely bind to almost any target) have been around for decades, they were derived from mice and did not function particularly well when administered to humans, causing allergic reactions and being rapidly removed from circulation. "Humanization" of these antibodies (genetically transforming them to be as similar to a human antibody as possible) has allowed the creation of a new family of highly effective humanized monoclonal antibodies. Trastuzumab
, a drug used to treat breast cancer, is a prime example.
, testicular cancer
, and Hodgkins disease, previously universally fatal, are now generally curable diseases. Conventional cytotoxic chemotherapy has shown the ability to cure some cancers, including testicular cancer
, Hodgkin disease, non-Hodgkin lymphoma
, and some leukemia
s. It has also proved effective in the adjuvant
setting, in reducing the risk of recurrence after surgery for high-risk breast cancer
, colon cancer, and lung cancer
, among others.
The overall impact of chemotherapy on cancer survival can be difficult to estimate, since improved cancer screening, prevention (e.g. anti-smoking campaigns), and detection all influence statistics on cancer incidence and mortality. In the United States
, overall cancer incidence rates were stable from 1995 through 1999, while cancer death rates decreased steadily from 1993 through 1999. Again, this likely reflects the combined impact of improved screening, prevention, and treatment. Nonetheless, cancer remains a major cause of illness and death, and conventional cytotoxic chemotherapy has proved unable to cure most cancers after they have metastasized
.
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
began in the 1940s
1940s
File:1940s decade montage.png|Above title bar: events which happened during World War II : From left to right: Troops in an LCVP landing craft approaching "Omaha" Beach on "D-Day"; Adolf Hitler visits Paris, soon after the Battle of France; The Holocaust occurred during the war as Nazi Germany...
with the first use of nitrogen mustard
Nitrogen mustard
The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, in principle these compounds can also be deployed as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by...
s and folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
antagonist drugs. Cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
drug development has exploded since then into a multi-billion dollar industry. The targeted therapy
Targeted therapy
Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...
revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.
The first efforts (1940–1950)
The beginnings of the modern era of cancer chemotherapy can be traced directly to the discovery of nitrogen mustardNitrogen mustard
The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, in principle these compounds can also be deployed as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by...
, a chemical warfare agent, as an effective treatment for cancer. Two pharmacologists, Louis S. Goodman and Alfred Gilman
Alfred Gilman (sr.)
See also Alfred G. Gilman.Alfred Gilman was an Americanpharmacologistat Yale University, School of Medicine, later, at Columbia College of Physicians and Surgeons and Albert Einstein College of Medicine. He published the classic textbook The Pharmacological Basis of Therapeutics with his...
, were recruited by the United States Department of Defense
United States Department of Defense
The United States Department of Defense is the U.S...
to investigate potential therapeutic applications of chemical warfare
Chemical warfare
Chemical warfare involves using the toxic properties of chemical substances as weapons. This type of warfare is distinct from Nuclear warfare and Biological warfare, which together make up NBC, the military acronym for Nuclear, Biological, and Chemical...
agents. A year into the start of their research a German air raid in Bari, Italy
Air Raid on Bari
The air raid on Bari was an air attack by German bombers on Allied forces and shipping in Bari, Italy on 2 December 1943 during World War II. In the attack, 105 German Junkers Ju 88 bombers of Luftflotte 2, achieving complete surprise, bombed shipping and personnel operating in support of the...
led to the exposure of more than one thousand people to the SS John Harvey
John Harvey (ship)
The John Harvey was a U.S. World War II Liberty Ship carrying a secret cargo of mustard gas, whose sinking by German planes in December 1943 at the port of Bari in south Italy caused the single release of chemical weapons in the course of the war by the Allies.The John Harvey was built at the...
's secret cargo composed of mustard gas bombs. Dr. Stewart Francis Alexander, a Lieutenant Colonel who was an expert in chemical warfare, was subsequently deployed to investigate the aftermath. Autopsies
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
of the victims suggested that profound lymphoid
Lymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
and myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
suppression had occurred after exposure. In his report Dr. Alexander theorized that since mustard gas all but ceased the division of certain types of Somatic cells
Somatic cell
A somatic cell is any biological cell forming the body of an organism; that is, in a multicellular organism, any cell other than a gamete, germ cell, gametocyte or undifferentiated stem cell...
whose nature it was to divide fast, it could also potentially be put to use in helping to suppress the division of certain types of cancerous cells.
Using this information, Goodman and Gilman reasoned that this agent could be used to treat lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, since lymphoma is a tumor of lymphoid cells. They first set up an animal model - they established lymphomas in mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
and demonstrated they could treat them with mustard agents. Next, in collaboration with a thoracic surgeon, Gustav Linskog, they injected a related agent, mustine (the prototype nitrogen mustard
Nitrogen mustard
The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, in principle these compounds can also be deployed as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. Nitrogen mustard gas was stockpiled by...
anticancer chemotherapeutic), into a patient with non-Hodgkin's lymphoma. They observed a dramatic reduction in the patient's tumour masses. Although this effect lasted only a few weeks, and then had to return for another set of treatment, this was the first step to the realization that cancer could be treated by pharmacological agents.
Another leap forward - The antifolates
Sidney Farber
Sidney Farber was a pediatric pathologist. He was born in 1903 in Buffalo, New York, the third oldest of a family of 14 children. He was a graduate of the University of Buffalo in 1923. He took his first year of medical school at the Universities of Heidelberg and Freiburg in Germany. He entered...
, a pathologist at Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
, studied the effects of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
on leukemia patients. Folic acid, a vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
crucial for DNA metabolism (he did not know the significance of DNA
History of molecular biology
The history of molecular biology begins in the 1930s with the convergence of various, previously distinct biological disciplines: biochemistry, genetics, microbiology, and virology...
at that time), had been discovered by Lucy Wills
Lucy Wills
Lucy Wills, MA , LRCP, MB BS was a leading English haematologist. She conducted seminal work in India in the late 1920s and early 1930s on macrocytic anaemia of pregnancy. Her observations led to her discovery of a nutritional factor in yeast which both prevents and cures this disorder...
, when she was working in India, in 1937. It seemed to stimulate the proliferation of acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
(ALL) cells when administered to children with this cancer. In one of the first examples of rational drug design (rather than accidental discovery), in collaboration with Harriett Kilte and Yellapragada Subbarao
Yellapragada Subbarao
Yellapragada Subbarao was an Indian biochemist who discovered the function of Adenosine Triphosphate as a energy source in the cell, and made important contributions to the treatment of cancer. Most of his career was spent in the United States...
of Lederle Laboratories, Farber used folate analogues. These analogues — first aminopterin
Aminopterin
Aminopterin , a 4-amino analog of folic acid, is an antineoplastic drug with immunosuppressive properties used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase...
and then amethopterin (now methotrexate) were antagonistic to folic acid, and blocked the function of folate-requiring enzymes. When administered to children with ALL in 1948, these agents became the first drugs to induce remission in children with ALL. Remissions were brief, but the principle was clear — antifolates could suppress proliferation of malignant cells, and could thereby re-establish normal bone-marrow function. It is worth noting that Farber met resistance to conducting his studies at a time when the commonly held medical belief was that leukemia was incurable, and that the children should be allowed to die in peace. Afterwards, Farber's 1948 report in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
was met with incredulity and ridicule. Remarkably, a decade later at the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
, Roy Hertz and Min Chiu Li discovered that the same methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
treatment alone could cure choriocarcinoma
Choriocarcinoma
Choriocarcinoma is a malignant, trophoblastic and aggressive cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs...
(1958), a germ-cell malignancy that originates in trophoblastic cells of the placenta. This was the first solid tumour to be cured by chemotherapy.
6-MP, vinca alkaloids and a national treatment effort by the US
Joseph Burchenal, at Memorial Sloan-Kettering Cancer CenterMemorial Sloan-Kettering Cancer Center
Memorial Sloan–Kettering Cancer Center is a cancer treatment and research institution founded in 1884 as the New York Cancer Hospital...
in New York
New York
New York is a state in the Northeastern region of the United States. It is the nation's third most populous state. New York is bordered by New Jersey and Pennsylvania to the south, and by Connecticut, Massachusetts and Vermont to the east...
, with Farber's help, started his own methotrexate study and found the same effects. He then decided to try to develop anti-metabolites in the same way as Farber, by making small changes in a metabolite needed by a cell to divide. With the help of George Hitchings and Gertrude Elion, two pharmaceutical chemists who were working at the Burroughs Wellcome Co. in Tuckahoe
Tuckahoe, Westchester County, New York
Tuckahoe is a village in the town of Eastchester in Westchester County, New York, United States. As of the 2010 census, the village's population was 6,486....
, many purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
analogues were tested, culminating in the discovery of 6-mercaptopurine (6-MP), which was subsequently shown to be a highly active antileukemic drug.
The Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
natural products group found that alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s of the Madagascar periwinkle (Vinca rosea), originally discovered in a screen for anti-diabetic drug
Anti-diabetic drug
Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents...
s, blocked proliferation of tumour cells. The antitumour effect of the vinca alkaloids (e.g. vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
) was later shown to be due to their ability to inhibit microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
polymerization, and therefore cell division.
The United States Congress
United States Congress
The United States Congress is the bicameral legislature of the federal government of the United States, consisting of the Senate and the House of Representatives. The Congress meets in the United States Capitol in Washington, D.C....
created a National Cancer Chemotherapy Service Center (NCCSC) at the NCI in 1955 in response to early successes. This was the first federal programme to promote drug discovery for cancer – unlike now, most pharmaceutical companies were not yet interested in developing anticancer drugs. The NCCSC developed the methodologies and crucial tools (like cell lines and animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s) for chemotherapeutic development.
Combination chemotherapy
In 1965, a major break-through in cancer therapy occurred. James Holland, Emil Freireich, and Emil FreiEmil Frei
Emil Frei is the former physician-in-chief of the Dana-Farber Cancer Institute. He advocates the controversial Cure Cancer movement that was born out of scientific dissent and that claims to be able to develop a cure for cancer that has no significant adverse effects.- Websites :* *...
hypothesized that cancer chemotherapy should follow the strategy of antibiotic therapy for tuberculosis with combinations of drugs, each with a different mechanism of action. Cancer cells could conceivably mutate to become resistant to a single agent, but by using different drugs concurrently it would be more difficult for the tumor to develop resistance to the combination. Holland, Freireich, and Frei simultaneously administered methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
(an antifolate), vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
(a Vinca alkaloid), 6-mercaptopurine
Mercaptopurine
Mercaptopurine is an immunosuppressive drug.It is a thiopurine.-Uses:...
(6-MP) and prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
— together referred to as the POMP regimen — and induced long-term remissions in children with acute lymphoblastic leukaemia (ALL). With incremental refinements of original regimens, using randomized clinical studies by St. Jude Children's Research Hospital
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital, founded in 1962, is a leading pediatric treatment and research facility focused on children's catastrophic diseases. It is located in Memphis, Tennessee. It is a nonprofit medical corporation chartered as a 501 tax-exempt organization under IRS regulations.In...
, the Medical Research Council
Medical Research Council (UK)
The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills...
in the UK (UKALL protocols) and German Berlin
Berlin
Berlin is the capital city of Germany and is one of the 16 states of Germany. With a population of 3.45 million people, Berlin is Germany's largest city. It is the second most populous city proper and the seventh most populous urban area in the European Union...
-Frankfurt
Frankfurt
Frankfurt am Main , commonly known simply as Frankfurt, is the largest city in the German state of Hesse and the fifth-largest city in Germany, with a 2010 population of 688,249. The urban area had an estimated population of 2,300,000 in 2010...
-Münster
Münster
Münster is an independent city in North Rhine-Westphalia, Germany. It is located in the northern part of the state and is considered to be the cultural centre of the Westphalia region. It is also capital of the local government region Münsterland...
clinical trials group (ALL-BFM protocols), ALL in children has become a largely curable disease.
This approach was extended to the lymphomas in 1963 by Vincent T. DeVita
Vincent T. DeVita
Vincent T. DeVita, Jr., MD is an internationally recognized pioneer physician in the field of oncology.DeVita earned his Bachelor of Science degree from the College of William and Mary in 1957. He was awarded his MD degree with distinction from the George Washington University School of Medicine in...
and George Canellos
George Canellos
George P. Canellos is a renowned American oncologist and cancer researcher. His research career spans many decades as well as several areas of therapeutic agents for the treatment of malignant diseases. He is perhaps most known for his work with Vincent T. DeVita in which he developed the...
at the NCI, who ultimately proved in the late 1960s that nitrogen mustard, vincristine, procarbazine and prednisone — known as the MOPP regimen — could cure patients with Hodgkin's and non-Hodgkin's lymphoma. Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously.
AdjuvantAdjuvantAn adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
therapy
As predicted by studies in animal models, drugs were most effective when used in patients with tumours of smaller volume. Another important strategy developed from this - if the tumour burden could be reduced first by surgery, then chemotherapy may be able to clear away any remaining malignant cells, even if it would not have been potent enough to destroy the tumor in its entirety. This approach was termed "adjuvant therapy".Emil Frei
Emil Frei
Emil Frei is the former physician-in-chief of the Dana-Farber Cancer Institute. He advocates the controversial Cure Cancer movement that was born out of scientific dissent and that claims to be able to develop a cure for cancer that has no significant adverse effects.- Websites :* *...
first demonstrated this effect - high doses of methotrexate prevented recurrence of osteosarcoma
Osteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
following surgical removal of the primary tumour. 5-fluorouracil, an inhibitor of DNA synthesis, was later shown to improve survival when used as an adjuvant to surgery in treating patients with colon cancer. Similarly, the landmark trials of Bernard Fisher
Bernard Fisher (scientist)
Bernard Fisher was Chairman of the National Surgical Adjuvant Breast Project at the University of Pittsburgh School of Medicine.-Notes:This article uses public domain text from the National Cancer Institute.-Sources:...
, chair of the National Surgical Adjuvant Breast and Bowel Project, and of Gianni Bonadonna, working in the Istituto Nazionale Tumori di Milano, Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
, proved that adjuvant chemotherapy
Adjuvant chemotherapy
Adjuvant therapy, also called adjuvant care, is treatment that is given in addition to the primary, main or initial treatment. The surgeries and complex treatment regimens used in cancer therapy have led the term to be used mainly to describe adjuvant cancer treatments...
after complete surgical resection of breast tumours significantly extended survival — particularly in more advanced cancer.
Zubrod's initiatives
In 1956, C. Gordon Zubrod, who had formerly led the development of antimalarial agents for the United States Army, took over the Division of Cancer Treatment of the NCI and guided development of new drugs. In the two decades that followed the establishment of the NCCSC, a large network of cooperative clinical trial groups evolved under the auspices of the NCI to test anticancer agents. Zubrod had a particular interest in natural products, and established a broad programme for collecting and testing plant and marine sources, a controversial programme that led to the discovery of taxanes (in 1964) and camptothecins (in 1966). Both classes of drug were isolated and characterized by the laboratory of Monroe Wall at the Research Triangle Institute.The taxanes
PaclitaxelPaclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
(Taxol) was a novel antimitotic agent that promoted microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
assembly. This agent proved difficult to synthesize and could only be obtained from the bark of the Pacific Yew tree
Taxus brevifolia
Taxus brevifolia is a conifer native to the Pacific Northwest of North America. It ranges from southernmost Alaska south to central California, mostly in the Pacific Coast Ranges, but with an isolated disjunct population in southeast British Columbia, most notably occurring on Zuckerberg Island...
, which forced the NCI into the costly business of harvesting substantial quantities of yew trees from public lands. After 4 years of clinical testing in solid tumours, it was found in 1987 (23 years after its initial discovery) to be effective in ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
therapy. Notably, this agent, although developed by the NCI in partnership with Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
, was exclusively marketed by BMS (who had utilized the synthetic methodology developed by Robert Holton at Florida State University) who went on to make over a billion dollars profit from Taxol.
The camptothecins
Another drug class originating from the NCI was the camptothecins. CamptothecinCamptothecin
Camptothecin is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I . It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata , a tree native to...
, derived from a Chinese ornamental tree, inhibits topoisomerase
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...
I, an enzyme that allows DNA unwinding. Despite showing promise in preclinical studies, the agent had little antitumour activity in early clinical trials, and dosing was limited by kidney toxicity
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
: its lactone ring is unstable at neutral pH, so while in the acidic environment of the kidneys it becomes active, damaging the renal tubules. In 1996 a more stable analogue, irinotecan
Irinotecan
Irinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
, won Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approval for the treatment of colon cancer. Later, this agent would also be used to treat lung and ovarian cancers.
Platinum-based agents
CisplatinCisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
, a platinum
Platinum
Platinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...
-based compound, was discovered by a Michigan State University
Michigan State University
Michigan State University is a public research university in East Lansing, Michigan, USA. Founded in 1855, it was the pioneer land-grant institution and served as a model for future land-grant colleges in the United States under the 1862 Morrill Act.MSU pioneered the studies of packaging,...
researcher, Barnett Rosenberg
Barnett Rosenberg
Barnett Rosenberg was an American chemist best known for the discovery of the anti-cancer drug cisplatin.Rosenberg graduated from Brooklyn College in 1948 and obtained his PhD in Physics at New York University in 1956...
, working under an NCI contract. This was yet another serendipitous
Serendipity
Serendipity means a "happy accident" or "pleasant surprise"; specifically, the accident of finding something good or useful without looking for it. The word has been voted as one of the ten English words hardest to translate in June 2004 by a British translation company. However, due to its...
discovery: Rosenberg had initially wanted to explore the possible effects of an electric field on the growth of bacteria. He observed that the bacteria unexpectedly ceased to divide when placed in an electric field. Excited, he spent months of testing to try to explain this phenomenon. He was disappointed to find that the cause was an experimental artifact
Artifact (error)
In natural science and signal processing, an artifact is any error in the perception or representation of any visual or aural information introduced by the involved equipment or technique....
– the inhibition of bacterial division was pinpointed to an electrolysis
Electrolysis
In chemistry and manufacturing, electrolysis is a method of using a direct electric current to drive an otherwise non-spontaneous chemical reaction...
product of the platinum electrode
Electrode
An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit...
rather than the electrical field. This accidental discovery, however, soon initiated a series of investigations and studies into the effects of platinum compounds on cell division, culminating in the synthesis of cisplatin. This drug was pivotal in the cure of testicular cancer
Testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...
. Subsequently, Eve Wiltshaw and others at the Institute of Cancer Research
Institute of Cancer Research
The Institute of Cancer Research is a cancer research institute located in London, United Kingdom and a constituent college of the federal University of London. The ICR was founded in 1909 as a research department of the Royal Marsden Hospital and joined the University of London in 2003...
in the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
extended the clinical usefulness of the platinum compounds with their development of carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
, a cisplatin derivative with broad antitumour activity and comparatively less nephrotoxicity.
Nitrosoureas
A second group with an NCI contract, led by John MontgomeryJohn Montgomery
John Montgomery or Jack Montgomery may refer to:*John Montgomery , U.S. pioneer in Tennessee*John Montgomery , U.S. merchant, Continental Congressman for Pennsylvania...
at the Southern Research Institute
Southern Research Institute
Southern Research Institute is a not-for-profit institute that conducts basic and applied research sponsored by both commercial and non-commercial organizations in areas such as Drug Discovery, Drug Development and Engineering and Environmental Sciences....
, synthesized nitrosoureas, an alkylating agent which cross-links DNA. Fludarabine
Fludarabine
Fludarabine or fludarabine phosphate is a chemotherapy drug used in the treatment of hematological malignancies. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.-Indications:Fludarabine is...
phosphate, a purine analogue which has become a mainstay in treatment of patients with chronic lymphocytic leukaemia, was another similar development by Montgomery.
Anthracyclines and epipodophyllotoxins
Other effective molecules also came from industry during the period of 1970 to 1990, including anthracyclineAnthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var...
s and epipodophyllotoxin
Epipodophyllotoxin
Epipodophyllotoxins are alkaloids naturally occurring in the root of American Mayapple plant .Some epipodophyllotoxin derivatives are currently used in the treatment of cancer. These include etoposide and teniposide. They act as anti-cancer drugs by inhibiting topoisomerase II....
s — both of which inhibited the action of topoisomerase II, an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
crucial for DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
synthesis.
Supportive care during chemotherapy
As is obvious from their origins, the above cancer chemotherapies are essentially poisonPoison
In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....
s. Patients receiving these agents experienced severe side-effects that limited the doses which could be administered, and hence limited the beneficial effects. Clinical investigators realized that the ability to manage these toxicities was crucial to the success of cancer chemotherapy.
Several examples are noteworthy. Many chemotherapeutic agents cause profound suppression of the bone marrow. This is reversible, but takes time to recover. Support with platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
and red-cell transfusions as well as broad-spectrum antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s in case of infection during this period is crucial to allow the patient to recover.
Several practical factors are also worth mentioning. Most of these agents caused very severe nausea (termed chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea...
(CINV) in the literature) which, while not directly causing patient deaths, was unbearable at higher doses. The development of new drugs to prevent nausea (the prototype of which was ondansetron
Ondansetron
Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
) was of great practical use, as was the design of indwelling intravenous catheters (e.g. Hickman line
Hickman line
A Hickman line is an intravenous catheter most often used for the administration of chemotherapy or other medications, as well as for the withdrawal of blood for analysis. Some types of Hickman lines are used mainly for the purpose of apheresis or dialysis...
s and PICC lines
Peripherally inserted central catheter
A peripherally inserted central catheter is a form of intravenous access that can be used for a prolonged period of time...
) which allowed safe administration of chemotherapy as well as supportive therapy.
A period of quiet
With the successes of combination chemotherapy and the discovery of many new agents, there was a feeling at this time that all cancers could be treated, if only one could administer the correct combination of drugs, at the correct doses and at the correct intervals. A search continued, with the pharmaceutical industry screening for new compounds and clinical scientists performing elaborate clinical trials with ever more complex combinations and higher doses.One important contribution during this period was the discovery of a means that allowed the administration of previously lethal doses of chemotherapy. The patient's bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
was first harvested, the chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
administered, and the harvested marrow then returned to patient a few days later. This approach, termed autologous bone marrow transplantation, was initially thought to be of benefit to a wide group of patients, including those with advanced breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. However, rigorous studies have failed to confirm this benefit, and autologous transplantation is no longer widely used for solid tumors. The proven curative benefits of high doses of chemotherapy afforded by autologous bone marrow rescue are limited to both Hodgkin's and selected non-Hodgkin's lymphoma patients who have failed therapy with conventional combination chemotherapy. Autologous transplantation continues to be used as a component of therapy for a number of other hematologic malignancies
Hematological malignancy
Hematological malignancies are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is technically a disease of the lymph...
.
The hormonal contribution to several categories of breast cancer subtypes was recognized during this time, leading to the development of pharmacological modulators (e.g. of oestrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
) such as tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
.
Although clinical oncologists appeared to have hit a wall at this point in terms of results, under the surface something extraordinary was happening: namely, elucidation of the mechanisms underlying cancer. Understanding of the machinery of the cell and advances in techniques to probe perturbations in its function allowed researchers to understand the genetic nature of cancer. It is important to realize that prior to this point, chemotherapeutic agents had been discovered essentially by chance, or by inhibiting the metabolic pathways crucial to cell division, but none were particularly specific to the cancer cell.
Targeted therapyTargeted therapyTargeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...
Tyrosine kinase inhibitors
The classic example of targeted development is imatinib mesylate (Gleevec), a small molecule which inhibits a signaling molecule kinaseKinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
. The genetic abnormality causing chronic myelogenous leukemia
Chronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
(CML) has been known for a long time to be a chromosomal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
creating an abnormal fusion protein, kinase BCR-ABL, which signals aberrantly, leading to uncontrolled proliferation of the leukemia cells. Imatinib precisely inhibits this kinase. Unlike so many other anti-cancer agents, this pharmaceutical was no accident. Brian Druker
Brian Druker
Brian J. Druker is a physician-scientist at the Oregon Health & Science University. He is the director of OHSU Knight Cancer Institute, JELD-WEN Chair of Leukemia Research, and professor of medicine...
, working in Oregon Health Science University, had extensively researched the abnormal enzyme kinase in CML. He reasoned that precisely inhibiting this kinase with a drug would control the disease and have little effect on normal cells. Druker collaborated with Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
chemist Nick Lydon, who developed several candidate inhibitors. From these, imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
was found to have the most promise in laboratory experiments. First Druker and then other groups worldwide demonstrated that when this small molecule is used to treat patients with chronic-phase CML, 90% achieve complete haematological remission. It is hoped that molecular targeting of similar defects in other cancers will have the same effect.
Monoclonal antibodies
Another branch in targeted therapyTargeted therapy
Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...
is the increasing use of monoclonal antibodies in cancer therapy. Although monoclonal antibodies (immune proteins which can be selected to precisely bind to almost any target) have been around for decades, they were derived from mice and did not function particularly well when administered to humans, causing allergic reactions and being rapidly removed from circulation. "Humanization" of these antibodies (genetically transforming them to be as similar to a human antibody as possible) has allowed the creation of a new family of highly effective humanized monoclonal antibodies. Trastuzumab
Trastuzumab
Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
, a drug used to treat breast cancer, is a prime example.
Effectiveness
The discovery that certain toxic chemicals administered in combination can cure certain cancers ranks as one of the greatest in modern medicine. Childhood ALLAcute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
, testicular cancer
Testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...
, and Hodgkins disease, previously universally fatal, are now generally curable diseases. Conventional cytotoxic chemotherapy has shown the ability to cure some cancers, including testicular cancer
Testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...
, Hodgkin disease, non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
, and some leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s. It has also proved effective in the adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
setting, in reducing the risk of recurrence after surgery for high-risk breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, colon cancer, and lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, among others.
The overall impact of chemotherapy on cancer survival can be difficult to estimate, since improved cancer screening, prevention (e.g. anti-smoking campaigns), and detection all influence statistics on cancer incidence and mortality. In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, overall cancer incidence rates were stable from 1995 through 1999, while cancer death rates decreased steadily from 1993 through 1999. Again, this likely reflects the combined impact of improved screening, prevention, and treatment. Nonetheless, cancer remains a major cause of illness and death, and conventional cytotoxic chemotherapy has proved unable to cure most cancers after they have metastasized
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
.
External links
- Cancer chemotherapy history
- Time line for cancer chemotherapy A time line of milestones in cancer chemotherapy from the National Cancer Institute that includes recollections of people involved with the NCI effort. This was put together on the occasion of the 50th anniversary of the Cancer Chemotherapy National Service Center (CCNSC).