tiazofurin and Leukemia

Topics: Antimetabolites, Antineoplastic; Deoxyguanine Nucleotides; Guanosine Triphosphate; Humans; IMP Dehydrogenase; Inosine Monophosphate; Leukemia; Neoplasms; Purines; Ribavirin; Signal Transduction

In cancer cells, particularly in leukaemic cells, guanylate biosynthesis is up-regulated as shown by the increased activities of IMP dehydrogenase, the rate-limiting enzyme of de novo GTP biosynthesis, and of the salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In enzyme pattern-targeted chemotherapy, tiazofurin inhibits IMP dehydrogenase activity in cancer cells and allopurinol-induced high serum hypoxanthine levels inhibit HGPRT activity. A triad of responses was observed in the blast cells of patients treated with tiazofurin infusions: chemotherapy, induced differentiation, and down-regulation of c-Ki-ras and c-myc oncogenes. Tiazofurin was synergistic in cytotoxicity and in causing differentiation with ribavirin, retinoic acid, and gemcitabine [corrected]. Induced differentiation plays an important role in the overall impact of antipurine agents.

Topics: Animals; Antimetabolites, Antineoplastic; Cell Differentiation; Deoxycytidine; Gemcitabine; Humans; Leukemia; Oncogenes; Ribavirin

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.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Humans; Leukemia; Pyrimidines; Ribavirin; Thymidine Kinase; Thymidylate Synthase; Zidovudine

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.

Topics: Antineoplastic Agents; Drug Evaluation; Humans; IMP Dehydrogenase; Leukemia; Ribavirin; Ribonucleosides

New light was thrown on the action of tiazofurin in the treatment of end-stage leukemic patients and in leukemic cells in tissue culture. 1. In a population of 21 consecutive patients 50% responded to tiazofurin treatment, confirming the usefulness of this therapy in end-stage leukemia. 2. In leukemic patients treated with tiazofurin and allopurinol reciprocal action was manifested in the increase in hypoxanthine and the decrease in uric acid concentrations in the plasma. On discontinuation of allopurinol, hypoxanthine levels steeply declined but uric acid concentration increased slowly, taking days to reach pretreatment level. 3. With a new and sensitive method the concentration of the active metabolite of tiazofurin, TAD, was measured in the mononuclear cells of tiazofurin-treated patients. Approximately 5 to 13% of the plasma tiazofurin level was observed as TAD in the mononuclear cells. This TAD concentration was sufficient to account for the inhibition of IMP DH in these cells. 4. Tiazofurin or retinoic acid caused differentiation of HL-60 leukemic cells and inhibition of cell proliferation. 5. By treating leukemic cells incubated with tiazofurin or retinoic acid also with guanosine it was elucidated that the mechanism of the two drugs differed since only the tiazofurin effects were counteracted by guanosine. 6. Tiazofurin and retinoic acid together in HL-60 cells provided synergistic impact on differentiation and cytotoxicity. 7. Tiazofurin resulted in down-regulation of the expression of ras and myc oncogenes in three systems: K562 human erythroleukemic cells, rat hepatoma 3924A cells and human HL-60 leukemia cells. 8. Because both tiazofurin and retinoic acid are licensed drugs, their potential use in combination chemotherapy may have clinical relevance in the treatment of end-stage leukemia where our earlier studies have demonstrated the usefulness of tiazofurin.

Topics: Animals; Antineoplastic Agents; Cell Line; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Leukemia; Oncogenes; Proto-Oncogenes; Ribavirin; Ribonucleosides; Tretinoin; Tumor Cells, Cultured

Methotrexate (MTX) followed by 6-mercaptopurine (6MP) is one of the best known combinations for the treatment of childhood acute lymphoblastic leukaemia. Tiazofurin (TF) and 6-thioguanine (TG) are also used as chemotherapy agents in the treatment of malignancies. We have examined the induction of apoptosis by combinations of these drugs to gain more insights into their efficacy in the treatment of malignancies.. The induction of apoptosis was examined in Molt-4, a human malignant acute lymphoblastic T-cell line. The cells were exposed to increasing drug concentrations at various exposure times. Annexin V/FITC and propidium iodide (PI) were used as markers for apoptosis and cell death. Annexin V/FITC positive and PI positive cells were detected by flow-cytometric analysis.. Sequential 24-h exposure with MTX (0.005-0.02 micro mol) followed by 6MP (1-10 micro mol) and 24-h exposure with TF (5-20 micro mol) followed by TG (0.5-2 micro mol) showed a more than additive induction of apoptosis compared with single-drug exposure. Simultaneous administration of the drugs does not show an additive effect on apoptosis.. The results of this study indicate that sequential administration of MTX before 6MP and of TF before TG may be essential for therapeutic success in the treatment of leukaemia.

Topics: Annexin A5; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Survival; Child; Coloring Agents; Humans; Leukemia; Mercaptopurine; Methotrexate; Models, Biological; Purines; Ribavirin; Thioguanine; Time Factors; Tumor Cells, Cultured

Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC(50) = 0.7 microM and IC(50) = 0.1 microM, respectively) as potently as mycophenolic acid (IC(50) = 0.3 microM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.

Topics: Adenine Nucleotides; Antineoplastic Agents; Cell Differentiation; Diphosphonates; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Isoenzymes; K562 Cells; Leukemia; Mycophenolic Acid; Structure-Activity Relationship

Topics: Animals; Antineoplastic Agents; Apoptosis; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Down-Regulation; Guanosine Triphosphate; History, 20th Century; Humans; Ischemia; Kidney Neoplasms; Leukemia; Models, Biological; Neoplasms; Ribavirin; Signal Transduction; Time Factors; Tumor Cells, Cultured

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), an oncolytic drug, inhibits IMP DH (inosine 5'-monophosphate dehydrogenase, EC 1.1.1.205), reduces signal transduction activity and IP3 (inositol 1,4,5-trisphosphate) concentration and arrests the cell cycle chiefly in S phase. Genistein (4',5,7-trihydroxyisoflavone), an inhibitor of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase, EC 2.7.1.68), tyrosine kinase and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both drugs, as single agents, induce differentiation. Since tiazofurin and genistein attack different enzymic targets and arrest the cell cycle at different phases and they each induce differentiation, we tested the hypothesis that tiazofurin might be synergistic with genistein in inducing differentiation. Human leukemic K-562 cells were grown in suspension culture and were seeded in 24-well culture plates. In growth inhibition assays for tiazofurin and genistein IC50s (drug concentration that inhibits 50% of cell proliferation) were 7 and 37 microM, respectively. For tiazofurin and genistein the concentrations of drug that induce differentiation in 50% of the cells were 35 and 45 microM, respectively. Various combinations of these two drugs were tested. Since tiazofurin decreased GTP concentration in cells by 50% at 12 hr after administration, genistein (10 to 30 microM) was added 12 hr after tiazofurin (5 to 15 microM). Synergistic action on differentiation was obtained from all tiazofurin and genistein combinations and in most combinations on growth inhibition. The percent of differentiating cells induced by genistein (10 microM) and tiazofurin (10 microM) as single agents increased 1.1- and 2.8-fold, respectively, of the control values. The two drugs together caused 5.9-fold elevation in inducing differentiation. Similar action was observed on inhibition of proliferation.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Cell Differentiation; Cell Survival; Culture Media; Drug Synergism; Genistein; Humans; Leukemia; Ribavirin; Signal Transduction; Tumor Cells, Cultured

The synthesis and biological activity of selenophenfurin (5-beta-D-ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of selenazofurin, are described. Glycosylation of ethyl selenophene-3-carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5-glycosylated regioisomers, as a mixture of alpha- and beta-anomers, and the beta-2,5-diglycosylated derivative. Deprotected ethyl 5-beta-D-ribofuranosylselenophene-3-carboxylate (12 beta) was converted into selenophenfurin by ammonolysis. The structure of 12 beta was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent decrease in GTP levels (58%). The results obtained confirm the hypothesis that the presence of heteroatoms such as S or Se in the heterocycle in position 2 with respect to the glycosidic bond is essential for both cytotoxicity and IMP dehydrogenase inhibitory activity in this type of C-nucleosides.

Topics: Animals; Antineoplastic Agents; Cell Division; Computer Simulation; Crystallography, X-Ray; Enzyme Inhibitors; Guanosine Triphosphate; Humans; IMP Dehydrogenase; Inosine Monophosphate; Leukemia; Lymphoma; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Molecular Structure; Neoplasms; Organoselenium Compounds; Ribavirin; Ribonucleosides; Tumor Cells, Cultured

Previous reports have established the synthesis of interleukin-6 (IL-6) and IL-6 receptors (IL-6R) in several human leukemia cells and found that IL-6 and the IL-6R could be expressed in cell lines with erythroid/megakaryocytic features. IL-6 is a pleiotropic cytokine involved in megakaryocytic differentiation. The finding that endogenous IL-6 levels in serum increased after 5-fluorouracil (5-FU) treatment suggests that IL-6 may play some role in the recovery of hematopoietic systems. This observation may assist the understanding of erythroid regeneration caused by antineoplastic agents such as tiazofurin. Tiazofurin inhibits the activity of IMP dehydrogenase. Its exposure to K562 cells at 10 microM tiazofurin stimulates erythroid differentiation. Stimulation of cells with tiazofurin gave a significant increase in IL-6 production. Its levels were quadrupled after 2 days of culture. Tiazofurin also caused a trivial reduction in the percentage of cells with the IL-6R. This evidence implies that tiazofurin produced no significant effect on the IL-6R. Tiazofurin also increased the percentage of benzidine-positive cells representing hemoglobin production, confirmed by GpA expression. We concluded that IL-6 is rate limiting in regard to hemoglobin production and that IL-3 could be used for clinical benefit to stimulate erythropoiesis and synergize with tiazofurin.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Hemoglobins; Humans; Interleukin-6; Leukemia; Ribavirin; Tumor Cells, Cultured

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.

Topics: Adenine Nucleotides; Antineoplastic Agents; Chromatography, High Pressure Liquid; Guanosine Triphosphate; Humans; Leukemia; Monocytes; Reproducibility of Results; Ribavirin; Sensitivity and Specificity

Tiazofurin was demonstrated to be an effective inhibitor of the growth of human cultured blast cells, and the high specific activities of IMP dehydrogenase (EC 1.1.1.205) were observed in all the cell extracts tested. IMP dehydrogenase has been purified to homogeneity from MOLT 4F human T-lymphoblast, and the Km values for IMP and NAD were 29 and 54 microM, respectively. The inhibitory mechanisms of thiazole-4-carboxamide adenine dinucleotide (TAD) and ribavirin 5'-monophosphate (RMP), the active forms of the antimetabolites tiazofurin and ribavirin, were investigated on the purified enzyme. RMP inhibits competitively with respect to IMP as well as XMP, and the inhibition by TAD was similar to that by NADH, which was uncompetitive with NAD. However, the Ki values of RMP (0.58 microM) and TAD (0.075 microM) were several orders of magnitude lower than those of XMP (85 microM) and NADH (94 microM). Thus, the drugs interact with the two distinct sites of IMP dehydrogenase with much higher affinities than the natural substrates and products. Preincubation of the purified enzyme with RMP enhanced its inhibitory effect in a time-dependent manner, and the enhancement was further increased by the addition of TAD. The combination of tiazofurin and ribavirin exerted a synergistic effect on the growth inhibition in MOLT 4F cells.

Topics: Adenine Nucleotides; Antimetabolites, Antineoplastic; Cell Division; Cell Line; Humans; IMP Dehydrogenase; Inosine Monophosphate; Ketone Oxidoreductases; Kinetics; Leukemia; NAD; Ribavirin; Ribonucleosides

Some of the current critical issues in the tiazofurin treatment of end-stage leukemia were presented and discussed. 1. Tiazofurin infusions (daily X 10 to 15) provided remissions in 50% of end-stage leukemic patients. The remissions, of 1 to 10 months' duration, varied from antileukemic effect or hematologic improvement to complete response and complete remission. The total survival of the responding patients was from about 1 to 15 months. 2. Our administration of tiazofurin in a 60-min infusion by pump decreased the incidence and severity of toxicity. 3. It was shown that tiazofurin dose does not need to be escalated at each relapse. Depending on the biochemical and hematological response in this novel protocol, 2,200 to 4,400 mg/m2 tiazofurin appeared to be sufficient to provide remissions. 4. A new role was identified for allopurinol, originally given to decrease uric acid in the plasma. Allopurinol markedly increased plasma hypoxanthine concentrations which competitively inhibited the activity of the salvage enzyme, guanine phosphoribosyltransferase, in the blast cells. Thus, the elevated hypoxanthine plasma levels inhibited guanine salvage. To maintain high hypoxanthine levels allopurinol (100 mg) was given every 4 to 6 hr. This provided combination chemotherapy with tiazofurin which inhibited IMP dehydrogenase activity and blocked the de novo biosynthesis of guanylates in the blast cells. 5. Preliminary evidence was obtained in the patients that tiazofurin induced differentiation of the bone marrow. Recent studies also showed that tiazofurin down-regulated the expression of the c-Ki-ras oncogene in K562 erythroleukemic cells. Therefore, tiazofurin treatment provides an impact by chemotherapy, induced differentiation, and, if applicable, through down-regulation of the ras oncogene. 6. Novel aspects of tiazofurin treatment include rational targeting and a continuously monitored trial by measurement of the activity of IMP dehydrogenase and of GTP and TAD concentrations in blast cells and of tiazofurin and hypoxanthine in plasma. 7. Since tiazofurin has not yet achieved lasting remissions in patients nor terminal differentiation of leukemic cells it probably will be advantageous to combine tiazofurin with other drugs to provide synergism. In preclinical tissue culture studies in HL-60 cells synergy was observed with retinoic acid. This may be of interest because retinoic acid also caused differentiation and down-regulation of the myc oncogene.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Down-Regulation; Drug Interactions; Female; Genes, ras; Guanine; Humans; Hypoxanthine; Hypoxanthines; Leukemia; Liver Neoplasms, Experimental; Male; Middle Aged; Ribavirin; Ribonucleosides; Tretinoin; Tumor Cells, Cultured; Uric Acid

The hypothesis was tested that the increased IMP dehydrogenase activity in human myelocytic leukemic cells, and along with it guanylate biosynthesis, might be a sensitive target to chemotherapy by tiazofurin. 1. IMP dehydrogenase activity in normal leukocytes was 3.1 +/- 0.5 (means +/- S.E.) nmol/hr/mg protein and in leukemic cells it was elevated 15- to 41-fold. The activity of guanine phosphoribosyltransferase in normal leukocytes was 389 +/- 27 nmol/hr/mg protein and in the leukemic cells it increased 2.8- to 6.8-fold. 2. IMP dehydrogenase was purified 4,900-fold to homogeneity from rat hepatoma 3924A with a yield of 30%. The kinetic properties of the hepatoma enzyme were similar to those of the enzyme in human myelocytic leukemic blast cells because of the similarity of the Km's for IMP (23 microM), NAD (44 and 65 microM); the Ki for TAD was 0.1 microM in both enzymes. 3. There was a selectivity of the in vitro response to tiazofurin in human normal and leukemic leukocytes. When labeled tiazofurin was incubated with leukocytes from normal, healthy volunteers and from leukemic patients, the leukemic leukocytes made 20- to 30-fold more TAD and the GTP content decreased as compared to normal leukocytes. This procedure proved to be a suitable predictive test in a clinical setting because patients with positive tests responded to tiazofurin whereas those with negative ones did not. 4. The National Cancer Institute approved a chemotherapeutic phase I/II trial which concentrates on treatment of refractory acute myelocytic leukemia. Tiazofurin is infused in a 60-minute period with a pump to insure uniform delivery. A novel aspect of the trial was that it was directed primarily by the biochemical impact of tiazofurin on IMP dehydrogenase activity and GTP concentration and the tiazofurin doses were to be adjusted accordingly. Patients received allopurinol as a routine precaution against possible accumulation of uric acid in the kidney. 5. In the first eight patients, there was one complete remission, two entered the chronic phase, two entered into partial remission, one did not respond, and two were not evaluable. In the five patients who responded, there was a rapid, profound decrease in IMP dehydrogenase activity of the blast cells and a gradual decline in GTP concentrations. The blast cell count followed the decrease in the GTP concentration. The white blood cell count was largely preserved. 6. Bone marrow aspirates and peripheral blood samples showed that w

Topics: Adenine; Aged; Allopurinol; Animals; Drug Evaluation; Female; Guanine; Guanosine Triphosphate; Humans; IMP Dehydrogenase; Ketone Oxidoreductases; Leukemia; Leukemia, Myeloid, Acute; Liver Neoplasms, Experimental; Male; Middle Aged; Rats; Ribavirin; Ribonucleosides; Tumor Cells, Cultured

This study reports the selective sensitivity to tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC-286193) of human leukemic leukocytes as compared to normal ones in bone marrow and peripheral blood samples by comparing the production of the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), from labeled tiazofurin and the depression of GTP concentration. When labeled tiazofurin was incubated with leukocytes obtained from healthy volunteers or from leukemic patients (acute non-lymphocytic leukemia or acute lymphoblastic leukemia), the TAD production was 27.0 +/- 8.3, 551.3 +/- 71.8 and 755.9 +/- 94.1 pmoles/10(9) cells per hr, respectively. Thus, the leukemic cells produced over 20-fold higher concentrations of TAD than the normal leukocytes. Incubation with tiazofurin in leukemic leukocytes decreased the GTP pools (to 48-79%), whereas there was no change in the normal leukocytes. These results indicate a selectivity of response to tiazofurin in human normal and leukemic leukocytes. The procedure reported in this work may be suitable as a rapid predictive test for the sensitivity of leukemic leukocytes to tiazofurin. Such a diagnostic test should be helpful in identifying neoplastic cells sensitive to tiazofurin in the Phase II trials now being developed.

Topics: Adenine Nucleotides; Adult; Aged; Antineoplastic Agents; Female; Guanosine Triphosphate; Humans; Leukemia; Leukocytes; Male; Middle Aged; Ribavirin; Ribonucleosides