History of cancer chemotherapy

Source: Wikipedia, the free encyclopedia.

antitumor antibiotic; vincristine, a spindle poison; dacarbazine, an alkylating agent; cyclophosphamide, a nitrogen mustard; doxorubicin, an anthracycline; and etoposide, a topoisomerase inhibitor
.

The era of cancer

folic acid antagonist drugs. The targeted therapy
revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.

Beginnings

The beginnings of the modern era of cancer chemotherapy can be traced directly to the German introduction of chemical warfare during World War I. Among the chemical agents used,

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 was to divide fast, it could also potentially be put to use in helping to suppress the division of certain types of cancerous cells.[2]

Using that information, Goodman and Gilman reasoned that this agent could be used to treat

tumor masses.[5][6] Although the effect lasted only a few weeks, and the patient had to return for another set of treatment, that was the first step to the realization that cancer could be treated by pharmacological agents.[3] The patient ultimately died of cancer on December 1, 1942, 96 days after his first dose.[4] Publication of the first clinical trials was reported in 1946 in The New York Times.[7]

Antifolates

Sidney Farber's work was instrumental in showing that effective pharmacological treatment of cancer was possible
Jane C. Wright pioneered the use of the drug methotrexate to treat breast cancer and skin cancer

Shortly after World War II, a second approach to drug therapy of cancer began.

New England Journal of Medicine was met with incredulity and ridicule.[8]

In 1947,

nasopharyngeal cancer, became one of the first human subjects of pteroyl triglutamate (also known by its brand name Teropterin, and similar to aminopterin) treatment. Dr. Richard Lewisohn of Mount Sinai Hospital in New York administered the drug, and over the course of several months, Ruth's condition began to improve. However, Ruth died the following year.[9]

In 1951,

chorioadenoma in 1956,[11] discovering that methotrexate alone could cure choriocarcinoma (1958), a germ-cell malignancy that originates in trophoblastic cells of the placenta. In 1960 Wright et al. produced remissions in mycosis fungoides.[12][13]

6-MP

6-mercaptopurine
(6-MP), which was subsequently shown to be a highly active antileukemic drug.

Vinca Alkaloids

The

anti-diabetic drugs, 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 alkaloys, and therefore cell division.

Cancer Chemotherapy National Service Center

The NCI, headed by Dr.

animal models
) for chemotherapeutic development.

Combination chemotherapy

In 1965, a major breakthrough in cancer therapy occurred.

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

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, called combination chemotherapy or polychemotherapy.

Adjuvant 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".

adjuvant chemotherapy
after complete surgical resection of breast tumours significantly extended survival — particularly in more advanced cancer.

Drug discovery at the NCI and elsewhere

Zubrod's initiatives

In 1956,

Research Triangle Institute
.

Taxanes

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.[citation needed
]

Camptothecins

Another drug class originating from the NCI was the camptothecins. Camptothecin, 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.

Platinum-based agents

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.

Nitrosoureas

A second group with an NCI contract, led by John Montgomery 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.

Anthracyclines and epipodophyllotoxins

Other effective molecules also came from industry during the period of 1970 to 1990, including

topoisomerase II, an enzyme crucial for DNA
synthesis.

Supportive care during chemotherapy

As is obvious from their origins, the above cancer chemotherapies are essentially poisons. 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 antibiotics 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 lines and PICC lines) which allowed safe administration of chemotherapy as well as supportive therapy.

Bone marrow transplantation

One important contribution during this period[

hematologic malignancies
.

Antihormone therapy

The hormonal contribution to several categories of breast cancer subtypes was recognized during this time[when?], leading to the development of pharmacological modulators (e.g. of oestrogen) such as tamoxifen.

Targeted therapy

bcr-abl kinase, which causes CML, inhibited by imatinib (small molecule).

Molecular genetics has uncovered signalling networks that regulate cellular activities such as proliferation and survival. In a particular cancer, such a network may be radically altered, due to a chance somatic mutation. Targeted therapy inhibits the metabolic pathway that underlies that type of cancer's cell division.

Tyrosine kinase inhibitors

Further information:
Bcr-Abl tyrosine kinase inhibitors

The classic example of

imatinib mesylate (Gleevec), a small molecule which inhibits a signaling molecule kinase. 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 Nicholas 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.

Monoclonal antibodies

Another branch in targeted therapy 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.

Effectiveness

The discovery that certain toxic chemicals administered in combination can cure certain cancers ranks as one of the greatest in modern medicine. Childhood ALL (

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.[16] 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.

See also

References

  1. ISBN 978-0-8135-1616-5
    .
  2. ISBN 978-0-19-530099-4
    .
  3. ^
    PMID 21247779
    .
  4. ^
    PMID 21698052
    .
  5. PMID 13947966
    .
  6. PMID 20997191
    .
  7. ^ "WAR GASES TRIED IN CANCER THERAPY: Army Branch Joins Research Groups in Study of Using Nitrogen Blister Chemicals". The New York Times. 6 Oct 1946. Retrieved 4 February 2016.
  8. PMID 18860765
    . Retrieved 2021-09-14.
  9. ^ Howard Markel (2014-08-15). "Home run king Babe Ruth helped pioneer modern cancer treatment". PBS. Retrieved 2018-06-20.
  10. PMID 14850976
    .
  11. S2CID 22939197
    .
  12. PMID 13786791
    .
  13. PMID 14202592
    .
  14. ^ "Milestone (1955): Creation of CCNSC". dtp.cancer.gov. Retrieved 2023-08-17.
  15. PMID 1462166
    .
  16. ^ Abeloff (2004). Clinical Oncology (3rd ed.). Churchill Livingston. pp. 408–413.

Further reading

External links

  • 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).
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