Genotoxic drugs are chemotherapy agents that affect nucleic acids and alter their function. These drugs may directly bind to DNA or they may indirectly lead to DNA damage by affecting enzymes involved in DNA replication.(1)Rapidly dividing cells are particularly sensitive to genotoxic agents because they are actively synthesizing new DNA. If enough damage is done to the DNA of a cell it will often undergo apoptosis, the equivalent of cellular suicide.
The genotoxic chemotherapy treatments include:
Alkylating agents: The first class of chemotherapy agents used. These drugs modify the bases of DNA, interfering with DNA replication and transcription and leading to mutations.(1)
Intercalating agents: These drugs wedge themselves into the spaces between the nucleotides in the DNA double helix. They interfere with transcription, replication and induce mutations.
Enzyme inhibitors: These drugs inhibit key enzymes, such as topoisomerases, involved in DNA replication inducing DNA damage.(1)
The goal of treatment with any of these agents is the induction of DNA damage in the cancer cells. DNA damage, if severe enough, will induce cells to undergo apoptosis, the equivalent of cellular suicide. The genotoxic chemotherapy drugs affect both normal and cancerous cells. The selectivity of the drug action is based on the sensitivity of rapidly dividing cells, such as cancer cells, to treatments that damage DNA.(1)The mode of action also explains many of the side effects of treatment with these drugs. Rapidly dividing cells, such as those that line the intestine or the stem cells in bone marrow, are often killed along with the cancer cells.(1)In addition to being cytotoxic (cell poisons), these drugs are also mutagenic (cause mutations) and carcinogenic (cause cancer). Treatment with these drugs carries with it the risk of secondary cancers, such as leukemia. These drugs are used to treat a variety of solid cancers and cancers of blood cells, often in combination with other drugs.(1)
For information on a particular drug, choose a link below.
A Closer Look at 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.