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Alkylating antineoplastic agent
 
 
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An alkylating antineoplastic agent is an alkylating agent that attaches an alkyl group to DNA
DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetics instructions used in the development and functioning of all known living organisms and some viruses....
.

Since cancer
Cancer

Cancer is a class of diseases in which a group of cell display uncontrolled growth , invasion , and sometimes metastasis . These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize....
 cells generally proliferate unrestrictively more than healthy cells do, cancer cells are more sensitive to DNA damage - such as being alkylated. Alkylating agents are used clinically to treat a variety of tumours. However, they are also inherently cytotoxic, leading to side effects particularly in healthy tissues where cell division is frequent, as in gastrointestinal tract or bone marrow, causing iatrogenic illness.






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An alkylating antineoplastic agent is an alkylating agent that attaches an alkyl group to DNA
DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetics instructions used in the development and functioning of all known living organisms and some viruses....
.

Since cancer
Cancer

Cancer is a class of diseases in which a group of cell display uncontrolled growth , invasion , and sometimes metastasis . These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize....
 cells generally proliferate unrestrictively more than healthy cells do, cancer cells are more sensitive to DNA damage - such as being alkylated. Alkylating agents are used clinically to treat a variety of tumours. However, they are also inherently cytotoxic, leading to side effects particularly in healthy tissues where cell division is frequent, as in gastrointestinal tract or bone marrow, causing iatrogenic illness. Alkylating agents are also carcinogenic in their own right.

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 tumour growth by cross-linking guanine
Guanine

Guanine is one of the five main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, thymine, and uracil. In DNA, guanine is paired with cytosine....
 nucleobase
Nucleobase

Nucleobases are the parts of DNA and RNA that may be involved in pairing . The main ones are cytosine, guanine, adenine , thymine and uracil , abbreviated as C, G, A, T, and U, respectively....
s in DNA
DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetics instructions used in the development and functioning of all known living organisms and some viruses....
 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 require activation

Some of them require conversion into active substances in vivo (e.g. cyclophosphamide
Cyclophosphamide

Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating antineoplastic agent, from the oxazophorines group. It is used to treat various types of cancer and some autoimmune disorders....
).

Cyclophosphamide
Cyclophosphamide

Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating antineoplastic agent, from the oxazophorines group. It is used to treat various types of cancer and some autoimmune disorders....
 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
Hemolysis

Hemolysis ?from the Greek Hemo-, Greek language meaning blood, -lysis, meaning to break open?is the breaking open of red blood cells and the release of hemoglobin into the surrounding fluid ....
, Wegener's granulomatosis
Wegener's granulomatosis

Wegener's granulomatosis is a form of vasculitis that affects the lungs, kidneys and other organs. Due to its end-organ damage, it can be a serious disease that requires long-term immune suppression....
 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 attacks its own cells....
s. High dosages cause pancytopenia
Pancytopenia

Pancytopenia is a medicine condition in which there is a reduction in the number of red blood cell and white blood cells, as well as platelets....
 and hemorrhagic cystitis
Cystitis

Cystitis is inflammation of the urinary bladder. The condition more often affects women, but can affect either sex and all age groups....
.

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-linkage
Cross-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 ....
 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.

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 biomolecules that catalysis chemical reactions. Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called Substrate , and the enzyme converts them into different molecules, the products....
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. Programmed Cell death involves a series of biochemical events leading to a characteristic cell Morphology and death, in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including Bleb , changes...
, cell suicide.

Examples

In the Anatomical Therapeutic Chemical Classification System
Anatomical Therapeutic Chemical Classification System

The Anatomical Therapeutic Chemical Classification System is used for the taxonomic classification of Medications. It is controlled by the World Health Organization Collaborating Centre for Drug Statistics Methodology, and was first published in 1976....
, alkylating agents are classified under L01A
ATC code L01

L01 Antineoplastic agents is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System.It is part of the anatomical group ATC code L....
.

Classical alkylating agents

Many of the agents are known as "Classical alkylating agents". These include true alkyl
Alkyl

An alkyl is a univalent Radical consisting of carbon and hydrogen atoms, arranged in a chain. The Alkyls form homologous series with the general formula CnH2n+1....
 groups, and have been known for a longer time than some of the other alkylating agents. Examples include melphalan
Melphalan

Melphalan hydrochloride is a chemotherapy medication belonging to the class of nitrogen mustard alkylating antineoplastic agents.Otherwise known as L-Phenylalanine Mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine....
 and chlorambucil
Chlorambucil

Chlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia. It is a nitrogen mustard alkylating antineoplastic agent and can be given orally....
.

The following three groups are almost always considered "classical".

  • 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 may also be used for chemical warfare purposes....
    s
    • Cyclophosphamide
      Cyclophosphamide

      Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating antineoplastic agent, from the oxazophorines group. It is used to treat various types of cancer and some autoimmune disorders....
    • Mechlorethamine
      Mechlorethamine

      Mechlorethamine also known as chlormethine, mustine, nitrogen mustard and HN2 and sold under the brand name Mustargen, is the prototype cancer chemotherapeutic drug....
       or mustine
    • Uramustine or uracil mustard
    • Melphalan
      Melphalan

      Melphalan hydrochloride is a chemotherapy medication belonging to the class of nitrogen mustard alkylating antineoplastic agents.Otherwise known as L-Phenylalanine Mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine....
    • Chlorambucil
      Chlorambucil

      Chlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia. It is a nitrogen mustard alkylating antineoplastic agent and can be given orally....
    • Ifosfamide
      Ifosfamide

      Ifosfamide is a nitrogen mustard alkylating antineoplastic agent used in the treatment of cancer.It is sometimes abbreviated "IFO"....


  • Nitrosoureas
    • Carmustine
      Carmustine

      Carmustine or BCNU is a Nitrogen mustard-related a-chloro-Nitrosourea compounds used as an alkylating antineoplastic agent in chemotherapy....
    • Streptozocin


  • Alkyl sulfonates
    • Busulfan
      Busulfan

      Busulfan is a chemotherapy drug that is a cell cycle non-specific alkylating antineoplastic agent . More specifically it belongs to a subclass of alkylating agents known as alkyl sulfonates....


Thiotepa
ThioTEPA

N,N'N'-triethylenethiophosphoramide, abbreviated "ThioTEPA," is an organophosphorus compound with the formula SP3.This cancer chemotherapeutic member of the alkylating antineoplastic agent group was characterized in 1953 and has been in use for since the 1960s....
 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 don't have an alkyl
Alkyl

An alkyl is a univalent Radical consisting of carbon and hydrogen atoms, arranged in a chain. The Alkyls form homologous series with the general formula CnH2n+1....
 group, but nevertheless damage DNA. They permanently coordinate to DNA to interfere with DNA repair, so they are sometimes described as "alkylating-like".

  • Platinum
    • Cisplatin
      Cisplatin

      Cisplatin, cisplatinum or cis-diamminedichloridoplatinum is a platinum-based chemotherapy medication used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas and germ cell tumors....
    • Carboplatin
      Carboplatin

      Carboplatin is a chemotherapy medication used against some forms of cancer . It was introduced in the late 1980s and has since gained popularity in clinical treatment due to its vastly reduced side-effects compared to its parent compound cisplatin....
    • Nedaplatin
      Nedaplatin

      Nedaplatin is a Platinum compound which produces less nausea, vomiting and nephrotoxicity....
    • Oxaliplatin
      Oxaliplatin

      Oxaliplatin is a platinum-based chemotherapy medication in the same family as cisplatin and carboplatin. It is typically administered in combination with fluorouracil and leucovorin in a combination known as FOLFOX for the treatment of colorectal cancer....
    • Satraplatin
      Satraplatin

      Satraplatin is a Platinum compound that is currently under investigation as one treatment of patients with advanced prostate cancer who have failed previous chemotherapy....
    • Triplatin tetranitrate


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 generally they include:

  • procarbazine
    Procarbazine

    Procarbazine is an antineoplastic chemotherapy drug for the treatment of Hodgkin's lymphoma and certain brain cancers . It is a member of a group of medicines called alkylating antineoplastic agent....


  • altretamine
    Altretamine

    Altretamine is an antineoplastic agent.It was approved by the FDA in 1990....


  • Some sources explicitly exclude the tetrazine
    Tetrazine

    Tetrazine is an unstable Chemical compound that consists of a six-membered aromatic ring containing four nitrogen atoms with the molecular formula Carbon2Hydrogen2Nitrogen4....
    s (dacarbazine
    Dacarbazine

    Dacarbazine 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....
    , mitozolomide
    Mitozolomide

    Mitozolomide is an antineoplastic. It is an imidazotetrazine derivative.Development of mitozolomide was discontinued during clinical trial#Phase II clinical trials after it was found to cause severe and unpredictable myelosuppression....
    , temozolomide
    Temozolomide

    Temozolomide is an oral alkylating antineoplastic agent which can be used for the treatment of Grade IV astrocytoma -- an aggressive brain tumor, also known as glioblastoma multiforme....
    ) from the nonclassical category. However, other sources list dacarbazine
    Dacarbazine

    Dacarbazine 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....
     as nonclassical, and some include temozolomide
    Temozolomide

    Temozolomide is an oral alkylating antineoplastic agent which can be used for the treatment of Grade IV astrocytoma -- an aggressive brain tumor, also known as glioblastoma multiforme....
    .


  • The platinum agents are also sometimes described as nonclassical.


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