A Textbook of Clinical Pharmacology and Therapeutics

●Introduction 367

●Pathophysiology of neoplastic cell growth 367

●Cytotoxic therapy: general principles 367

●Resistance to cytotoxic drugs 369

●Common complications of cancer chemotherapy 369

●Drugs used in cancer chemotherapy 371

CHAPTER 48

48 Cancer chemotherapy

cells, neoplastic cells are immortal and do not have a pro-

grammed finite number of cell divisions before they become

senescent. The element of cell replication responsible for this

programme is the telomere, located at the end of each chromo-

some. Telomeres pair and align at mitosis. Telomeres are pro-

duced and maintained by telomerase in germ cells and

embryonic cells. Telomerase loses its function in the course of

normal cell development and differentiation. In healthy somatic

cells, a component of the telomere is lost with each cell division,

and such telomeric shortening functions as an intrinsic cellular

clock. Approximately 95% of cancer cells re-express telomerase,

allowing them to proliferate endlessly.

Many drugs used to treat cancer interfere with synthesis of

DNA and/or RNA, or the synthesis and/or function of cell cycle

regulatory molecules, resulting in cell death (due to direct cyto-

toxicity or to programmed cell death – apoptosis) or inhibition of

cell proliferation. These drug effects are not confined to malig-

nant cells, and many anti-cancer agents are also toxic to normal

dividing cells, particularly those in the bone marrow, gastro-

intestinal tract, gonads, skin and hair follicles. The newest, so-

called ‘molecularly targeted’, anti-cancer agents target ligands or

receptors or pivotal molecules in signal transduction pathways

involved in cell proliferation, angiogenesis or apoptosis.

Key points

Principal properties of neoplastic cells

• Abnormal growth with self-sufficient growth signalling
  and insensitivity to anti-growth signals


• Immortalization


• Invasion and metastasis


• Evasion of apoptosis


• Sustained angiogenesis


• DNA instability.

CYTOTOXIC THERAPY: GENERAL PRINCIPLES

The number of cytotoxic drugs available has expanded rapidly

and their cellular and biochemical effects are now better defined,

facilitating rational drug combinations. This has been crucial in

INTRODUCTION

In 2004, there were approximately 153 000 deaths from cancer in
the UK. Malignant disease needs a multidisciplinary approach.
In addition to surgery, radiotherapy and chemotherapy, atten-
tion to psychiatric and social factors is also essential. Accurate
staging is important and where disease remains localized cure,
using surgery or radiotherapy, may be possible. In some cases,
chemotherapy is given following surgery in the knowledge that
widespread microscopic dissemination almost certainly has
occurred (this is termed ‘adjuvant chemotherapy’). If the
tumour is widespread at presentation, systemic chemotherapy
is more likely to be effective than radiotherapy or surgery,
although these may be used to control local disease or reduce
the tumour burden before potentially curative chemotherapy.

PATHOPHYSIOLOGY OF NEOPLASTIC CELL

GROWTH

Clones of neoplastic cells expand, invade adjacent tissue and
metastasize via the bloodstream or lymphatics. Pathogenesis
depends on both environmental (e.g. exposure to carcinogens)
and genetic factors which derange the molecular mechanisms
that control cell proliferation. The hallmarks of a malignant cell
are autonomous growth signalling coupled with insensitivity to
anti-growth signals, immortalization, invasion and metastasis,
evasion of apoptosis, sustained angiogenesis and DNA instabil-
ity. In approximately 50% of human cancers, genetic mutations
contribute to the neoplastic transformation. Some cancer cells
overexpress oncogenes (first identified in viruses that caused
sarcomas in poultry). Oncogenes encode growth factors and
mitogenic factors that regulate cell cycle progression and cell
growth. Alternatively, neoplastic cells may overexpress growth
factor receptors, or underexpress proteins (e.g. wild-type p53
and the retinoblastoma protein-Rb) coded by tumour suppressor
genes that inhibit cellular proliferation. The overall effect of such
genetic and environmental factors is to shift the normal balance
to dysregulated cell proliferation. Unlike normal adult somatic