mercaptopurine and Leukemia--Lymphocytic--Chronic--B-Cell

S-allylthio-6-mercaptopurine and its ribose derivative were tested for anti-leukemic activity, using a human- mouse B-CLL model. The novel prodrugs contain two components, a purine analog, which interferes with DNA synthesis, and an S-allylthio, readily engaging in thiol-disulfide exchange reactions. The latter component targets the redox homeostasis which is more sensitive in leukemic cells, than in normal B-cells. Upon administration, the prodrug permeates cells, instantly reacts with free thiol, forming S-allyl mixed disulfides and releasing purine. Several cycles of thiol-disulfide exchange reactions occur, thus extending the duration of the prodrug effects. The concerted action of 2 components, as compared with purine alone, boosted in vitro apoptotis in B-CLL cells from 10% to 38%, and decreased in vivo engraftment of B-CLL from 30% to 0.7%.

Topics: Allyl Compounds; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; B-Lymphocytes; Cell Membrane Permeability; Disease Models, Animal; Disulfides; DNA; Drug Synergism; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mercaptopurine; Mice; Mice, Inbred ICR; Oxidation-Reduction; Prodrugs; Sulfhydryl Compounds; Sulfinic Acids

Current trends in the search for chemical compounds having an inhibitory action on the growth of malignant cells are reviewed in this article. Several agents are sufficiently promising that clinical trials with them are in progress. One of these, an aromatic nitrogen mustard (C.B. 1348), appears to be useful as an adjunctive therapeutic measure in patients with malignant lymphoma, chronic lymphocytic leukemia, and mycosis fungoides who have become refractory to other methods of treatment. The introduction of certain purine antagonists, of which 6-mercaptopurine has been given the most extensive clinical trial, has opened up a new field of experimental and clinical investigation. 6-mercaptopurine and related compounds appear to be particularly useful in the treatment of acute leukemia in adults, but they are also useful, together with the folic acid antagonists and the steroid hormones, in the management of acute leukemia in children. While at present chemotherapeutic agents currently under investigation rarely cause significant regression of inoperable primary or metastatic solid tumors, the possibility of eventual more effective control in many types of malignant disease is not as dismal as it was a decade ago.

Topics: Adult; Antineoplastic Agents; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Mercaptopurine; Mycosis Fungoides; Neoplasms