Cyclophosphamide is one of the most widely used alkylating agents. One significant advantage of this compound relates to its high oral bioavailability. As a result, it can be administered via the oral and intravenous routes with equal clinical efficacy. It is inactive in its parent form and must be activated to cytotoxic metabolites by liver microsomal enzymes (Figure 54–4). The cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide.
The major toxicities of the individual alkylating agents are outlined in Table 54–2 and discussed below.
These drugs appear to be non-cross-resistant with other alkylating agents; all require biotransformation, which occurs by nonenzymatic decomposition, to metabolites with both alkylating and carbamoylating activities. The nitrosoureas are highly lipid-soluble and are able to readily cross the blood-brain barrier, making them effective in the treatment of brain tumors. Although the majority of alkylations by the nitrosoureas are on the N7 position of guanine in DNA, the critical alkylation responsible for cytotoxicity appears to be on the O6 position of guanine, which leads to
FIGURE 54–4 Cyclophosphamide metabolism.
TABLE 54–2 Alkylating agents and platinum analogs: Clinical activity and toxicities.
CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia.
G-C crosslinks in DNA. After oral administration of lomustine, peak plasma levels of metabolites appear within 1–4 hours; central nervous system concentrations reach 30–40% of the activity present in the plasma. Urinary excretion appears to be the major route of elimination from the body. One naturally occurring sugar-containing nitrosourea, streptozocin, is interesting because it has minimal bone marrow toxicity. This agent has activity in the treatment of insulin-secreting islet cell carcinoma of the pancreas.
Several other compounds have mechanisms of action that involve DNA alkylation as their cytotoxic mechanism of action. These agents include procarbazine, dacarbazine, and bendamustine. Their clinical activities and toxicities are listed in Table 54–2.
Procarbazine is an orally active methylhydrazine derivative, and in the clinical setting, it is used in combination regimens for Hodgkin’s and non-Hodgkin’s lymphoma as well as for brain tumors.
The precise mechanism of action of procarbazine is uncertain; however, it inhibits DNA, RNA, and protein biosynthesis; prolongs interphase; and produces chromosome breaks. Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and H2O2, which may be responsible for DNA strand scission. A variety of other drug metabolites are formed that may be cytotoxic. One metabolite is a weak monoamine oxidase (MAO) inhibitor, and adverse events can occur when procarbazine is given with other MAO inhibitors as well as with sympathomimetic agents, tricyclic antidepressants, antihistamines, central nervous system depressants, antidiabetic agents, alcohol, and tyramine-containing foods.
There is an increased risk of secondary cancers in the form of acute leukemia, and its carcinogenic potential is thought to be higher than that of other alkylating agents.