Substances that resemble structurally essential constituents of normal metabolic processes in the cell fall within the large number of cancer drugs known as antimetabolites. Such a compound is taken up by the cell, where it competes with the natural metabolite for its enzyme and thus blocks one or more specific biosyn-thetic pathways in the production of cellular DNA.


Methotrexate, an antimetabolite, has been most effective in treating choriocarcinoma in women and acute leukemia in children. Its chemical structure is similar to that of the natural metabolite, folic acid, and ft takes part more readily than folic acid in chemical reactions needed for normal cellular processes. In this way, DNA synthesis is inhibited.

Methotrexate is an antagonist to one of the B vitamins, folic acid, which has among its properties that of playing an important role in the production of normal white blood cells. The principal effect of methotrexate is to inhibit the activity of the enzymes that catalyze the con-version of folic acid to a compound called tetra-hydrofolic acid. This compound is a key precursor in the synthesis of the purines and pyrimidines thatare precursors of DNA. The enzymes combine more readily with methotrexate than with the natural substances folic acid and the intermediate compound in the conversion process, dihydrofolic acid; as a result DNA synthesis is inhibited.

Methotrexate is resistant to metabolic alteration in the body and is largely excreted unchanged in the urine. The compound produces its major toxic effects in normal rapidly proliferating tissues, the bone marrow, lining of the gastrointestinal tract, and hair follicles. Clinically, its most significant anticancer effects have been obtained in treatment of choriocarcinoma in women and systemic and meningeal acute leukemia in children.

6-Mercaptopurine (MP) is readily converted by susceptible cells to 6-mercaptopurine ribonucleotide, and in this form interferes in a way not yet completely understood with various mechanisms concerned with purine metabolism. The result is inhibition of DNA synthesis.

The major toxic effect of MP is bone marrow depression. Its usefulness against malignant disease is in acute lymphocytic and granulocytic (myelocytic) leukemia, chronic granulocytic leukemia, and choriocarcinoma. Preliminary clinical studies have suggested that a combination of MP and a closely related compound, 6-methylmercaptopurine riboside, has an activity against acute granulocytic leukemia greater than the effect of either agent alone, and these studies are continuing.

5-Fluorouracil (FU) and a related compound, 5-fluorodeoxyuridine (FUDR), are pyrimidine antagonists. An observation that rat liver cancers utilized the pyrimidine base, uracil, to a greater extent than normal rat liver led to the design and synthesis of these antimetabolites. FU and FUDR alter cell function by effects on RNA, and DNA synthesis; the latter is probably the more important effect. The fluorinated pyrimidines are converted in the cell to other products, of which the key compound is apparently fluorodeoxyuridine monophosphate; this inhibits the enzyme, thymidylate synthetase, and so blocks the synthesis of DNA.

Side effects of FU and the slightly less toxic FUDR are observed in normal rapidly proliferating tissue, particularly bor.e marrow and the lining of the gastrointestinal tract. Manifestation of toxicity seems to be prerequisite to an objective antitumor response. Palliative effects have been produced in patients with a variety of cancers, including those of the large bowel, breast, stomach, uterine cervix, and ovary.

Cytosine Arabinoside is a relatively new antimetabolite that inhibits DNA synthesis.

The drug depresses the bone marrow, but its toxicity is not as serious as that associated with some of the other agents that produce this effect. Clinical studies are just beginning to show the range of anticancer activity of cytosine arabinoside; to date it has been found effective in inducing remissions in acute granulocytic leukemia in adults and children, acute lymphocytic leukemia refractory to other drugs, and acute undifferentiated leukemia of childhood.