A Textbook of Clinical Pharmacology and Therapeutics

380 CANCER CHEMOTHERAPY

Mechanism of action

Paclitaxelbinds to the β-subunit of tubulin and antagonizes
the depolymerization of microtubules, halting mitosis. Cells
are blocked in the G 2 /M phase of the cell cycle and undergo
apoptosis.

Adverse effects

These include the following:

• hypersensitivity reactions;


• bone marrow suppression (dose-dependent and reversible);


• myalgias and arthralgias;


• sensory peripheral neuropathy;


• cardiac dysrhythmias;


• nausea and vomiting;


• alopecia.

Pharmacokinetics

Paclitaxelis poorly absorbed orally and requires intravenous
administration. It is inactivated by hepatic CYP450 and 5%
of the parent drug is excreted in the urine. The dose should be
reduced in hepatic dysfunction.
Docetaxelis a semi-synthetic taxane derivative with a sim-
ilar anti-tumour spectrum as paclitaxel. It causes myelosup-
pression and peripheral fluid retention, but less cardio- and
neurotoxicity than paclitaxel.

MOLECULARLY TARGETED AGENTS

This recently developed family of compounds is grouped
together because they were developed to target specific
molecules or cellular processes on or within the malignant
cell. It is likely this heterogeneous group of compounds will

grow considerably, as much research is being undertaken in

tumour biology and defining targets. The agents discussed

here include tyrosine kinase inhibitors (TKIs) (e.g. imatinib,

gefitinibanderlotinib), multi-targeted TKIs (sorafenib,suni-

tinib), proteasome inhibitors (bortezomib) and histone

deacetylase inhibitors (vorinostat). Several of these drugs

have yet to be licensed in the UK or Europe, but it is important

to be aware of them as they are important advances in what

had, until recently, been a rather static area of therapeutics.

TYROSINE KINASE INHIBITORS (TKIS)

Tyrosine kinases are critical components of many signal trans-

duction pathways. They signal from the cell membrane or

cytoplasm to the nucleus-modulating DNA synthesis and gene

transcription. There are approximately 500 protein tyrosine

kinases coded in the human genome. They are classified

into tyrosine kinases, serine-threonine kinases and tyrosine-

serine-threonine kinases. The tyrosine kinases are further sub-

divided into non-receptor tyrosine kinases and receptor

tyrosine kinases. Abnormal activity of tyrosine kinases was

found in many cancers and this has proven a useful drug target

(Figure 48.8).

NON-RECEPTOR TYROSINE KINASE INHIBITORS

(CYTOPLASMIC TKIS)

IMATINIB

Uses

Imatinib mesylate is primarily used to treat Philadelphia-

positive chronic myeloid leukaemia (CML) and gastro-intestinal

stromal tumours (GIST). It is administered orally on a daily

basis. Initial response rates are high, but after 12 months of ther-

apy about 90% of CML patients develop drug-resistant clones.

(a) (b) (c)

O

OC

2‘CHOH

HC N

H

HO

12

13

OCOCH 3

H OCOCH 3

OH

OC

O

O

O

5‘CO

1110 9

8 7

Figure 48.7:Taxus brevifolia(a, b), the source of paclitaxel. The chemical structure is shown in panel (c). ((a) Source: Pacific Yew (Taxus
brevifolia) O’Daniel Tigner, Canadian Forest Tree Essences, provided courtesy of Tree Canada Foundation. (b) © Natural History Museum,
London. Reproduced with permission.)