Alkylating antineoplastic agent
Encyclopedia
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to DNA
.
The alkyl group is attached to the guanine
base of DNA, at the number 7 nitrogen atom of the purine
ring.
Since cancer
cells, in general, proliferate faster and with less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage — such as being alkylated. Alkylating agents are used to treat several cancers. However, they are also toxic to normal cells (cytotoxic), leading to damage, in particular in cells that divide frequently
, as those in the gastrointestinal tract, bone marrow, testicles and ovaries, which can cause loss of fertility. Alkylating agents are also carcinogenic. Hyperthermia is especially effective at enhancing the effects of alkylating agents.
, ("mustard gas") and related chemical weapons in World War I
. The nitrogen mustards were the first alkylating agents used medically, as well as the first modern cancer chemotherapies. Goodman, Gilman, and others at Yale began studying nitrogen mustards at Yale in 1942, and, following the sometimes dramatic but highly variable responses of experimental tumors in mice to treatment, these agents were first tested in humans late that year. Use of methyl bis (B-chloroethyl)emine hydrochloride (mechlorethamine, mustine) and tris (B-chloroethy) amine hydrochloride for Hodgkin's disease lymphosarcoma, leukemia, and other malignancies resulted in striking but temporary dissolution of tumor masses. Because of secrecy surrounding the war gas program, these results were not published until 1946. These publications spurred rapid advancement in the previously non-existent field of cancer chemotherapy, and a wealth of new alkylating agents with therapeutic effect were discovered over the following two decades.
A common myth holds that Goodman and Gilman were prompted to study nitrogen mustards as a potential treatment for cancer following a 1943 incident in Bari, Italy, where survivors exposed to mustard gas became leukopenic
. In fact, animal and human trials had begun the previous year, Gilman makes no mention of such an episode in his recounting of the early trials of nitrogen mustards , and the marrow suppressing effects of mustard gas had been known since the close of World War I.
nucleobase
s in DNA
double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically.
).
Cyclophosphamide
is one of the most potent immunosuppressive substances. In small dosages, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, Wegener's granulomatosis
, and other autoimmune disease
s. High dosages cause pancytopenia
and hemorrhagic cystitis
.
of the DNA strands, which prevents uncoiling of the DNA double helix. If the two guanine residues are in the same strand, the result is called limpet attachment of the drug molecule to the DNA. Busulfan
is an example of a dialkylating agent: it is the methanesulfonate diester of 1,4-butanediol
. Methanesulfonate can be eliminated as a leaving group
. Both ends of the molecule can be attacked by DNA bases, producing a butylene crosslink between two different bases.
Monoalkylating agents can react only with one 7-N of guanine.
Limpet attachment and monoalkylation do not prevent the separation of the two DNA strands of the double helix but do prevent vital DNA-processing enzyme
s from accessing the DNA. The final result is inhibition of cell growth or stimulation of apoptosis
, cell suicide.
, alkylating agents are classified under L01A.
and chlorambucil
.
The following three groups are almost always considered "classical".
Thiotepa
and its analogues are usually considered classical, but can be considered nonclassical.
These agents also bind at N7 of guanine.
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...
.
The alkyl group is attached to the guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
base of DNA, at the number 7 nitrogen atom of the 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....
ring.
Since 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...
cells, in general, proliferate faster and with less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage — such as being alkylated. Alkylating agents are used to treat several cancers. However, they are also toxic to normal cells (cytotoxic), leading to damage, in particular in cells that divide frequently
Labile cell
In cellular biology, labile cells are cells that multiply constantly throughout life. They spend little or no time in the quiescent G0 phase of the cell cycle, but regularly perform cell division.This is the case for only a minority of cells in the body...
, as those in the gastrointestinal tract, bone marrow, testicles and ovaries, which can cause loss of fertility. Alkylating agents are also carcinogenic. Hyperthermia is especially effective at enhancing the effects of alkylating agents.
History
Before their use in chemotherapy, alkylating agents were better known for their use as sulfur mustardSulfur mustard
The sulfur mustards, or sulphur mustards, commonly known as mustard gas, are a class of related cytotoxic, vesicant chemical warfare agents with the ability to form large blisters on exposed skin. Pure sulfur mustards are colorless, viscous liquids at room temperature...
, ("mustard gas") and related chemical weapons in World War I
World War I
World War I , which was predominantly called the World War or the Great War from its occurrence until 1939, and the First World War or World War I thereafter, was a major war centred in Europe that began on 28 July 1914 and lasted until 11 November 1918...
. The nitrogen mustards were the first alkylating agents used medically, as well as the first modern cancer chemotherapies. Goodman, Gilman, and others at Yale began studying nitrogen mustards at Yale in 1942, and, following the sometimes dramatic but highly variable responses of experimental tumors in mice to treatment, these agents were first tested in humans late that year. Use of methyl bis (B-chloroethyl)emine hydrochloride (mechlorethamine, mustine) and tris (B-chloroethy) amine hydrochloride for Hodgkin's disease lymphosarcoma, leukemia, and other malignancies resulted in striking but temporary dissolution of tumor masses. Because of secrecy surrounding the war gas program, these results were not published until 1946. These publications spurred rapid advancement in the previously non-existent field of cancer chemotherapy, and a wealth of new alkylating agents with therapeutic effect were discovered over the following two decades.
A common myth holds that Goodman and Gilman were prompted to study nitrogen mustards as a potential treatment for cancer following a 1943 incident in Bari, Italy, where survivors exposed to mustard gas became leukopenic
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
. In fact, animal and human trials had begun the previous year, Gilman makes no mention of such an episode in his recounting of the early trials of nitrogen mustards , and the marrow suppressing effects of mustard gas had been known since the close of World War I.
Agents acting nonspecifically
Some alkylating agents are active under conditions present in cells; and the same mechanism that makes them toxic allows them to be used as anti-cancer drugs. They stop tumor growth by crosslinking guanineGuanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
s in 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...
double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically.
Agents requiring activation
Some of the substances require conversion into active substances in vivo (e.g., cyclophosphamideCyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
).
Cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
is one of the most potent immunosuppressive substances. In small dosages, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, Wegener's granulomatosis
Wegener's granulomatosis
Wegener's granulomatosis , more recently granulomatosis with polyangiitis , is an incurable form of vasculitis that affects the nose, lungs, kidneys and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression...
, and other autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s. High dosages cause pancytopenia
Pancytopenia
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
and hemorrhagic cystitis
Cystitis
Cystitis is a term that refers to urinary bladder inflammation that results from any one of a number of distinct syndromes. It is most commonly caused by a bacterial infection in which case it is referred to as a urinary tract infection.-Signs and symptoms:...
.
Dialkylating agents, limpet attachment, and monoalkylating agents
Dialkylating agents can react with two different 7-N-guanine residues, and, if these are in different strands of DNA, the result is cross-linkageCross-link
Cross-links are bonds that link one polymer chain to another. They can be covalent bonds or ionic bonds. "Polymer chains" can refer to synthetic polymers or natural polymers . When the term "cross-linking" is used in the synthetic polymer science field, it usually refers to the use of...
of the DNA strands, which prevents uncoiling of the DNA double helix. If the two guanine residues are in the same strand, the result is called limpet attachment of the drug molecule to the DNA. Busulfan
Busulfan
Busulfan is a cancer drug, in use since 1959.Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates...
is an example of a dialkylating agent: it is the methanesulfonate diester of 1,4-butanediol
1,4-Butanediol
1,4-Butanediol is the organic compound with the formula HOCH2CH2CH2CH2OH. This colorless viscous liquid is derived from butane by placement of alcohol groups at each end of the chain. It is one of four stable isomers of butanediol.-Synthesis:...
. Methanesulfonate can be eliminated as a leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
. Both ends of the molecule can be attacked by DNA bases, producing a butylene crosslink between two different bases.
Monoalkylating agents can react only with one 7-N of guanine.
Limpet attachment and monoalkylation do not prevent the separation of the two DNA strands of the double helix but do prevent vital DNA-processing 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...
s from accessing the DNA. The final result is inhibition of cell growth or stimulation of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, cell suicide.
Examples
In the Anatomical Therapeutic Chemical Classification SystemAnatomical Therapeutic Chemical Classification System
The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. It is controlled by the WHO Collaborating Centre for Drug Statistics Methodology , and was first published in 1976....
, alkylating agents are classified under L01A.
Classical alkylating agents
Many of the agents are known as "Classical alkylating agents". These include true alkyl groups, and have been known for a longer time than some of the other alkylating agents. Examples include melphalanMelphalan
Melphalan hydrochloride is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.An alkylating agent adds an alkyl group to DNA...
and chlorambucil
Chlorambucil
Chlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia...
.
The following three groups are almost always considered "classical".
- Nitrogen mustardNitrogen mustardThe 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- CyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
- Mechlorethamine or mustine (HN2) (trade name Mustardgen)
- Uramustine or uracil mustard
- MelphalanMelphalanMelphalan hydrochloride is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.An alkylating agent adds an alkyl group to DNA...
- ChlorambucilChlorambucilChlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia...
- IfosfamideIfosfamideIfosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
- Cyclophosphamide
- Nitrosoureas
- CarmustineCarmustineCarmustine or BCNU is a mustard gas-related β-chloro-nitrosourea compound used as an alkylating agent in chemotherapy...
- LomustineLomustineLomustine is an alkylating nitrosourea compound used in chemotherapy. It is in the same family as streptozotocin. This is a highly lipid soluble drug, and thus crosses the blood brain barrier. This property makes it ideal for treating brain tumors, and is its primary use...
- Streptozocin
- Carmustine
- Alkyl sulfonates
- BusulfanBusulfanBusulfan is a cancer drug, in use since 1959.Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates...
- Busulfan
Thiotepa
ThioTEPA
N,N'N'-triethylenethiophosphoramide is an alkylating agent used to treat cancer.ThioTEPA is an organophosphorus compound with the formula SP3. It is an analogue of N,N',N- triethylenephosphoramide . This molecule features tetrahedral phosphorus and is structurally akin to phosphate...
and its analogues are usually considered classical, but can be considered nonclassical.
Alkylating-like
Platinum-based chemotherapeutic drugs (termed platinum analogues) act in a similar manner. These agents do not have an alkyl group, but nevertheless damage DNA. They permanently coordinate to DNA to interfere with DNA repair, so they are sometimes described as "alkylating-like".- Platinum
- CisplatinCisplatinCisplatin, 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...
- CarboplatinCarboplatinCarboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
- NedaplatinNedaplatinNedaplatin is a platinum compound which is used for cancer chemotherapy. It produces less nausea, vomiting and nephrotoxicity than other platinum-containing drugs.-References: Shionogi & Co. March 2007....
- OxaliplatinOxaliplatinOxaliplatin is a coordination complex that is used in cancer chemotherapy. These platinum-based drugs are usually classified as alkylating agents, although they are not actually alkylating groups ....
- SatraplatinSatraplatinSatraplatin is a platinum compound that is currently under investigation as one treatment of patients with advanced prostate cancer who have failed previous chemotherapy. It has not yet received approval from the U.S. Food and Drug Administration...
- Triplatin tetranitrate
- Cisplatin
These agents also bind at N7 of guanine.
Nonclassical
Certain alkylating agents are sometimes described as "nonclassical". There is not a perfect consensus on which items are included in this category, but, in general, they include:- procarbazineProcarbazineProcarbazine Procarbazine Procarbazine (Matulane (US), Natulan (Canada), Indicarb (India) is an antineoplastic chemotherapy drug for the treatment of Hodgkin's lymphoma and certain brain cancers (such as Glioblastoma multiforme). It is a member of a group of medicines called alkylating agents. It...
- altretamineAltretamineAltretamine is an antineoplastic agent. It was approved by the FDA in 1990.-Uses:It is used to treat refractory ovarian cancer.It is not considered a first-line treatment, but it can be useful as salvage therapy...
- Some sources explicitly exclude the tetrazineTetrazineTetrazine is an unstable compound that consists of a six-membered aromatic ring containing four nitrogen atoms with the molecular formula C2H2N4. The name tetrazine is used in the nomenclature of derivatives of this compound...
s (dacarbazineDacarbazineDacarbazine is an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas.Dacarbazine is a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl...
, mitozolomideMitozolomideMitozolomide is an antineoplastic. It is an imidazotetrazine derivative.Development of mitozolomide was discontinued during Phase II clinical trials after it was found to cause severe and unpredictable bone marrow suppression. Temozolomide, which has been in clinical use since 1999, is a less...
, temozolomideTemozolomideTemozolomide Temozolomide Temozolomide (brand names Temodar and Temodal is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma — an aggressive brain tumor, also known as glioblastoma multiforme as well as melanoma, a form of skin cancer...
) from the nonclassical category. However, other sources list dacarbazineDacarbazineDacarbazine is an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas.Dacarbazine is a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl...
as nonclassical, and some include temozolomideTemozolomideTemozolomide Temozolomide Temozolomide (brand names Temodar and Temodal is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma — an aggressive brain tumor, also known as glioblastoma multiforme as well as melanoma, a form of skin cancer...
.
- The platinum agents are also sometimes described as nonclassical.