Biology of Disease

Alkylating agents that have two reactive groups are bifunctional and can

cross-link two biomolecules. Cross-linking the two strands of DNA is the

major cause of toxicity of these drugs since this prevents the separation of the

strands which is required for the synthesis of new DNA. Examples of alkylating

agents include the nitrogen mustards, such as cyclophosphamide, melphalan,

ifosfamide and chlorambucil, and the nitrosoureas, for example bis-chloro-

ethyl nitrosourea (BCNU; carmustine) and cyclohexyl-chloroethyl nitroso-

urea (CCNU; lomustine). Some examples of their use is shown in Table 17.7.

Purine and pyrimidine analogs are drugs that resemble one of the bases

found in DNA and/or RNA. When present during nucleic acid synthesis, they

interfere with the synthesis of DNA, though the site at which they exert their

effects depends on the drug itself. Pyrimidine analogs include 5-fluorouracil or

5-FU (Figure 17.26) and cytidine arabinoside (ara-C). Purine analogs include

6-mercaptopurine (6-MP) and 6-thioguanine. Table 17.8 lists some of their

uses in cancer treatment.

Microtubules form the mitotic spindle, which is essential for the process

of chromosome separation during mitosis and meiosis. The formation of a

spindle requires microtubules to polymerize from tubulin subunits, whereas

separation of chromosomes requires depolymerization. Any drug which

interferes with either of these processes will interfere with cell division. The

first drug shown to prevent polymerization was colchicine, originally obtained

from the autumn crocus, Colchicum officinale, though this is too toxic for

Figure 17.25(A) Note the similar structures of i) dihydrofolate and ii) the anticancer drug, methotrexate. (B)

Molecular model of dihydrofolate reductase with a bound methotrexate molecule. PDP file 1RG7.

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