Molecular Life Sciences (2014)
DNA alkylation leads to mutations and cancer, so at first it might seem unusual to use this as a mechanism to treat cancers. The strategy is that DNA is not rapidly expanding in most cells but is in growing tumor cells. Many of the drugs used in cancer therapy are cross-linking agents, which can be particularly detrimental to the activity of DNA polymerases. Further, the only other options for treating cancer are usually surgery, radiation therapy, and possibly alternate drugs. DNA repair can work against therapy, and in some cases, drugs such as O6-benzylguanine have been used to boost the action of alkylating agents. A finite level of DNA damage can occur at non-tumor sites, and this can explain the increased incidence of later tumors (10–20 years) in individuals who have been given chemotherapy.
Although most of the focus of this section is on the detrimental effects of DNA damage due to the introduction of mutations (leading to cancer and other diseases), damage to DNA is also utilized in the treatment of cancer. The concept is an old one. In adults, most of the tissues in the body are quiescent and not making DNA rapidly. For tumors to grow, they must synthesize DNA. Therefore, blocking DNA synthesis is a viable strategy for arresting tumor growth. Therefore, many of the drugs used to treat cancers are alkylating agents (Connors 1984; Lawley and Phillips 1995; Fig. 1). A further strategy for enhancement of the effects of these drugs is the use of chemicals that block DNA repair, e.g., O6-alkylguanine DNA alkyltransferase (Pauly et al. 2008).
Utilization of DNA damage
Many of the alkylating agents used to treat cancer are mustards (structures with the moiety –N- CH2CH2-X or –S-CH2CH2X, where X is a halide or other good leaving group), epoxides, or other reactive group. In other cases, oxidation or other bioactivation causes the formation or release of a reactive entity (e.g., cyclophosphamide, mitomycin C). For oncology drugs known to alkylate DNA, positive genotoxicity assays are not considered a major problem because of the mode of action.
A major problem with the use of alkylating agents to treat cancer is that these chemicals are relatively nonspecific, i.e., most will also alkylate proteins (causing toxic side effects) and also DNA in cells other than the tumor. One issue is that patients who are cured of tumors have an increased risk of acquiring a cancer at another site (Kaldor et al. 1990). Although it is not possible to directly implicate DNA alkylation in this phenomenon, the known chemistry and biology of DNA alkylation is entirely consistent with the explanation. Because of the severe side effects of alkylating agents, there is considerable interest in the development of more selective drugs to treat cancers by inhibiting specific enzymes in cell-signaling mechanisms relevant to cancer growth.
Fig. 1. Some drugs used in cancer chemotherapy that form DNA adducts
Connors TA (1984) Carcinogenicity of medicines. In: Searle CE (ed) Chemical carcinogens, vol 2, 2nd edn. American Chemical Society, Washington, DC, pp 1241–1278
Kaldor JM, Day NE, Pettersson F et al (1990) Leukemia following chemotherapy for ovarian cancer. New Engl J Med 322:1–6
Lawley PD, Phillips DH (1995) DNA adducts from chemotherapeutic agents. Mutat Res 355:13–40 Pauly GT, Loktionova NA, Fang Q et al (2008) Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine. J Med Chem 51:7144–7153