so-called antimetabolites, such as araC, an analogue of the pyrimidine bases. This incorporates into forming DNA and prevents the further addition of deoxynucleotides. Other compounds belonging to this group are

methotrexate (an analogue of folic acid) and fluoruracil (an analogue of uracil), which inhibit thymidylate synthase and dihydrofolate reductase, so depleting cells of dATP, dTTP, and dGTP. Lastly, there are compounds that interact with the tubulin cytoskeleton that arrest mitosis at the level of metaphase.

The purine pathway to chemotherapy

New drugs come to light in many different ways. Some are compounds extracted from natural sources (bacteria, fungi, sponges, plants). Some are designed. The classic examples are the antihistamine H2 antagonists, blockers of gastric acid secretion that were synthesized by James Black and his colleagues according to an entirely logical pharmacological rationale.

Many are synthesized randomly and then selected for therapeutic potential in high-throughput screening tests. Others are derivatives of synthetic compounds made for industrial purposes (dyes, for example) but found to have therapeutic activities as well.

The so-called antimetabolites had their origin in screening the therapeutic effects of industrial dyes, but it was design that turned them into useful anticancer and antiviral agents. Gerhard Dogmagk, in the 1930s, discovered that the dye prontosil rubrum had bacteriostatic effects. Its active component was later found to be sulfanilamide. In 1940, Woods and Fildes put forward the antimetabolite theory to explain its action. They suggested that proliferation of bacteria is arrested because of a lack of available nucleotides. This is

due to the inhibition of folate synthesis by sulfanilamide, a mimetic of the physiological substrate p-aminobenzoic acid (PABA).

Such findings inspired Gertrude Elion and George Hitchings to design analogues of purines and pyrimidines with the express intention of blocking nucleotide synthesis or nucleotide incorporation into nucleic acids. Such drugs could be useful in diseases that involve proliferation of some sort, such as cancer and bacterial and viral infections. Included in their rich portfolio are 6-mercaptopurine (the first antimetabolite used in the treatment of leukaemia and still applied as an immunosuppressant in its precursor form of azathioprine), trimethoprim (a bacterial dihydrofolate reductase inhibitor), and aciclovir, the first effective antiviral agent.

Good drugs and bad

The doses at which most, if not all, of the substances so far mentioned exert their therapeutic effects overlap those at which they are manifestly toxic. With a therapeutic index of about 1, these might be regarded as distinctly bad

Gerhard Domagk was awarded the Nobel Prize in Physiology or Medicine in 1939 ‘for the discovery of the antibacterial effects of prontosil’,

and Gertrude Elion and George Hitchings shared the Prize in 1988 with Sir James Black, ‘for their discoveries of important principles for drug treatment’.

bone marrow and the epithelia) to recover from the assault. The success of combination chemotherapy can be explained in part because a much smaller proportion of the cancer cells escape the treatment. They are unlikely to have resistance genes to all of the compounds employed. The onset of drug

resistance is a limiting aspect of all forms of chemotherapy (including, of course, the treatment of infectious diseases with antibiotics and antiviral compounds).

The development of resistance in cancer cells occurs in a number of ways:

•Elimination of the drug by transport proteins (P-glycoprotein).

•Expression of proteins that prevent the inhibitory action of the drug.

•Expression of enhanced amounts of DNA repair enzymes.

•Cells may have mutated target enzymes that are insensitive to the therapeutic agent.

•Cells might modify the drug and render it inoffensive.

Cancer chemotherapy does not in itself make cells resistant. Rather, it selects those pre-existing resistant cells, which, after treatment has ceased, can re-populate the host as drug-resistant clones. This is the phenomenon of relapse. Some cancer cells escape therapy because at the time of treatment they were not engaged in a proliferation cycle, or they were concealed in a hiding place and so eluded the drug. This is yet another reason why repeated treatment is advantageous.

Another aspect of success in cancer treatment is early diagnosis. If successful cancer therapy removes 99.9% of the transformed cells, then the earlier the diagnosis, the fewer surviving cells will be left behind, reducing the chance of relapse. Perhaps these few transformed cells are kept under control by the immune system.6 Another argument for early diagnosis arises from the high mutability of cancer cells (see page 306). While many of these mutations are silent, others are likely to kill the cell, but there may be a few that propel cell transformation towards a more malignant or drug-resistant phenotype.7 This chance increases with time and with the proliferation of cells. It is for this reason that screening programmes for the early detection of bowel, breast, prostate, and cervical cancers are heavily promoted.

The current forms of chemotherapy, as well as the application of newer drugs such as those described below, suffer from our insufficient knowledge of the precise identity of most tumours. Ideally, one needs to know which resistance genes and which oncogenes are expressed. There is also a lack of prognostic and predictive markers which provide patient and doctor with an early indication (weeks rather than months) of the expected success or failure of a chemotherapeutic regime. Predictive markers in particular are imperative, because, as already mentioned, time is of the essence if the treatment is to be successful.

Beyond chemotherapy, other weapons in the oncologist’s armoury include surgery, radiation, endocrine, and immunotherapy.

Combination chemotherapy can be judged a success or a failure depending on your particular viewpoint. Over the period 1971–2000, the

average 10 year survival rate for cancer of the prostate has increased from about 20% to 50%. Other forms of cancer, for example of pancreas and lung, have proved far more obstinate, showing hardly any improvement (England and Wales figures: see http://info. cancerresearchuk.org).