A Textbook of Clinical Pharmacology and Therapeutics

368 CANCER CHEMOTHERAPY
Taxanes
Bleomycin
�ve
G 2 phase
Cyclin B/cell division
Vinca alkaloids
Taxanes
�ve
M phase
Cyclins A and B
cycle protein 2
CDK 2 /Cyclin A
S phase
�ve
several malignancies, especially lymphomas and leukaemias.
There are two main groups of cytotoxic drugs, classified by their
effects on cell progression through the cell cycle (see Figure 48.1).
CELL CYCLE PHASE-NON-SPECIFIC DRUGS
These drugs act at all stages of proliferation, but not in the
G0-resting phase. Because of this, their dose–cytotoxicity relationships
follow first-order kinetics (cells are killed exponentially
with increasing dose). The linear relationship between
dose and log cytotoxicity (Figure 48.2a) is exploited in the use of
high-dose chemotherapy. Cytotoxic drugs are given at very
high doses over a short period, thus rendering the bone marrow
aplastic, but at the same time achieving a very high tumour cell
kill. Clinical efficacy has been established in haematological
malignancies (e.g. leukaemias, lymphomas) using such agents.
Alkylating agents are examples of cycle-non-specific drugs
(e.g. cyclophosphamide, melphalan) as are nitrosoureas
(e.g. cis-chloroethylnitrosourea (CCNU), lomustine and bischloroethylnitrosourea
(BCNU), carmustine).
CELL CYCLE PHASE-SPECIFIC DRUGS
These drugs act only at a specific phase in the cell cycle. Therefore,
the more rapid the cell turnover, the more effective they are.
Their dose–cytotoxicity curve is initially exponential, but at
higher doses the response approaches a maximum (see Figure
48.2b). Table 48.1 classifies the commonly used cytotoxic drugs
according to their effect on the cell cycle. Until the kinetic behaviour
of human tumours can be adequately characterized in
individual patients the value of this classification is limited.
The distinction between cell cycle phase-non-specific and
phase-specific drugs, although clear-cut in animal and in vitro
experiments, is also probably an over-simplification.
and E
E 2F Cyclins D
G 1 phase
G 0 phase
�ve
Glucocorticosteroids
Antimetabolites (6-MP, MTX, 5-fluorouracil, etc.)
Topoisomerase inhibitors (I/II) – Anthracyclines, camptothecins, etoposide
(a)
Log % cells surviving
(b)
Log % cells surviving
Figure 48.1: The cell cycle regulatory systems and
sites of drug actions. 6-MP, 6-mercaptopurine; MTX,
methotrexate.
Dose
Dose
Figure 48.2: The dose–response relationship (a) for a cell cycle
phase-non-specific drug and (b) for a cell cycle phase-specific
drug.