Clinical Pharmacology and Therapeutics

382 CANCER CHEMOTHERAPY
MULTI-TARGETED TKIs
Sorafenib and sunitinib are used in the USA as single oral
agents to treat advanced renal cell carcinoma.
Sorafenib increases median survival by approximately 12
months in patients with advanced refractory renal cell cancer.
It is a small molecule ATP mimetic and competitive inhibitor
of Raf kinase, the VEGF receptor tyrosine kinase and the
platelet-derived growth factor receptor (PDGFR) tyrosine
kinase. It undergoes hepatic oxidation mediated by CYP3A
and glucuronidation (UGT1A1). Adverse effects include skin
rash, hand–foot skin reactions, diarrhoea, hypertension and
bleeding.
Sunitinib doubled the survival time of imatinib-resistant
GIST tumours and improved survival in advanced renal cell
cancer. It is a small molecule ATP mimetic and competitive
inhibitor of signalling through multiple tyrosine receptor
kinases, including platelet-derived growth factor receptor and
vascular endothelial growth factor receptor. These kinases are
important in angiogenesis. It is metabolized by CYP3A.
Adverse effects include diarrhoea, hypertension, skin discoloration,
mucositis, fatigue and hypothyroidism. Less frequently,
neutropenia, thrombocytopenia and decreases in left
ventricular ejection fraction have been noted.
PROTEASOME INHIBITORS
Bortezomib is the first member of this class. It is effective in
treating refractory multiple myeloma. It is a reversible competitive
inhibitor of the proteolytic function of the chymotrypsinlike
activity of the 20S core subunit of the proteasome. The
proteasome can be considered the cellular ‘garbage can’ for
proteins. Proteins once ubiquitinated are destined to be
degraded by the proteasome and exit the proteasome as small
peptides. Proteasome inhibition affects a number of cellular
functions, but a major effect is to disable IκB degradation. IκB
binds to NF-κB and prevents this transcription factor moving
to the nucleus, silencing NF-κB-mediated gene transcription.
Additonally, proteasome inhibition disrupts the homeostasis
of key regulatory proteins (p21, p27 and p53) involved in cell
cycle progression and proliferation. Bortezomib is administered
intravenously. It undergoes hepatic metabolism via
CYP3A and CYP2D6. Adverse effects include thrombocytopenia,
fatigue, peripheral neuropathy, neutropenia, gastrointestinal
disturbances.
HISTONE DEACETYLASE INHIBITORS
Vorinostat (suberoylanilide hydroxamic acid, SAHA) is effective
against refractory cutaneous T-cell lymphoma, producing
a 30% response rate with a median response of 168 days.
Many tumour cells overexpress histone deacetylase enzymes
which deacetylate histones. Vorinostat inhibits these enzymes,
blocking the transcription of genes involved in cell cycle progression.
Vorinostat is administered orally. It undergoes
hepatic glucuronidation and oxidation. Adverse effects include
gastro-intestinal disturbances, fatigue, hyperglycaemia, hyperlipidaemia,
bone marrow suppression (anaemia, thrombocytopenia
and neutropenia) and pulmonary embolism.
ANTI-BCL-2 OLIGONUCLEOTIDE
Oblimersen is under review by the FDA as an ‘orphan drug’
for chronic lymphocytic leukaemia. It is an oligonucleotide
that binds mRNA for the anti-apoptotic protein Bcl-2 and
causes it to be degraded, thus promoting apoptosis in cells
overexpressing Bcl-2.
MONOCLONAL ANTIBODIES
Cancer cells express a range of proteins that are suitable targets
for monoclonal antibodies. The development of monoclonal
antibodies against specific antigens (targets) has been
facilitated by advances in hybridoma technology (i.e. immunizing
mice with human tumour cells and screening the
hybridomas for antibodies of interest). Because murine antimouse
antibodies have a short half-life and induce human
anti-mouse antibody immune response, they are usually
chimerized or humanized for therapeutic use (Chapter 16).
The nomenclature for therapeutic monoclonal antibodies is to
have the suffix ‘-ximab’ for chimeric antibodies and ‘-umab’
for humanized antibodies. Trastuzumab, one of the first
agents demonstrated to have clinical benefit in cancer therapy,
is discussed below. Other monoclonal antibodies that are used
therapeutically in cancer are detailed in Table 48.10. All are
administered intravenously.
Figure 48.9 shows an example of the 3D structure of a monoclonal
antibody.
TRASTUZUMAB
Uses
Trastuzumab is a humanized monoclonal antibody (molecular
weight approximately 100 kDa) that is used as a single agent or
in combinations (e.g. with paclitaxel) to treat metastatic breast
cancer that over-expresses the target-HER2/neu (Erb-2, i.e.
EGFR-1) – about 30% of such cancers do this.
Mechanism of action
This monoclonal antibody binds tightly to the Her-2/Neu
(Erb-B2) glycoprotein, a member of the epidermal growth factor
family of cellular receptors (EGFR). EGFR encodes its own
tyrosine kinase which, upon receptor–ligand binding, normally
autophosphorylates the receptor causing downstream
signalling which increases proliferation, metastatic potential
and evasion of apoptosis. Trastuzumab binding inhibits such
downstream signalling of the EGFR receptor.
Adverse effects
These include the following:
• infusion reactions involving fever, chills, nausea,
dyspnoea, rashes;