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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Cytotoxic Drugs: Alkylating Drugs and Platinum-Based Agents
Introduction and Therapeutic Uses
Alkylating agents have been identified as the first anticancer drugs developed; furthermore, these agents continue to be used today.8
Shown below, alkylating agents are represented by many different structural classes and these drugs act by forming covalent linkages with numerous important biomolecules.8
Among the most important target
sites would be DNA bases.
Interaction of alkylating agents and DNA probably represent the basis for their cytotoxic and therapeutic activity.
Most of the drug effectiveness results from interactions with cells that are rapidly dividing, although these drugs react with cellular constituents in all cell cycle phases.8
Much of the time, alkylating agents are administered as part of a combination chemotherapy protocols.8
These agents can target of many different types of cancer.
Probably the most frequently used drug among the alkylating agent to cyclophosphamide.
Some cancers are treated with combination treatment containing more than a single alkylating-type agent.
In addition, cyclophosphamide has been used to treat immune-related pathologies as well as to prepare bone marrow for autologous marrow transplants.8
Classification:
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Alkyl Sulfonates |
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Busulfan (Busulfex, Myleran) |
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Ethyleneimine, Methylmelamines |
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Altretamine (Hexalen) |
Thiotepa (Tepadina) |
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Nitrogen Mustards |
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Cyclophosphamide (Cytoxan) |
Chlorambucil (Leukeran) |
Mechlorethamine (Valchlor) |
Melphalan (Alkeran) |
Ifosphamide (Ifex) |
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Nitrosoureas |
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Carmustine (Bicnu, Gliadel) |
Streptozotocin (Zanosar) |
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Triazenes |
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Dacarbazine (DTIC-Dome) |
Temozolomide (TMZ) |
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Alkylating drugs were among the
first anticancer agents and remain frequently used in chemotherapeutic
protocols.10
These drugs target DNA.10
Alkylating agents result in:
DNA strand cross-linking
DNA strand breaks and
Abnormal base pairing.
These effects inhibit cell division.
Other possible mechanisms have been described.
These drugs are considered "cell cycle phase nonspecific" indicating that they promote cell death interactions and various cell-cycle locations, although the alkylating drugs appear more cytotoxic in the late G1 or S phases of the cell cycle.10,12
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Chemotherapeutic alkylating drugs form highly reactive carbonium intermediates.4
These intermediates can link to phosphates, sulfhydryl groups, amines and hydroxyl groups.4
Therapeutic effects and
cytotoxicities depend on alkylation of oxygen, reactive amines
or phosphates on DNA.
The N7 atom of guanine is a favorite site for covalent bonding with bifunctional alkylating drugs.
The site may be the key target resulting in drug efficacy.
DNA interaction with the alkylating agent mechlorethamine belonging to the group of nitrogen mustards, often results in guanine alkylation at the N7 location.4
Following N7 guanine alkylation, mispairing of guanine with thymine instead of cytosine may occur.
Another possibility is disruption of the imidazole ring causing ring opening and ultimately removal of the damaged guanine.
Molecular repair mechanisms targeting this damage stretch of the DNA, damage due to mispairing and/or imidazole ring opening may cause strand breakage.
A third possibility with bifunctional alkylating agents (e.g. nitrogen mustards) is alkylation of not one but two guanine residues which produces cross-linkage of either to nucleic acid chains or of one nucleic acid to a protein.
The prototype drug in the alkylating chemotherapy group is the bischloroethylamines (nitrogen mustards).13
Mechlorethamine (Mustine) historically was the first agent frequently used in clinically.
The drug was described by its original "code name" HN2 or by the expression nitrogen mustard.13
Resistance to the action of alkylating drugs may be mediated by
several mechanisms.3
These mechanisms include:
Increased expression and/or DNA repair enzyme activity which increases cellular capacity to repair damaged DNA
Reduced transmembrane transport of the alkylating agent into the cell or increase in transport of the drug out of the cell, and
Metabolic inactivation of the alkylating drug. For example, reduced mechlorethamime transport into the cell has been shown.3
Some tumor cells resistant to melphalan also exhibit reduced active transport.15
However, most alkylating agents enter the cell by diffusion and most alkylating chemotherapeutic drugs are not acted on by the "multiple-drug-resistance" export transporter systems.
Cellular inactivation of alkylating drugs may proceed by several mechanisms.15
In the case of nitrogen mustards aldehyde dehydrogenase detoxifies cyclophosphamide and ifosfamide.15
Aldehyde dehydrogenase is found both in:
Bone marrow precursor cells and in
Gastrointestinal epithelial cells and
Activity of the enzyme is protective in these organs from nitrogen mustard toxicity.
Aldehyde dehydrogenase has also been shown to confer:
Cyclophosphamide resistance in
Human leukemia cells and
Human ovarian, breast and
Colon malignant cells.
Cellular resistance of alkylating agents and increased
glutathione cellular levels and levels of the enzyme glutathione
transferase has been noted.
Glutathione (GSH), a thiol-containing tripeptide, reacts with electro-deficient molecules thus protecting cells from these electrophiles.
Increased GSH in cells found resistant to the alkylating agent melphalan.
This result may be due to an increase in γ-glutamylcysteine synthase, which catalyzes the rate-limiting step in de novo GSH synthesis.
Glutathione S-transferases (GST) catalyze reactions between electrophiles and glutathione however, most electrophiles react with glutathione spontaneously (at high rates thus reducing the need for enzyme-mediated catalysis).
Glutathione conjugates of some alkylating chemotherapy agents have been identified with their synthesis increased by glutathione-S-transferase.15
Glutathione-S-transferase is characterized by multiple isoforms or isozymes.
Specific isoenzymes may catalyze conjugation of different alkylating drugs.
For example, the α-GST isozyme promotes glutathione conjugation of melphalan, phosphoramide mustard, and chlorambucil.15
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Cytotoxicity associated with bifunctional alkylating drugs seems to be associated mainly with interstrand DNA cross-linking.4
In addition to
mechlorethamine, other bifunctional alkylating drugs include
chlorambucil,
mitomycin, and platinum compounds.11
These example agents also react with the N7 of guanine.
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