Alkylating drugs

Bendamustine is a useful antineoplastic drug for the treatment of non-Hodgkin s lymphomas, multiple myeloma and as a partner drug in the combination therapy of some solid tumors. The cross-resistance with other alkylating drugs is not complete. Myelosuppression and lymphocytopenia is its main dose-limiting toxicity. 

Dekant W, Martens G, Vamvakas S, et al. 1987. Bioactivation of tetrachloroethylene. Role of glutathione S-transferase-catalyzed conjugation versus cytochrome P-450-dependent phospholipid alkylation. Drug Metab Dispos Biol Fate Chem 15 702-709. 

The alkylating drugs are the oldest category of chemotherapy agents. Globally, cytoxocity results from inhibition of DNA replication because interlinked strands do not separate. 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

J. Hovinen, R. Silvennoinen, J. Vilpo, Detoxification of an Alkylating Drug, (V,(V-Bis(2-chloroethyl)-P-aminophenylbutyric Acid (Chlorambucil), in Human Gastric Juice and Saliva , Chem. Res. Toxicol. 1998, 11, 91 - 93. 

Chemicals such as l,2-dibromo-3-chloropropane can disrupt spermatogenesis, leading to impaired reproductive function, including sterility. Men and women undergoing cancer chemotherapy with alkylating drugs are at increased risk for sterility. 

Glucophage was taken with meals and never less than 6 hours before sleeping. Individuals with kidney problems did not take Glucophage and most athletes were aware of the fact that in some cases stacking with oral 17-alfa-alkylated drugs could induce even greater liver damage. 

Another alkylating drug in clinical use is mitomycin C. As a natural product isolated from Stremtomyces lavendulae, mytomycin C is an aziridine compound, which is closely related to nitrogen mustards. This compound is best known to the DNA repair field as a DNA interstrand crosslinking agent. Mytomycin C has been used to treat breast cancer and cancers of the gastrointestinal tract. 

Replication of the measles vaccine virus may be potentiated in patients with immune deficiencies and by the suppressed immune responses that occur with leukemia, lymphoma or generalized malignancy, or during therapy with corticosteroids, alkylating drugs, antimetabolites or radiation such patients should not be immunized (4). 

However, in a phase II stndy of the combination of novobiocin and high-dose cyclophosphamide and thio-tepa, followed by antologons bone marrow support in women with chemosensitive advanced breast cancer, there was no significant increase in progression-free snr-vival and overall snrvival compared with historical controls treated with high-dose alkylating drugs alone (3). 

There are no known contraindications to the use of IPV. OPV should not be given to persons who are immunocompromised due to immunodeficiency diseases, leukemia, lymphoma or generalized malignancy or who are immunosuppressed due to therapy with glucocorticoids, alkylating drugs, antimetabolites, or radiation. If poliomyelitis immunization is indicated in such persons, IPV should be used. OPV should also be avoided when immunizing household contacts of immunocompromised patients. 

The immunostaining procedure described below can be applied, in principle, to the quantification of any stabilized drug/protein - DNA adduct or complex where antibodies are available for that adduct or complex. The protocol provided below describes the detection and measurement of the adducts formed between the bifunctional alkylating drug melphalan and DNA, where monoclonal antibodies have been elicited against the adducts (3). 

Since alkylating agents are very reactive, they will react with any good nucleophile and so they are not very selective in their action. They will alkylate proteins and other macromolecules as well as DNA. Nevertheless, alkylating drugs have been useful in the treatment of cancer. Tumour cells often divide more rapidly than normal cells and so disruption of DNA function will affect these cells more drastically than normal cells. 

None of these drugs can claim to be a magic bullet since there are serious, dose-limiting adverse effects associated with their administration. However, like the alkylating drugs discussed in the previous section, there is often some selective toxicity towards cancer cells, and there are countless thousands of children (in particular) who owe their lives to these drugs. 

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