Clinical Evaluation of a New Antimetabolite, 6-Mercaptopurine, in the Treatment of Leukemia and Allied Diseases

Abstract

1. A new antimetabolite, 6-mercaptopurine, has been shown to produce good clinical and hematologic remissions in fifteen out of forty-five children with acute leukemia. Another ten showed partial remissions and clinical improvement. 2. Remissions in adults with acute leukemia have occasionally been brought about by 6-mercaptopurine, and in a few cases it has produced temporary remissions in both the early and the late stages of chronic myelocytic leukemia. 3. The compound has been effective in some children whose disease was resistant to the folic acid antagonists, as shown by the fact that out of twenty-four children with acute leukemia whose disease had been proved to be resistant to amethopterin, five had good clinical and hematologic remissions and five had partial remissions with some marrow and clinical improvement. Some benefit was seen in eight out of eighteen patients whose disease was resistant to ACTH and cortisone. 4. In children the daily oral administration of 2.5 mg./Kg. rarely caused toxic manifestations, but continued therapy at this dose in adults or at higher levels in children occasionally produced bone marrow depression or gastrointestinal symptoms. 5. There is evidence that the therapeutic resistance of the acute leukemias to 6MP develops somewhat more rapidly than it does to the folic acid antagonists but there is, as yet, no laboratory or clinical evidence of cross resistance between these two types of antimetabolites. 6. In a total of thirty-five patients with lymphomas and miscellaneous carcinomas and sarcomas, 6MP did not produce any definite clinical improvement at doses which produced hematologic toxicity. 7. Although 6-mercaptopurine acts as a purine antagonist in certain forms of bacteria, the exact mechanism of its action in leukemia is at present unknown. Since its mode of action appears to differ from that of other agents previously employed clinically in the treatment of leukemia, this compound would appear to be of fundamental as well as practical interest.

Part VIII. Folic acid antagonists

“…138 Since the time of the clinical introduction of folic antagonists, 6-mercaptopurine has been found to be an effective drug, even in patients in whom acute leukemia is unresponsive or no longer responsive to folic acid antagonists. 139 A concurrent controlled study of these two compounds was undertaken to assess in man some of the chemotherapeutic principles that have been developed in animals with responsive tumors.…”

Symposium on the experimental pharmacology and clinical use of anti metabolites

“…The usual starting dose is 2.5 mg. per kilogram per day in both children and adults. 16 In patients with leukemia, this dose is continued for 4 weeks and then increased to 5 mg. per kilogram if no clinical improvement or definite evidence of leukocyte depression has occurred.…”

“…Although the results in the treatment of acute leukemia in adults with purine analogues have not been as impressive as in children, these drugs were the first agents to produce remissions in the older age group (over 40) with some regularity. 16 Because of this fact and because of the relatively long remissions occasionally obtained, 6MP, 6CP, or TG is the initial agent of choice in treating these adults whenever pOSSible. (In children who are not acutely ill, one of these purine analogues or amethopterin is equally effective.…”

Pharmacokinetics of two 6‐mercaptopurine liquid formulations in children with acute lymphoblastic leukemia

“…6-Mercaptopurine (6-MP) was first used in pediatric cancer Abbreviations: ALL, acute lymphoblastic leukemia; AUC, area under the curve; BA, bioavailability; FDA, Food and Drug Administration; 6-MP, 6-mercaptopurine; PK, pharmacokinetics; TGN, thioguanine nucleotide; TPMT, thiopurine methyltransferase in 1953. 2 The antileukemic effect of 6-MP occurs via its antagonism to the synthesis of purines critical for DNA and RNA synthesis. 3 As a single agent, 6-MP was able to induce disease remission in some children with leukemia, something that had rarely been achieved before its introduction.…”

“…3 As a single agent, 6-MP was able to induce disease remission in some children with leukemia, something that had rarely been achieved before its introduction. 2 Today, oral 6-MP remains a mainstay of pediatric ALL maintenance therapy. Adherence to and proper administration of oral 6-MP during ALL maintenance therapy is associated with a decreased risk of disease relapse.…”