Saturday 18 June 2011

ANTI CANCER AGENTS MECHANISM


Mechanisms of Alkylating Agents
 

Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.


In the first mechanism an alkylating agent (represented in the figure below as a pink star) attaches alkyl groups (small carbon compounds-depicted as pink triangles) to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases (frame 3 of the diagram below). Alkylated bases prevent DNA synthesis and RNA transcription from the affected DNA.




A second mechanism by which alkylating agents cause DNA damage is the formation of cross-bridges, bonds between atoms in the DNA (pink linkages below). In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Bridges can be formed within a single molecule of DNA (as shown below) or a cross-bridge may connect two different DNA molecules. Cross-linking prevents DNA from being separated for synthesis or transcription. 




The third mechanism of action of alkylating agents is the induction of mispairing of the nucleotides leading to mutations. In a normal DNA double helix, A always pairs with (is across from) T and G always pairs with C. As the figure below shows, alkylated G bases may erroneously pair with Ts. If this altered pairing is not corrected it may lead to a permanent mutation. 


 



Carboplatin and Cisplatin

 

Mechanism of action:

These related drugs covalently bind to DNA with preferential binding to the N-7 position of guanine and adenine. They are able to bind to two different sites on DNA producing cross-links, either intrastrand (within the same DNA molecule; >90%) or interstrand (bewteen two different DNA molecules; <5%). The modification of the DNA (formation of DNA adducts) results in inhibition of DNA synthesis and transcription. Binding of the drugs to nuclear and cytoplasmic
proteins may also result in cytotoxic effects. 



Drug resistance:
 

Resistance may arise in the form of reduced accumulation of the drugs within the target cells due to alterations in cellular transport. There also may be an increased inactivation of the drugs due to increased activity of several detoxifying enzymes. Enhanced DNA repair enzyme activity may also reduce the effectivenes of these drugs.

For more on drug resistance, go to the Drug Resistance section of Cancer Treatments.




Carmustine


Mechanism of action:
 
Like the other alkylating agents in the nitrosourea family, this drug alkylates DNA, causing inter- and intra-strand cross-linking. Carmustine is very rapidly taken up into the cells and degraded. Metabolism of the drug occurs in the liver prior to excretion in the urine or breath.


Drug resistance:
 

Expression of Glutathione S-transferase can be increased, leading to inactivation of many alkylating agents. The cell's DNA repair mechanisms may counteract the damage done by carmustine. Alterations in the transport of the drug into or out of the cell can reduce intracellular concentrations of the drug.



Cyclophosphamide and Ifosfamide


Cyclophosphamide
 

History:
 

Cyclophosphamide was first synthesized in 1958 by Arnold and Bourseaux; the compound, as well as a few analogs, were synthesized with the knowledge of the structure and activities of pre-existing anti-cancer drugs.


Mechanism of action: 

Cyclophosphamide is the most commonly used alkylating agent. Upon cellular uptake, it is extensively metabolized. The drug is first transformed to hydroxylated intermediates by the cytochrome P-450 system. The hydroxylated intermediates undergo breakdown to form the active compounds, phosphoramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step.


Drug Resistance:
 

Resistance results from increased DNA repair, decreased drug uptake, and reaction of the drug with anti-oxidants such as thiols. Cross-resistance, however, does not always occur.


Ifosfamide


Mechanism of action:  

Ifosfamide's mechanism of action is very similar to that of cyclophosphamide but slower. Ifosfamide is hydroxylated upon cellular uptake. It is most commonly usd as third-line therapy, in combination with other antineoplastic drugs, for germ cell testicular cancer and is always given with Mesna (Uromitexan., Mesnex.) to prevent ifosfamide-induced hemorrhagic cystitis.



Doxorubicin


History and development of the drug: 
 
Doxorubicin is an anthracycline antibiotic first isolated from the fungus Streptomyces peucetius by the Farmitalia Research Laboratories of Milan in the early 1960's. This discovery occurred immediately after they had discovered the first anthracycline, daunorubicin. Although the structures of these two drugs are essentially the same (they differ by only one hydroxyl or OH group), daunorubicin is only useful for acute leukemia and doxorubicin can be used for a wide range of cancers. In the late 1960's the drug showed antitumor activity in clinical trials but toxicity was found in normal cells. In 1974, doxorubicin was approved for treatment in the United States. Research then focused on developing derivatives of doxorubicin that had the same or improved antitumor effects with less cardiac toxicity. The newer drugs have the same general anthracyline ring structure but they have been modified slightly. Over 2,000 analogs have been tested as antitumor agents in the last thirty years. Some of these are currently in clinical trials, but doxorubicin remains the most widely administered of the anthrocyclines. Several other attempts have been made to reduce the toxicity of these drugs. In one, the drugs are administered in an inactive or prodrug form. These drugs can be activated when they reach the target cells. Another approach involves encasing the drug in a phospholipid carrier system. This reduces exposure of normal tissues to the drug and therefore reduces heart damage caused by the drug. Researchers have also looked at combining doxorubicin with another drug that would alleviate the cardiotoxicity. Dexrazoxane (DXZ), a member of the bisoxopiperazine drug class, eliminates free radical production and decreases cardiomyopathy. Research has also looked at ways to overcome resistance to the drug, perhaps by inhibiting MDR-1.


Mechanism of action:
 

Doxorubicin is a Class I anthracycline antibiotic which means that it blocks RNA and DNA synthesis equally. Cells in S-phase are most sensitive to the drug. The drug has two main mechanisms by which it causes cell death:

  • Intercalation: Doxorubicin intercalates between adjacent nucleotides along the DNA forming a tight DNA-drug interaction. This interaction disrupts DNA synthesis and transcription.
  • Enzyme inhibition: Doxorubicin binds and inhibits topoisomerase II,a key enzyme involved in DNA synthesis.
  • Metabolism of the drug also generates oxygen free radicals which damage DNA and prevent DNA synthesis.

Cardiotoxicity:
 

The cardiotoxicity that results from administering doxorubicin is thought to result primarily from the generation of damaging free oxygen radicals but might be partly due to the inhibition of topoisomerase II. The free oxygen radicals cause the peroxidation of lipid membranes and inhibit mitochondrial respiration. They also induce calcium release in the heart by altering the calcium sensitivity of a calcium release channel called the ryanodine receptor. Myocardial tissue also lacks an enzyme that destroys free radicals and is therefore more susceptible than other body tissues.


Drug resistance:
 

Primary and secondary resistance to doxorubicin is a major clinical problem that has not been resolved. Resistance to doxorubicin occurs through multiple mechanisms. An increase in the activity of the multidrug resistance gene (MDR-1) is a significant problem. The protein product, MDR (also: P-glycoprotein), is a transmembrane pump that causes drug efflux and reduced drug accumulation within cells. Decreased expression of topoisomerase II or mutations that reduce the binding of the enzyme with doxorubicin lower the effectivenss of the drug. Increases expression anti-oxidants such as gluthathione and gluthathione-dependent proteins cause an increase in glutathione peroxidase activity and a reduction in drug activity.




Etoposide


Etoposide is derived from the Podophyllum (mandrake) plant that grows in the southeastern United States.


Mechanism of action:
 
Etoposide damages DNA by inhibiting topoisomerase II, an enzyme that normally unwinds DNA during replication to relieve tension in the unwinding DNA strands. Etoposide stops the action of topoisomerase II after it creates a nick in one strand of the DNA. The nicked DNA is unable to unwind and eventually breaks. The graphic below is a depiction of how topoisomerase normally makes a nick in one strand of the DNA and then unwinds it before it is resealed. 







Drug resistance:
 
The topoisomerase II gene can mutate so that Etoposide binds less effectively to the enzyme product. Increased DNA repair can revert the damage done by the drug. An increase in the activity of transmembrane pumps, which push the drug back out of the cell and decrease movement of the drug into the cell, may also alter the effectiveness of etoposide.

For more on Drug Resistance see the section of that name under Cancer Treatments.

5 comments:

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