Page 968 - Basic _ Clinical Pharmacology ( PDFDrive )

954 SECTION VIII Chemotherapeutic Drugs

The latter effect leads to DNA strand breakage through scission Cyclophosphamide is one of the most widely used alkylating
of the sugar-phosphate backbone of DNA. Cross-linking of DNA agents. One significant advantage of this compound relates to its
appears to be of major importance to the cytotoxic action of alkyl- high oral bioavailability. As a result, it can be administered via the
ating agents, and replicating cells are most susceptible to these oral and intravenous routes with equal clinical efficacy. It is inac-
drugs. Thus, although alkylating agents are not cell cycle-specific, tive in its parent form and must be activated to cytotoxic metabo-
cancer cells are most susceptible to this class of drugs in late G lites by liver microsomal enzymes (Figure 54–4). The cytochrome
1
and S phases of the cell cycle. P450 mixed-function oxidase system converts cyclophosphamide
to 4-hydroxycyclophosphamide, which is in equilibrium with
Resistance aldophosphamide. These active metabolites are delivered to both
tumor and normal tissue, where nonenzymatic cleavage of aldo-
The mechanism of acquired resistance to alkylating agents may phosphamide to the cytotoxic forms—phosphoramide mustard
involve increased capability to repair DNA lesions through and acrolein—occurs. The liver appears to be protected through
increased expression and activity of DNA repair enzymes, the enzymatic formation of the inactive metabolites 4-ketocyclo-
decreased cellular transport of the alkylating drug, and increased phosphamide and carboxyphosphamide.
expression or activity of glutathione and glutathione-associated The major toxicities of the individual alkylating agents are
proteins, which are needed to conjugate the alkylating agent, or outlined in Table 54–2 and discussed below.
increased glutathione S-transferase activity, which catalyzes the
conjugation.

Adverse Effects NITROSOUREAS
The adverse effects associated with alkylating agents are generally These drugs appear to be non-cross-resistant with other alkylating
dose-related and occur primarily in rapidly growing tissues such agents; all require biotransformation, which occurs by nonenzy-
as bone marrow (myelosuppression), gastrointestinal tract (diar- matic decomposition, to metabolites with both alkylating and
rhea), and reproductive system. Nausea and vomiting also can be carbamoylating activities. The nitrosoureas are highly lipid-soluble
a serious issue with a number of these agents. In addition, they and are able to readily cross the blood-brain barrier, making them
are potent vesicants and can damage tissues at the site of admin- effective in the treatment of brain tumors. Although the major-
istration as well as produce systemic toxicity. As a class, alkylating ity of alkylations by the nitrosoureas are on the N7 position of
agents are carcinogenic in nature, and there is an increased risk of guanine in DNA, the critical alkylation responsible for cytotoxic-
secondary malignancies, especially acute myelogenous leukemia. ity appears to be on the O6 position of guanine, which leads to

NH O
P O
O N(CH 2 CH Cl) 2 CH
2
2
Cyclophosphamide H N O
CH 2 P
CH 2 O N(CH CH Cl) 2
2
2
Liver cytochrome
P450 oxidase Aldophosphamide
(active)
OH
Aldehyde oxidase Nonenzymatic
NH O
P
O N(CH CH Cl) 2 H N O CH 2 CH CHO
2
2
2
4-Hydroxycyclophosphamide O P Acrolein
(active) (cytotoxic)
HOC CH 2 CH 2 O N(CH CH Cl) 2 +
2
2
Carboxyphosphamide
O H N O
(inactive) 2
NH O
P
P
HO N(CH CH Cl) 2
2
2
O N(CH CH Cl) 2 Phosphoramide mustard
2
2
4-Ketocyclophosphamide (cytotoxic)
(inactive)
FIGURE 54–4 Cyclophosphamide metabolism.