Conventional antileukemic
chemotherapy in relapsed or refractory acute
leukemia or myeloid
blast crisis of
chronic granulocytic leukemia (CGL) is not curative and remissions, if attained, are usually of short duration. The primary goal of antileukemic
therapy in these patients should be the identification of agents that are more selective and better targeted in their action.
Tiazofurin is known to inhibit
inosine 5'-phosphate
dehydrogenase (IMPDH), the rate limiting
enzyme of de novo
guanine ribonucleotide synthesis. The activity of this
enzyme is markedly increased in leukemic cells. To prevent de novo
GTP synthesis, it is also necessary to block the
guanine-salvaging activity of
hypoxanthine-guanine phosphoribosyltransferase (
HGPRT). This was achieved by increasing the plasma levels of
hypoxanthine through the administration of
allopurinol. Twenty-seven patients with end stage
leukemia or myeloid
blast crisis of CGL were treated with
tiazofurin. Assays of IMPDH activity and
GTP concentrations in leukemic cells, as well as
hypoxanthine levels in the serum, provided a method to monitor the impact of
tiazofurin/
allopurinol therapy and to adjust
drug doses. In these poor prognosis patients seven attained a complete response (CR), 3 had a hematologic improvement and an antileukemic effect was seen in 4. An excellent correlation was observed between biochemical and clinical activity of
tiazofurin/
allopurinol, with biochemical responses preceding clinical results. However, clinical responses were usually short-lived with IMPDH activity starting to increase soon after discontinuation of
therapy, but patients responding again after reinstitution.
Tiazofurin therapy was generally well tolerated in patients with less than 15 days of treatment and no other major medical complications. Although an antiproliferative effect was observed in some patients, bone marrows remained cellular in most cases with a marked shift from blasts to granulocytes. Severe
neutropenia was absent in the majority of cases and patients could be discharged in good clinical condition immediately after completion of
therapy.
Tiazofurin/
allopurinol therapy provided a rational, biochemically targeted and biochemically monitored approach to the treatment of poor prognosis
leukemia and should serve as a paradigm in
enzyme pattern-targeted
chemotherapy.