A Textbook of Clinical Pharmacology and Therapeutics

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, mustineis actively transported by some cells.

MUSTINE (MECHLORETHAMINE)

Uses

Mustineis used in combination cytotoxic regimes (e.g. in
refractory Hodgkin’s disease).

Mechanism of action

Mustineforms highly reactive ethyleneimine ions that alkyl-
ate 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

Mustineis given intravenously. The reactive ethyleneimine

ion forms spontaneously due to cyclization in solution. The

plasmat1/2is approximately 30 minutes.

Other oral agents in this class of nitrogen mustards include

carmustine(BCNU) and lomustine(CCNU).

CYCLOPHOSPHAMIDE

Uses

Cyclophosphamideis an oxazaphosphorine alkylating agent

(ifosfamide is another). It is an inactive prodrug given

orally or intravenously. Several combination cytotoxic regi-

mens include cyclophosphamide. Very high marrow ablative

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)

T

T

T

A A T

A

C C

C C

C

C

G G

G G

G

G

G

Alkylating

agent

DNA

i.e.

A

Figure 48.4:Mechanism of intramolecular bridging of DNA

by alkylating agents. A, adenine; C, cytosine; G, guanine;

T, thymidine.