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328 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 329

or demethylation; thus, doses of etoposide require modification for Although platinum analogues are not true alkylating agents in that
patients with compromised renal or hepatic function. The plasma they form metal adducts rather than carbon adducts with DNA, RNA,
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half-life of etoposide is 15 hours. The clinical activity of etoposide is and protein, their range of toxicities and mechanisms of resistance have
highly schedule dependent. Single conventional doses are essentially much in common with the classical alkylators. They have few indica-
without antitumor effect as compared to consecutive daily doses for 3 to tions in hematologic malignancy, aside from carboplatin and its role
5 days. The pharmacokinetics of teniposide are very similar to those of in high-dose chemotherapy for lymphomas. Their DNA adducts are
etoposide, with a terminal plasma half-life of 20 to 48 hours. However, subject to repair by nucleotide excision repair and double-strand break
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little parent drug appears intact in the urine, and dose modification for repair, processes dependent on functional p53 activity. Polymorphisms
patients with renal dysfunction is unnecessary. of the repair pathways, especially the mismatch repair process, may
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be associated with drug resistance, whereas errors in double-strand
Adverse Effects break repair (as found in BRCA1- and BRCA2-solid tumors), may create
When administered intravenously, both etoposide and teniposide sensitivity to platinating drugs.
should be infused over a 30-minute period to avoid hypotensive epi-
sodes. The major toxicity of both drugs is leukopenia, which is rapidly Mechanism of Action
reversible; thrombocytopenia is less common. Nausea and vomiting All alkylating agents (Fig. 22–4) have in common the generation of
often follow etoposide administration. Alopecia may occur with both highly reactive carbonium intermediates that attack electron-rich sites
drugs. Other toxicities, such as fever, mild elevation of liver function on DNA, such as the N-7, O-2, and O-6 positions of guanine and the
tests, and peripheral neuropathy, are relatively uncommon. Because the N-1, N-3, and N-7 positions of adenine. For many of these agents, the
major toxicity of etoposide is limited to the marrow, this drug is a valu- alkylating group must undergo a preliminary activation reaction medi-
able component of high-dose regimens used with marrow transplanta- ated either by chemical rearrangement of the molecule, as in the case
tion. In high-dose etoposide protocols (1.5 g/m or greater given over of nitrogen mustard and the nitrosoureas, or by metabolic activation
2
3 to 5 days) oropharyngeal mucositis becomes a prominent toxicity. followed by chemical rearrangement, as for cyclophosphamide, ifosfa-
Less-frequent high-dose toxicities include hepatocellular damage and, mide, and procarbazine. Most alkylating agents have two reactive sites,
rarely, anaphylactic-like symptoms, probably related to the formulation usually two chloroethyl groups, enabling them to form intrastrand and,
vehicle. Secondary AML associated with translocation at 11q23 or the less frequently, interstrand crosslinks.
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PML gene may follow etoposide treatment in children with ALL and A second class of alkylating drugs, exemplified by busulfan,
in adults with solid tumors. 120 dimethyltriazenoimidazole carboxamide (DTIC) and the closely related
temozolomide, and procarbazine, produce only single-strand alkyla-
tion but may be highly carcinogenic, as, for example, procarbazine. In
AGENTS ACTIVE THROUGHOUT general, all the commonly used alkylating drugs, including cyclophos-
phamide, ifosfamide, melphalan, chlorambucil, and the methylating
THE CELL CYCLE drugs, produce the same spectrum of myelosuppressive, carcinogenic,
and genotoxic actions, and depend on an intact mismatch repair system
THE ALKYLATING DRUGS to recognize their adducts and initiate apoptosis.

These drugs are important in the treatment of hematopoietic malig- Experimental systems have elucidated the mechanisms of resis-
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nancies either as single agents or as components of standard- or high- tance to alkylating agents. Some mechanisms are specific for certain
dose regimens. Their role as treatment for both acute and chronic alkylating agents (e.g., impaired uptake of nitrogen mustard as a conse-
hematologic malignancies results from their unique mechanism of quence of an alteration in the membrane carrier for choline, or deletion
cell killing and their lack of cell-cycle specificity. They may eradicate of the amino acid carrier used by melphalan), whereas others appear
noncycling cells that escape cycle-active components of the treat- to be less specific (e.g., drug inactivation associated with an increase in
ment. Although these agents share the common property of forming intracellular sulfhydryl compounds, and enhanced nucleotide-excision
covalent bonds with electron-rich sites on DNA (oxygen and nitro- repair of DNA adducts). The primary resistance mechanisms for vari-
gen substituents), they exhibit important differences in their intrinsic ous alkylating drugs, as documented in experimental tumors, include
reactivity, route of cellular uptake, favored sites of alkylation on DNA increased degradation by aldehyde dehydrogenase (specifically for
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bases, and the specific mechanism of DNA repair that determines cell cyclophosphamide) ; increased conjugation of the reactive interme-
survival. These differences are borne out in experimental settings, diates with glutathione or glutathione transferase (all chloroethylating
where cross-resistance to alkylating agents is incomplete. Thus, pro- agents and platinum analogues); increased repair of the O-6 guanine
tocols employing multiple alkylators, particularly in high-dose regi- alkyl lesions by a specific alkyl transferase (nitrosoureas, procarba-
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mens, have a rational basis. Alkylating agents differ as well in their zine, temozolomide, and dacarbazine) ; increased nucleotide excision
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patterns of toxicity. The majority of these drugs cause myelosuppres- repair (all platinum derivatives and chloroethylating agents, except
sion and mucositis as their primary acute toxicities, as well as delayed possibly nitrosoureas); decreased uptake (melphalan, nitrogen mus-
pulmonary fibrosis and late secondary leukemias. These secondary tard); decreased ability to recognize DNA damage because of defective
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leukemias often arise after a period of myelodysplasia, are usually mismatch repair, especially the loss of the MLH6 component (most
highly drug resistant AML, and carry defects in chromosomes 5 or 7. alkylating agents and platinum derivatives); and defective recognition
Busulfan, bischloroethylnitrosourea (BCNU), or cyclophosphamide of DNA alkylation and strand breaks and initiation of apoptosis (p53
are most likely to cause vascular endothelial damage (hepatic venooc- loss-of- function mutants), which affects all alkylators. The basis of alky-
clusive disease) when used in high doses. However, these same drugs lating agent resistance in the clinic is still incompletely understood.
are often used in high-dose regimens, as they cause less mucositis than
other alkylating agents. 4-Hydroperoxycyclophosphamide, an acti- Clinical Pharmacology
vated analogue of cyclophosphamide, appears to spare marrow stem In general, the alkylating agents and their reactive intermediates have
cells relative to tumor cells and has been used for in vitro purging of short residence times in the systemic circulation and within cells. They
marrow in autologous transplantation. 122 are eliminated predominantly by hydrolysis of the reactive site, by

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