UMLS:C0023473 - FACTA Search

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Query: UMLS:C0023473 (chronic myeloid leukemia)
18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer cells have an increased ability to synthesize GTP (guanosine triphosphate) because of increased activity of IMP DH (inosine 5'-phosphate dehydrogenase, EC 1.1.1.205). Because IMP DH activity is rate limiting for de novo biosynthesis of GTP, this enzyme was suggested as a sensitive target for chemotherapy. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is converted in the cells into the active metabolite, TAD, (thiazole-4-carboxamide adenine dinucleotide) which potently inhibits IMP DH activity. By adding TAD to tissue extracts one can determine the extent of inhibition of IMP DH. We applied the IMP DH assay method to extracts of normal ovaries (N = 11) and epithelial ovarian carcinomas (N = 10). The IMP DH activity (mean +/- SE) in ovarian carcinoma was 21.1 +/- 5.8 which was markedly higher than that observed in normal ovaries (2.9 +/- 0.7 nmol/hr/mg protein) (P < 0.05%). The inhibition by TAD of IMP DH activity in ovarian carcinomas (N = 4) was 81%. The results indicate that IMP DH activity is elevated sevenfold in ovarian carcinomas as compared to normal ovary and can be inhibited by exposure to tiazofurin (TAD). Similar high IMP DH activity and inhibition of the activity by TAD was observed in patients with chronic granulocytic leukemia in blast crisis among whom 70 to 80% remissions were reported. Since there is increased IMP DH activity in human ovarian carcinomas and in OVCAR-5 cells and tiazofurin and TAD inhibit IMP DH activity of these cells and the proliferation of human ovarian carcinoma xenografts in the mouse, tiazofurin may merit serious consideration for a Phase II trial for patients with recurrent/refractory epithelial ovarian carcinoma.
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PMID:Inhibition by tiazofurin of inosine 5'-phosphate dehydrogenase (IMP DH) activity in extracts of ovarian carcinomas. 135 69

Tiazofurin is an oncolytic nucleoside analog that has shown therapeutic activity in end-stage acute non-lymphocytic leukemia and in chronic granulocytic leukemia in blast crisis. Tiazofurin is anabolized to the active metabolite, TAD, which inhibits IMP dehydrogenase activity, leading to a reduction in guanylate pools and to the cessation of neoplastic cell proliferation. The drug exhibits potent cytostatic and cytotoxic activity against hepatoma 3924A cells in culture. In growth-inhibition and clonogenic assays, the 50% inhibitory concentration of tiazofurin was 3.8 and 4.2 microM, respectively. Dipyridamole, an inhibitor of nucleoside transport, curtails the salvage of nucleosides and bases for nucleotide biosynthesis. Dipyridamole exhibited cytotoxicity against hepatoma 3924A cells, with an LC50 of 24 microM and an IC50 of 29 microM being recorded. A combination of tiazofurin and dipyridamole provided synergistic cytotoxicity in hepatoma 3924A cells in culture. This synergistic activity was dependent on the order of addition of the drugs. Simultaneous addition of the two drugs produced antagonism, whereas preincubation of cells with tiazofurin or dipyridamole followed by addition of the second drug resulted in synergy. TAD concentrations were significantly higher (129% and 135%) in cells that had been pretreated with tiazofurin or dipyridamole before the addition of the second agent as compared with cells that had been treated simultaneously (113%). These studies indicate the importance of the order of the addition of drugs to obtain a synergistic response in combination chemotherapy and suggest the need for a careful selection of drug modulation in clinical trials of tiazofurin and dipyridamole.
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PMID:Schedule-dependent synergistic action of tiazofurin and dipyridamole on hepatoma 3924A cells. 145 Dec 38

Tiazofurin, 2-beta-D-ribofuranosylthiazole-4-carboxamide, is cytotoxic to murine and human tumor cells. In earlier Phase-I/-II trials performed in other centers in patients with solid tumors, the drug was given mainly as a 10-min bolus or as a continuous i.v. infusion for 5 days. These protocols were associated with serious side effects, including neurotoxicity, pleuropericarditis, and occasional myelosuppression. In our study, 26 patients with end-stage leukemia were treated with tiazofurin with 1-hr daily i.v. infusions, resulting in lower incidence and less severity of side effects. In this group, 7 attained complete remission and 7 showed hematologic responses. Out of 12 evaluable patients with myeloid blast crisis of chronic granulocytic leukemia, 10 (83%) responded to therapy, with 6 attaining complete response. We present pharmacokinetic parameters of our clinical study and examine some of the reasons for the lower toxicity found in our trials. In leukemic patients during and after infusion at doses of 1,100, 2,200 and 3,300 mg/m2 tiazofurin peak plasma concentrations were 245, 441 and 736 microM, respectively, values one-half of those calculated from other reports with a 10-min bolus administration. In our 1-hr infusion method, biphasic pharmacokinetics were noted with alpha t1/2 and beta t1/2 of 0.5 and 6.2 hr, and tiazofurin was eliminated at a faster rate than in previous trials with continuous infusion. The area under the curve with our 1-hr infusion was 52% of that reported for the same dose given by continuous infusion. Our 1-hr infusion method and prompt and effective treatment of side effects enabled us to administer higher doses and larger total amounts of tiazofurin in longer treatment cycles than in any previous trials elsewhere. Tiazofurin therapy using 1-hr infusion may be feasible for other carefully selected types of malignancies.
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PMID:Clinical pharmacokinetic study of tiazofurin administered as a 1-hour infusion. 156 87

The increased activity in cancer cells of inosine 5'-monophosphate dehydrogenase (IMP DH, EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, was suggested as a sensitive target for chemotherapy. Tiazofurin (NSC 286193), through its conversion to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), is a strong inhibitor of IMP DH. In our clinical trial, tiazofurin caused return to the chronic phase in patients with chronic granulocytic leukemia in blast crisis (Tricot, G.; Jayaram, H.N.; Weber, G.; Hoffman, R. Tiazofurin: Biological effects and clinical uses. Int. J. Cell Cloning 8:161-170; 1990). In K562 human leukemic cells, tiazofurin down-regulated the expression of c-Ki-ras and c-myc oncogenes, which was followed by induced differentiation. We now report down-regulation by tiazofurin of the c-Ki-ras oncogene in a patient with chronic granulocytic leukemia in blast crisis. A single tiazofurin infusion (2,200 mg/m2) on days one and two decreased IMP dehydrogenase activity (the apparent t1/2 was 30 min), GTP concentration (the apparent t1/2 was 6 hr), and expression of ras (the apparent t1/2 was 8 hr) and c-myc (the apparent t1/2 was 38.5 hr) oncogenes in the leukemic cells. No further tiazofurin was given, because on days three and four the chemotherapeutic impact became evident in a tumor-lysis syndrome and the blast cells were cleared from the periphery by day five. The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis.
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PMID:Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient. 170 12

An overview was presented of our approach of inhibition of de novo and salvage pathways in pyrimidine and purine metabolism. 1. Combination of acivicin, an inhibitor of de novo biosynthesis, and dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in hepatoma and colon carcinoma cells. 2. AZT, a competitive inhibitor of the salvage enzyme, thymidine kinase, and 5-FU or MTX provided synergistic cytotoxicity in hepatoma 3924A. In human colon carcinoma HT-29 cells AZT and methotrexate yielded synergistic cytotoxicity and thymidine and hypoxanthine together provided protection from the action of these drugs. 3. These observations are significant because in rat hepatoma 3924A and in human cell lines HT-29, HL-60 and K562 thymidine kinase activity was 16- to 67-fold higher than that of dTMP synthase. Therefore, inhibition of dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. In leukemic patients treated with tiazofurin, an inhibitor of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, and with allopurinol, which inhibits GPRT activity through raising plasma hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in IMP dehydrogenase activity and GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by tiazofurin through the decrease of GTP concentration has now been shown in K562, HL-60 and hepatoma cells and in patients with chronic granulocytic leukemia in blast crisis. Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. In 27 consecutive patients 50% responded positively to tiazofurin treatment. From this group, 10 out of 12 patients (83%) with chronic granulocytic leukemia in blast crisis responded to tiazofurin treatment.
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PMID:Regulation of de novo and salvage pathways in chemotherapy. 187 99

Tiazofurin is an oncolytic agent which has shown therapeutic activity in end-stage acute nonlymphocytic leukemia (ANLL) and blast crisis of chronic granulocytic leukemia (CGL-BC). Tiazofurin is anabolized to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), which inhibits IMP dehydrogenase activity, leading to reduction of guanylate pools and cessation of cancer cell proliferation. The concentration of TAD in neoplastic cells of patients treated with tiazofurin should be a good indicator of sensitivity to the drug and also might herald the emergence of drug-resistant cells. Therefore, the precise quantitation of TAD in cancer cells during tiazofurin treatment is essential. In this paper we report a highly sensitive method for the determination of TAD in biological samples. With this technique, in addition to TAD, thirteen other biologically relevant adenine, guanine, cytosine and uridine nucleotides can be separated and quantitated accurately. TAD standard was separated on a Waters Partisil 10-SAX column in a RCM-10 module using an ammonium phosphate buffer system. TAD eluted at 21 min with a limit of detection of 15 pmol and linearity up to 3 nmol. The coefficient of variation was 0.6 +/- 0.1% for retention time and 2 +/- 0.3% for TAD concentration. Recovery of TAD was 96% with reproducibility of 98%. To examine the applicability of this method to a clinical setting, blood samples were obtained from a patient with CGL-BC and leukocytes were separated on a Ficoll-Hypaq gradient, extracted with trichloroacetic acid, and an aliquot was analyzed on HPLC. The TAD peak was identified by comparing the retention time and spectral analysis of the standard. After the patient was treated with a 2200 mg/m2 (12.7 mM) dose of tiazofurin, the TAD concentrations in the mononuclear cells at 2, 6, and 24 hr were 23.1, 13.6, and 0.8 microM. TAD levels at 2, 6, and 24 hr after a tiazofurin dose of 3300 mg/m2 (21.1 mM) were 42.8, 26.1, and 1.4 microM respectively.
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PMID:Determination of thiazole-4-carboxamide adenine dinucleotide (TAD) levels in mononuclear cells of leukemic patients treated with tiazofurin. 198 37

Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation.
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PMID:New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA. 206 23

Inosine 5'-phosphate dehydrogenase (IMPDH) activity is increased in all cancer cells. It is the rate-limiting enzyme of guanosine triphosphate (GTP) biosynthesis, and therefore, a sensitive target of chemotherapy. Tiazofurin selectively blocks IMPDH activity. Tiazofurin was found to have an antiproliferative effect on tumor cells in vitro and in the murine system. Based on these findings, Phase I trials were started elsewhere in patients with solid tumors, but were discontinued because of toxicity. In leukemic patients, we were able to demonstrate a good correlation between biochemical parameters (i.e., decline in IMPDH activity and GTP concentrations in blast cells) and clinical response. The most consistent responses to therapy were seen in patients with myeloid blast crisis of chronic myeloid leukemia. Severe toxicity was seen in the earlier patients in the study. However, better patient selection, limitation of treatment duration and earlier recognition and treatment of complications have now made it possible to administer tiazofurin without undue toxicity.
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PMID:Tiazofurin: biological effects and clinical uses. 218 14

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), a selective inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, provided in end stage leukemic patients a rapid decrease of IMP dehydrogenase activity and GTP concentration in the blast cells and a subsequent decline in blast cell count. Sixteen consecutive patients with end stage acute nonlymphocytic leukemia or myeloid blast crisis of chronic granulocytic leukemia were treated with tiazofurin. Allopurinol was also given to inhibit xanthine oxidase activity to decrease uric acid excretion and to elevate the serum concentration of hypoxanthine, which should competitively inhibit the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the salvage enzyme of guanylate synthesis. Assays of IMP dehydrogenase activity and GTP concentration in leukemic cells provided a method to monitor the impact of tiazofurin and allopurinol and to adjust the drug doses. In this group of patients with poor prognosis, five attained a complete hematological remission and one showed a hematological improvement. A marked antileukemic effect was seen in two other patients. All five evaluable patients with myeloid blast crisis of chronic granulocytic leukemia reentered the chronic phase of their disease. Five patients with acute nonlymphocytic leukemia were refractory to tiazofurin and three were unevaluable for hematological effect because of early severe complications. Responses with intermittent 5- to 15-day courses of tiazofurin lasted 3-10 months. Tiazofurin had a clear antiproliferative effect, but the pattern of hematological response indicated that it appeared to induce differentiation of leukemic cells. In spite of toxicity with severe or life-threatening complications in 11 of 16 patients, tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational, biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy.
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PMID:Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity. 256 8

Several new cytostatic drugs have entered clinical Phase I-II studies for treatment of leukemia: most promising are pyrimidine analogues such as 5-Azacytosine arabinoside, 5-Aza-2-deoxycytidine, 5-Azacytidine, cyclocytidine, and 2'-2'-difluorodeoxycytidine. They act on different biochemical levels towards DNA-synthesis. Fludarabine is a purin analogue and seems very active in treating CLL. Tiazofurin is an antimetabolite counter-acting nicotinic acid with most promising activity in CML blast crisis. Other substances include deoxycoformycin, an adenosine analogue for treatment of T-cell neoplasias, 1, 25-dihydroxy vitamin D 3 as differentiation inducer, and homoharringtonine, an alkylating agent widely used for treating de novo AML in China. New anthracyclines are THP-adriamycin, fluoroadriamycin, and 4-demethoxydaunorubicin. Amsacrine (mAMSA) finally, is a synthetic aminoacridine with DNA-intercalating properties. The intact acridine ring appears essential for antitumor activity. The plasma clearance of both total amsacrine and unchanged parent species is biphasic. There is a considerable influence of hepatic and renal impairment on plasma clearance. Clinical toxicities include marked myelosuppression, gastrointestinal symptomes, phlebitis, mucocutaneous lesions, occasionally alopecia and neurotoxities. It is a very active drug, particularly in treating AML. Studies using mAMSA alone or in combination revealed comparable results to the anthracyclines. The E.O.R.T.C. Leukemia Cooperative Group has used successfully mAMSA in several trials: relapsed and refractory AML, intensive maintenance treatment during first remission in AML, and, still on-going, during intensive consolidation randomized against BMT in AML-patients under the age of 45 years, and randomized against standard consolidation between the age of 45 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New drugs in the treatment of acute and chronic leukaemia: current role of mAMSA. 269 2

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