B Current data for incidence and survival are for the period 19972001 as reported by Ries4 Historic data for incidence is for the period 194750 as reported by Devesa122 data for 5year survival encompass 1950544

period 1950-2001, for a net increase of 85.9% from approx 253 cases to 470 cases per 100000, but 5-year survival rates improved from 35% to 65% over the same period for all cancers (Table 1). The increased incidence in the USA over time, and in developed nations, can be attributed largely to increased life expectancy in the populations. The impact of antimetabolite oncolytics is reflected in significantly improved survival rates for the indications for which these drugs are used, most notably in leukemias and lymphomas. Antimetabolites have only more recently been approved for use in solid tumors of the lung, pancreas, and colon/rectum and although survival rates for these cancers have doubled over 50 years, the rates remain low relative to leukemia and lymphoma.

7.03.2 Disease Basis

Cancers are characterized by abnormal cell proliferation, but the causes for this are myriad, even for cancers in the same tissue. Antimetabolite oncology agents work by interfering with the formation or utilization of a normal cellular metabolite. Most antimetabolites interfere with the enzymes involved in the synthesis of new DNA, are incorporated into the newly formed DNA, or in some cases both processes are important to an agent's efficacy. As a result, many antimetabolites are derivatives of the building blocks of DNA itself, such as the nucleoside based inhibitors, or analogs of critical cofactors such as the antifolates. A variety of key cellular pathways can be disrupted with antimetabolite therapy, via inhibition of the thymidine and purine nucleotide biosynthesis pathway and inhibition of ribonucleoside reductase. Given their mechanisms of action, it is not surprising that the observed benefits of antimetabolites are often accompanied by significant toxicity, due to the fact that the affected cellular metabolites are critical to both normal and cancer cells. Single antimetabolite agents can act on a single pathway, or on multiple pathways at once, but in either instance, they are often used in combination with other therapies in the clinic.

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