A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

372 CANCER CHEMOTHERAPY
3. DNA-binding agents;
4. topoisomerase inhibitors;
5. microtubular inhibitors (vinca alkaloids and taxanes);
6. molecularly targeted agents; small molecules and
monoclonal antibodies;
7. hormones;
8. biological response modifiers.
ALKYLATING AGENTS
Alkylating agents are particularly effective when cells are
dividing rapidly, but are not phase-specific. They combine
with DNA and thus damage malignant and dividing normal
cells (see Table 48.5). If a tumour is sensitive to one alkylating
agent, it is usually sensitive to another, but cross-resistance
does not necessarily occur. The pharmacokinetic properties of
the different drugs are probably important in this respect. For
example, although most alkylating agents diffuse passively
into cells, mustine is actively transported by some cells.
MUSTINE (MECHLORETHAMINE)
Uses
Mustine is used in combination cytotoxic regimes (e.g. in
refractory Hodgkin’s disease).
Mechanism of action
Mustine forms highly reactive ethyleneimine ions that alkylate
and cross-link guanine bases in DNA (Figure 48.4) and
alkylate other macromolecules, including proteins.
Adverse effects
Adverse effects are listed in Table 48.5.
Pharmacokinetics
Mustine is given intravenously. The reactive ethyleneimine
ion forms spontaneously due to cyclization in solution. The
plasma t 1/2 is approximately 30 minutes.
Other oral agents in this class of nitrogen mustards include
carmustine (BCNU) and lomustine (CCNU).
CYCLOPHOSPHAMIDE
Uses
Cyclophosphamide is an oxazaphosphorine alkylating agent
(ifosfamide is another). It is an inactive prodrug given
orally or intravenously. Several combination cytotoxic regimens
include cyclophosphamide. Very high marrow ablative
Alkylating
agent
T
C
G
G
G
T
DNA
A
C
G
C
A
i.e.
Figure 48.4: Mechanism of intramolecular bridging of DNA
by alkylating agents. A, adenine; C, cytosine; G, guanine;
T, thymidine.
A
C
G
C
A
T
G
C
G
T
Table 48.5: Comparative pharmacology of classical alkylating agents
Drug Route of Nausea and Granulocytopenia Thrombocytopenia Special
administration vomiting toxicity
Mustine i.v. Tissue necrosis if extravasated
Cyclophosphamide Oral/i.v. Alopecia (10–20%)
Chemical cystitis (reduced by mesna)
Mucosal ulceration
Impaired water excretion
Interstitial pulmonary fibrosis
Ifosfamide i.v. Chemical cystitis (reduced by mesna)
Alopecia
Chlorambucil Oral Bone marrow suppression
Melphalan Oral 0 Chemical cystitis (very rare)
Busulfan Oral 0 Skin pigmentation
Interstitial pulmonary fibrosis
Amenorrhoea
Gynaecomastia (rare)