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Max Summerhayes, PhD, MRPharmS, is scientific advisor
at Roche Products Ltd
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SUMMARY
Targeted therapy is sometimes discussed as if it were a new concept
but this is clearly not the case because all cancer treatments must have
a target (known or unknown) and even “non-selective” cytotoxic
drugs must have a greater impact on malignant cells than on normal ones.
Without some degree of
selectivity, it would be impossible to destroy tumour cells without killing,
or at least causing unacceptable harm to, the patient.
In the case of conventional cytotoxic drugs, targeting is often achieved
by means of scheduling. Healthy tissues damaged by cytotoxic agents generally
recover more quickly than cancerous ones and this property is
exploited by giving pulses of chemotherapy every three to four weeks,
which allows sufficient recovery of normal tissues between doses with
the minimum possible regrowth of the tumour. Treatment scheduling is
not usually considered drug targeting, but it is vital to focus the destructive
power of chemotherapy where it is required. However, it is not the only
way in which “non-selective” cytotoxic agents are targeted.
Some have inherently greater activity than others against specific
tumour types. For example, among the platinum analogues oxaliplatin,
but not carboplatin or cisplatin, is a useful drug for treating colorectal
cancer. In addition, nephrotoxicity, although dose-limiting for cisplatin,
is not a prominent side effect of the other two drugs. Differences of
this type imply that conventional cytotoxic drugs can be, to a significant
degree, targeted to specific types of cancerous and healthy tissue.
Despite these observations, and the fact that the concept of targeted
therapy is as old as Paul Ehrlich’s quest for a “magic bullet” in
the early years of the 20th century, conventional cytotoxic drugs are
not generally
regarded as targeted therapies. This may
reflect the process that led to their development as clinical agents.
Generally, conventional cytotoxics emerged from programmes involving
the synthesis and screening of large numbers of compounds for cytotoxic
activity or the serendipitous discovery that a compound has such activity.
In other words, development was driven by the properties of the available
agents rather than a knowledge of the cancerous and healthy tissues with
which they would interact.
In recent years, however, considerable effort has been expended in exploiting
our growing knowledge of physiological and pathological processes to
design agents with properties that render
them selectively active against tumour cells. These approaches can be
divided into two main types: pharmaco-kinetic and pharmacodynamic targeting.
Full text article (PDF 80K)
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The
Pharmaceutical Journal