Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to convert the bone-marrow population from Philadelphia-chromosome (Ph-1) positivt to partially or wholly Ph-1 negative, thioguanine was used as primary therapy in seven patients with chronic granulocytic leukaemia (C.G.L.). Although eight episodes of neutropenia were induced, prolonged remission or conversion to Ph-1-negativity was not achieved in any patient. However, thioguanine was at least as effective as busulphan for initial therapy in C.G.L., and had the advantage of rapid reversibility of haemopoietic depression when discontinued. Thioguanine merits further evaluation as an agent for the management of C.G.L. in its chronic phase.
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PMID:Thioguanine as primary treatment for chronic granulocytic leukaemia. 4 57

No more than 150 cases of neonatal leukemia had been reported in the literature. Seven additional cases are reported herein. The incidence of neonatal leukemia has been of one in 50,000. Its incidence among the group of neonates requiring hospitalization has been of 0.075%. The seven neonates with leukemia consist of five males and two females. Two of them had an associated Down's syndrome. Abdominal distension, hepatomegaly, splenomegaly, cutaneous manifestations and purpura were the most frequent clinical findings in our patients. Severe anemia was present in only three patients. Thrombocytopenia was recognized in six of them. A high white blood cell count was present in five patients. The number of blast cells in their peripheral blood smear ranged between 16 and 100%. A remarkable myeloid dominance was observed. One patient died two hours after birth and his diagnosis was made at autopsy. Three patients were diagnosed before the age of three weeks. The three patients with myeloid leukemia were treated with DNR and Ara-C. A complete hematological remission was achieved in two of them. One patient died of a Pn. carinii pneumonia one month after the remission was induced. The remainder patient of this group had a Down's syndrome and the leukemia had been confirmed by hepatic biopsy. After two years of maintenance with Ara-C and Thioguanine he is alive and both, peripheral blood and bone marrow, remains normal. A lymphocitic leukemia was seen in only two patients. One was treated with prednisolone and VCR, and the other with prednisolone, VR and L-Asp. In both cases a good response to the chemotherapy was observed. Autopsy was performed in all patients who died but one. The pathological findings are analyzed. The low survival among patients with neonatal leukemia may be influenced by the toxic side effects of the used chemotherapy. All aspects of the medical treatment including drugs of choice and the usefullness of isolation devices are further discussed.
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PMID:[Neonatal leukemia. Report of seven cases (author's transl)]. 106 63

The results of four consecutive trials designed by the GIMEMA group for the treatment of ANLL in elderly patients are reviewed. Complete remission (CR) has been achieved in 20.8% of patients older than 60 years treated with 5-day courses of ARA-C plus thioguanine, in 22.7% of patients treated with high dose ARA-C (HDARAC) plus Asparaginase, in 39.5% of patients aged 55 to 80 receiving either Idarubicin or Daunorubicin in combination with Cytarabine in a standard 3+7 protocol and in 51% of patients older than 60 years treated with intermediate dose ARA-A (IDARAC) plus Mitoxantrone. From 1988, patients ineligible for aggressive chemotherapy entered a study of palliative treatment with Thioguanine and ARA-C. This 18 year GIMEMA experience showed that: CR can be obtained only with regimens producing marrow aplasia, the inclusion of anthracyclines or Mitoxantrone improves the CR rate, without prohibitive toxicity, haematological toxicity is very high in elderly patients and account for the most frequent cause of treatment failure namely death in aplasia, palliative treatment does not improve the quality of life and prolongs median survival only slightly. When comparing the results of these trials, it appears that in the GIMEMA group the capability of offering effective treatment to elderly patients with ANLL has continuously improved and that IDARAC plus Mitoxantrone is so far the most active and best tolerated regimen. Death in aplasia remains a major problem and future trials will be aimed at exploiting the possibility of reducing the haematological toxicity by using recombinant colony stimulating factors.
Leukemia 1992
PMID:Treatment of acute non lymphoid leukemia (ANLL) in elderly patients. The GIMEMA experience. 157 48

6-Thioguanine (TG) incorporation into DNA has been associated with cytotoxicity and DNA damage in Chinese hamster ovary (CHO) and murine leukemia L1210 cells. According to alkaline elution analysis, single-strand breaks (SSB) occur in both cell types. DNA-protein and interstrand crosslinks are prominent features of TG effects in L1210, CEM, and HL-60 but not CHO cells. To assess which DNA strand experiences SSB in CHO cells, the cells were synchronized by growth to confluence (late G1, S). The cells were then diluted into fresh medium so that they underwent a round of division during a subsequent 16-hr interval. They were treated with TG during this first cell cycle, and mitotic cells were harvested at the end of the first cycle using colcemid. SSB were determined in parental DNA (radiolabeled with thymidine during growth to confluence), TG-containing DNA (radiolabeled with [14C]TG during drug exposure), and daughter DNA (labeled with thymidine during the second cell cycle). SSB occurred in TG-containing DNA late in the second cell cycle after drug exposure and in the DNA synthesized from a TG-DNA template (daughter DNA). This observation is consistent with the known delayed cytotoxicity and chromosomal aberrations seen in CHO cells. The SSB suggest relatively normal elongation of DNA containing TG but altered synthesis and/or ligation from a TG-DNA template. This premise was tested in synchronized CHO cells. The DNA strand incorporating TG elongated naturally; however, DNA elongation was impaired in the cell cycle following TG treatment. The results are consistent with SSB in daughter DNA synthesized from a TG-DNA template due to inability to elongate the newly-synthesized strand.
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PMID:Characterization of the DNA damage in 6-thioguanine-treated cells. 239 Jan 3

91 patients with acute nonlymphoblastic leukemia (ANLL) were treated with Homoharringtonine, Cytosine arabinnoside, Thioguanine (HAT) and/or Daunorubicin, (Adriamycin) Cytosine arabinnoside, Thioguanine D(A) AT protocols. The total CR rate was 68.1% with a median remission duration of 20.3 months, and the expectant survival rate in 5 years (Kaplan-Meier method) was 39%. The CR rate and the CR duration projected by HAT and D (A) AT protocols were very similar. After 20 prognostic factors from both clinical and laboratory examinations prior to treatment had been analysed, we concluded that (1) The CR rate was improved by increasing the dose of induction chemotherapy; (2) The patients might have longer remission and survival if they obtained remission in 2 courses of treatment; (3) The remission durations were comparable between the individuals receiving and not receiving maintenance chemotherapy.
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PMID:[Analysis of the therapeutic efficacy and prognostic factors of intensive chemotherapy in 91 patients with acute nonlymphoblastic leukemia]. 240 Nov 66

Most drugs available for cancer chemotherapy exert their effects through cytodestruction. Although significant advances have been attained with these cytotoxic agents in several malignant diseases, response is often accompanied by significant morbidity and many common malignant tumours respond poorly to existing cytotoxic therapy. Development of chemotherapeutic agents with non-cytodestructive actions appears desirable. Considerable evidence exists which indicates that (a) the malignant state is not irreversible and represents a disease of altered maturation, and (b) some experimental tumour systems can be induced by chemical agents to differentiate to mature end-stage cells with no proliferative potential. Thus, it is conceivable that therapeutic agents can be developed which convert cancer cells to benign forms. To study the phenomenon of blocked maturation, squamous carcinoma SqCC/Y1 cells were employed in culture. Using this system it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.
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PMID:The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach. 389 54

Schmid et al. (Cancer Treat. Rep., 60: 23-27, 1976) reported rapid emergence of resistance of L1210 leukemia cells in mice to two schedules of six antimetabolites and much slower development of resistance to a third schedule. Such rapid development of resistance to six drugs presents a striking puzzle, and one whose solution gives some insights into the basis for general emergence of drug resistance. Our approach was to examine the consequences of applying these drugs singly or in pairs and, from the results, to infer interactions in six-drug combinations. 6-Thioguanine (TG) and 6-mercaptopurine are the key drugs since, as shown by Schmid et al., resistance of leukemic cells appeared to six-drug combinations at the same time as did resistance to the purine analogs; sensitivity to the other drugs remained. We demonstrated that cells which emerged were resistant to both of the purine analogs, owing to a deficiency of the activating enzyme hypoxanthine-guanine phosphoribosyltransferase. TG resistance arose in the presence of TG because of an overgrowth of TG-resistance mutants that were present as one cell in 10(4) in the original L1210 population. L1210 cultures were prepared free of TG-resistant mutants. With these cells, TG administered shortly after inoculation was very effective in delaying their death. The cells that finally grew out were still TG sensitive. Simultaneous treatment with all the drugs greatly delayed appearance of TG resistance in vivo and in vitro. Methotrexate alone was responsible for this result, owing to its ability preferentially to kill TG-resistant cells. The other three drugs were not effective in delaying TG resistance. Methotrexate was effective only if it was added daily; one large injection was ineffective. Therefore, TG and methotrexate added daily for 6 days (simultaneous schedule) was the most effective drug regimen tested.
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PMID:Basis of observed resistance of L1210 leukemia in mice: methotrexate, 6-thioguanine, 6-methylmercaptopurine riboside, 6-mercaptopurine, 5-fluorouracil, and 1-beta-D-arabinofuranosylcytosine administered in different combinations. 719 6

6-Thioguanine (6-TG) was administered as a continuous i.v. infusion for 7 days to 24 patients with relapsed or refractory acute leukemia or in the blast phase of chronic granulocytic leukemia. The daily dose of 6-TG was escalated from 37.5 mg/m2 to 160 mg/m2. Stomatitis was dose-related and dose-limiting with a maximum tolerated dose of 120 mg/m2 daily. Cutaneous reactions were dose-related but not dose-limiting. The recommended dose for phase II trials in acute leukemia is 120 mg/m2 per day as a continuous infusion for 7 days. There were two complete and four partial remissions among all patients. At the suggested phase II dose of 120 mg/m2 there were two complete remissions and one partial remission in five evaluable patients.
Leukemia 1995 May
PMID:Phase I study of continuous infusion 6-thioguanine in patients with acute leukemia. 776 38

The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug-at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL). Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy. Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered. In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.
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PMID:Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia? 831 12

6-Thioguanine (6-TG) therapy in childhood acute lymphoblastic leukaemia results in chronic hepatotoxicity and portal hypertension. We report follow-up data in a cohort of 10 children with acute lymphoblastic leukaemia and 6-TG-related hepatotoxicity described initially in 2006. Clinically significant portal hypertension was present in the majority of patients several years after cessation of 6-TG treatment. These data reflect the natural history of noncirrhotic portal hypertension and emphasises the need to incorporate ongoing surveillance in the transition arrangement to adult services in this select group of patients.
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PMID:Long-term follow-up of children with 6-thioguanine-related chronic hepatoxicity following treatment for acute lymphoblastic leukaemia. 2170 7


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