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

The semicarbazones, thiosemicarbazones and acetyl-hydrazones of phthalimide, o-benzosulfimide, naphthalimide and diphenimide demonstrated potent cytotoxicity against murine and human leukemia cell growth and cultured cell growth from human solid tumors. The major site of inhibition in L1210 leukemia cells was DNA synthesis after 60 min incubated with the agents at 25, 50 and 100 microM. De novo synthesis of purines at the regulatory enzyme sites of PRPP amidotransferase and IMP dehydrogenase were the major targets of the agent. Thymidylate synthetase, dihydrofolate reductase and ribonucleoside reductase activities were inhibited by the agents in a manner which would contribute to the overall reduction of DNA synthesis and cell death. d(NTP) pools were significantly reduced and the evidence suggests that the agents interacted with DNA affording DNA strand scission which would interfere with both template utilization by the polymerases and also ultimately reduce nucleic acid synthesis.
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PMID:Cytotoxicity of imides-N-alkyl semicarbazones, thiosemicarbazones, acetylhydrazones and related derivatives. 775 77

We report our experience giving aerosolized pentamidine as prophylaxis for Pneumocystis carinii pneumonia (PCP) to 9 children (mean age, 7.33 years; range 3-17 years) with leukemia who were unable to tolerate trimethoprim-sulfamethoxazole (TMP-SMX) due to allergy or myelosuppression. The dose of pentamidine was modified for each child to correct for weight and approximate alveolar ventilation. We were able to administer the drug to younger children by using a cushioned face mask in place of the standard mouthpiece. One child experienced moderate coughing with administration of pentamidine. He and four others with a past medical history suggestive of reactive airways disease were pretreated with inhaled albuterol. No other adverse effects were noted. Treatment lasted an average of 8.11 +/- 4.1 months per child; no case of PCP occurred. We conclude that aerosolized pentamidine can be administered to even very young children and may be of benefit to all immunosuppressed children unable to use TMP-SMX prophylaxis. The adjusted dose used here appears to be safe, but further studies regarding drug delivery and efficacy are needed.
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PMID:The use of aerosolized pentamidine for prophylaxis of Pneumocystis carinii pneumonia in children with leukemia. 783 21

To verify a recently developed in vitro tumor chemosensitivity assay (TCA) based on adenosine triphosphate (ATP) measurement for detection of methotrexate (MTX) sensitivity or resistance in human leukemias and solid tumors in which the antifol is indicated, we investigated the ability of the assay to discriminate between sensitivity and resistance to this antifolate in human leukemia cell lines sensitive (parental CCRF-CEM/S) and resistant (CCRF-CEM/E, CCRF-CEM/T and CCRF-CEM/P sublines) to MTX by virtue of known biochemical mechanisms. Correlation experiments with a standard cell growth inhibition assay and a radiometric method for measurement of thymidylate (dTMP) synthesis ([5-3H]-2'-deoxyuridine tritium release assay) were performed. No significant differences were observed in the IC50 values for the four cell lines tested as determined by cell growth evaluation (cell number counts) and the ATP-TCA after a 72 h MTX exposure. After short-term (4 h) high-dose MTX exposure, no significant correlation between ATP-TCA and the classic [5-3H]-2'-deoxyuridine tritium release assay was observed in both CCRF-CEM/S and CCRF-CEM/P cells. CCRF-CEM/T and CCRF-CEM/E displayed, instead, complete resistance with both methods. When using conditions proposed for clinical application (long-term exposure, i.e. 144 h) the ATP-TCA permitted the identification of cell lines highly resistant to MTX (CCRF-CEM/F and CCRF-CEM/E), while intermediate MTX resistance due to altered polyglutamylation was not detectable. Detection of this kind of resistance was obtained, as expected, using a short-term exposure (4 h) to MTX followed by a long-term efflux (72 h) in drug-free medium. On the basis of these results, ATP-TCA appears to be a suitable method for the evaluation of cytotoxicity induced by MTX.
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PMID:Evaluation of methotrexate sensitivity in human leukemia cell lines by an adenosine triphosphate bioluminescence assay. 939 21

The role of photoproduct structure, 3' --> 5' exonuclease activity, and processivity on polynucleotide synthesis past photoproducts of thymidylyl-(3' --> 5')-thymidine was investigated. Both Moloney murine leukemia virus reverse transcriptase and 3' --> 5' exonuclease-deficient (exo-) Vent polymerase were blocked by all photoproducts, whereas Taq polymerase could slowly bypass the cis-syn dimer. T7 RNA polymerase was able to bypass all the photoproducts in the order cis-syn > Dewar > (6-4) > trans-syn-II. Klenow fragment could not bypass any of the photoproducts, but an exo- mutant could bypass the cis-syn dimer to a greater extent than the others. Likewise T7 DNA polymerase, composed of the T7 gene 5 protein and Escherichia coli thioredoxin, was blocked by all the photoproducts, but the exo- mutant Sequenase 2.0 was able to bypass them all in the order cis-syn > Dewar > trans-syn-II > (6-4). No bypass occurred with an exo- gene 5 protein in the absence of the thioredoxin processivity factor. Bypass of the cis-syn and trans-syn-II products by Sequenase 2.0 was essentially non-mutagenic, whereas about 20% dTMP was inserted opposite the 5'-T of the Dewar photoproduct. A mechanism involving a transient abasic site is proposed to account for the preferential incorporation of dAMP opposite the 3'-T of the photoproducts.
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PMID:The ability of a variety of polymerases to synthesize past site-specific cis-syn, trans-syn-II, (6-4), and Dewar photoproducts of thymidylyl-(3'-->5')-thymidine. 970 33

Methotrexate (MTX) is not cytotoxic to patient-derived acute lymphoblastic leukemia (ALL) cells in total-cell-kill assays, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, putatively due to the rescue effects of hypoxanthine and thymidine released from dying cells. This was mimicked by a diminished methotrexate (MTX) cytotoxicity for the cell lines HL60 and U937 in the presence of hypoxanthine, thymidine, or lysed ALL cells. However, enzymatic depletion or inhibition of nucleoside membrane transport did not result in MTX dose-dependent cytotoxicity in patient samples. Alternatively, a thymidylate synthase inhibition assay (TSIA), based on inhibition of the TS-catalyzed conversion of 3H-dUMP to dTMP and 3H2O, correlated with the MTT assay for antifolate sensitivity in four human leukemia cell lines with different modes of MTX resistance. For 86 ALL patient samples, TSI50 values after 21 hours exposure to MTX were not different between T- and c/preB-ALL (P =.46). After 3 hours incubation with MTX followed by an 18-hour drug-free period, T-ALL samples were 3.4-fold more resistant to MTX compared with c/preB-ALL samples (P =.001) reflecting the clinical differences in MTX sensitivity. TSI50 values correlated with MTX accumulation (r = -.58, P <.001). In conclusion, the TSIA, but not the MTT assay, can measure dose-response curves for MTX in patient-derived ALL cells and showed relative MTX resistance in T-ALL compared with c/preB-ALL.
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PMID:Differential methotrexate resistance in childhood T- versus common/preB-acute lymphoblastic leukemia can be measured by an in situ thymidylate synthase inhibition assay, but not by the MTT assay. 992 Aug 57

4-Hydroxyproline di- and tri-peptides and N-cbz-hydroxypropyl- glycinamides were observed to be potent cytotoxic agents against the growth of suspended single cells, L-1210, Tmolt3, and HeLa-S3. The agents were not as potent against the growth of cultured solid tumor cells. Selected derivatives were investigated for their mode of action in Tmolt3 leukemia cells. The compounds selectively inhibited DNA synthesis at 50 and 100 microM. The target site of action of the agents appeared to be the purine de novo pathway with marked inhibition of the activities of the two regulatory enzymes of the pathway, i.e. PRPP amido-transferase and IMP dehydrogenase. d[NTP] pools were reduced by the agents consistent with their overall reduction of DNA synthesis. Other marginally inhibited targets of the agents were r-RNA polymerase and TMP-kinase activities. The DNA molecule itself did not appear to be a target of these agents.
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PMID:Substituted 4-hydroxyproline di- and tri-peptides as cytotoxic agents. 1007 36

Convenient procedures are described for the synthesis of 5-substituted N(4)-hydroxy-2'-deoxycytidines 5a,b,d-h via transformation of the respective 5-substituted 3', 5'-di-O-acetyl-2'-deoxyuridines 1a-c,e-h. These procedures involved site-specific triazolation or N-methylimidazolation at position C(4), followed by hydroxylamination and deblocking with MeOH-NH(3). Nucleosides 5a,b,d-h were selectively converted to the corresponding 5'-monophosphates 6a,b,d-h with the aid of the wheat shoot phosphotransferase system. Conformation of each nucleoside in D(2)O solution, deduced from (1)H NMR spectra and confirmed by molecular mechanics calculations, showed the pentose ring to exist predominantly in the conformation S (C-2'-endo) and the N(4)-OH group as the cis rotamer. Cell growth inhibition was studied with two L5178Y murine leukemia cell lines, parental and 5-fluoro-2'-deoxyuridine (FdUrd)-resistant, the latter 70-fold less sensitive toward FdUrd than the former. With FdUrd-resistant L5178Y cells, 5-fluoro-N(4)-hydroxy-2'-deoxycytidine (5e) caused almost 3-fold stronger growth inhibition than FdUrd; 5e was only some 3-fold weaker growth inhibitor of the resistant cells than of the parental cells. Thymidylate synthase inhibition was studied with two forms of the enzyme differing in sensitivities toward 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), isolated from parental and FdUrd-resistant L1210 cell lines. All N(4)-hydroxy-dCMP (6a,b,d-h) and dUMP analogues studied were competitive vs dUMP inhibitors of the enzyme. Analogues 6b,d-h and 5-hydroxymethyl-dUMP, similar to N(4)-hydroxy-dCMP (6a) and FdUMP, were also N(5), N(10)-methylenetetrahydrofolate-dependent, hence mechanism-based, slow-binding inhibitors. 5-Chloro-dUMP, 5-bromo-dUMP, and 5-iodo-dUMP, similar to dTMP, did not cause a time-dependent inactivation of the enzyme. Instead, they behaved as classic inhibitors of tritium release from [5-(3)H]dUMP. 5-Bromo-dUMP and 5-iodo-dUMP showed substrate activity independent of N(5), N(10)-methylenetetrahydrofolate in the thymidylate synthase-catalyzed dehalogenation reaction. The =N-OH substituent of the pyrimidine C(4) prevented the enzyme-catalyzed release from the C(5) of Br(-) and I(-) (the same shown previously for H(+)). While FdUMP and 6a showed a higher affinity and greater inactivation power with the parental cell than FdUrd-resistant cell enzyme, an opposite relationship could be seen with 5-hydroxymethyl-dUMP.
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PMID:5-Substituted N(4)-hydroxy-2'-deoxycytidines and their 5'-monophosphates: synthesis, conformation, interaction with tumor thymidylate synthase, and in vitro antitumor activity. 1110 56

Antifolates are the oldest of the antimetabolite class of anticancer agents and were one of the first modern anticancer drugs. The first clinically useful antifolate, described in 1947, was 2,4-diamino-pteroylglutamate (4-amino-folic acid; aminopterin; AMT) which yielded the first-ever remissions in childhood leukemia. AMT was soon superseded by its 10-methyl congener, methotrexate (MTX), based on toxicity considerations; MTX remains, with one limited exception, the only antifolate anticancer agent in clinical use to this date. Because of the safety and utility of MTX, considerable effort has been invested in attempting to design more therapeutically selective antifolates or antifolates with a wider tumor spectrum. Initially, the design was based on the burgeoning knowledge of folate-dependent pathways and the determinants of the mechanism of action of MTX. These determinants include transport, the tight-binding inhibition of its target (the folate-dependent enzyme dihydrofolate reductase (DHFR)), and metabolism of MTX to poly-gamma-glutamate (Glu(n)) metabolites. These early studies led to the development of other antifolate DHFR inhibitors of two types: (1). "classical" analogs that use the same cellular transport systems as MTX and are also metabolized to Glu(n); and (2). "nonclassical" (i.e., lipophilic) analogs that do not require transport systems and that are not metabolized to Glu(n). Although several of these analogs have undergone clinical trial, none is proved superior to MTX. Detailed examination of the mechanisms of cytotoxicity and selectivity of MTX showed that inhibition of both dTMP synthesis and de novo purine synthesis, secondary to DHFR inhibition, led to DNA synthesis inhibition and subsequent cell death; inhibition of other folate-dependent pathways did not appear necessary for cell death. Further studies showed that the contribution of inhibition of dTMP or purine synthesis to cell death varied in different cell types. These data suggested that inhibition of one of these pathways individually might (at least in some cases) be therapeutically superior to the dual inhibition induced by MTX. Thus in rational design and in structure-based design studies, two new classes of antifolate enzyme inhibitors were elaborated-direct inhibitors of thymidylate synthase (TMPS) and direct inhibitors of one or both of the two folate-dependent enzymes of de novo purine synthesis. Members of each class included both classical and nonclassical types. After preclinical evaluation, several of these have moved into clinical trials. To date only one new TMPS inhibitor has successfully completed clinical trials and been approved for routine use; this drug, Tomudex (D1694, raltitrexed) is currently approved only in Europe and only for the treatment of colon cancer. This still represents a step forward for antifolates, however, since MTX is well-known to be ineffective in colon cancer; thus Tomudex extends the tumor range of antifolates. Antifolate development continues. Based on the immense body of knowledge now extant on antifolates, specific aspects of the mechanism of action have been the focus. Newer antifolates have been described that inhibit more than one pathway in folate metabolism, that have improved delivery, or that inhibit other targets in folate metabolism. These new analogs are in various stages of preclinical and clinical development.
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PMID:Anticancer antifolates: current status and future directions. 1452 44

Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) is a serious opportunistic infection in children and adolescents with cancer. It was the most common cause of death among children receiving chemotherapy prior to the inclusion of PCP prophylaxis as part of standard care for children with leukemia. The incidence of PCP has decreased significantly since initiation of prophylaxis; however, breakthrough cases continue to occur. Hematologic malignancies, brain tumors necessitating prolonged corticosteroid therapy, hematopoietic stem cell transplantation, prolonged neutropenia, and lymphopenia are the most important risk factors for PCP in children not infected with HIV. Of children with leukemia, 15-20% may develop PCP in the absence of prophylaxis. Infection with P. jiroveci occurs early in life in most individuals. However, clinically apparent disease occurs almost exclusively in immunocompromised persons. Dyspnea, cough, hypoxia, and fever are the most common presenting symptoms of PCP. Chest radiography and high-resolution CT scans of the chest demonstrate a characteristic ground-glass pattern. Induced sputum analysis and bronchoalveolar lavage are the diagnostic procedures of choice. Gomori's methenamine-silver stain, Geimsa or Wright's stain, and monoclonal immunofluorescent antibody stains are most commonly used to make a diagnosis. However, identification of P. jiroveci DNA using polymerase chain reaction assays in bronchoalveolar lavage fluid is more sensitive. Trimethoprim-sulfamethoxazole (TMP-SMZ; cotrimoxazole) is the recommended drug for the treatment of PCP. Patients who are intolerant of TMP-SMZ or who have not responded to treatment after 5-7 days of therapy with TMP-SMZ should be treated with pentamidine. A short course of corticosteroids is recommended for moderate to severe cases of PCP within the first 72 hours after diagnosis. Mutations in the dihydropteroate synthetase gene may confer resistance to TMP-SMZ; however, the clinical relevance of these mutations is not well established. TMP-SMZ is the most commonly used agent for prophylaxis. Myelosuppression is the most important adverse effect of TMP-SMZ and the most frequent cause for choosing alternative prophylactic agents in children undergoing chemotherapy. Alternative agents for chemoprophylaxis include dapsone, aerosolized pentamidine, and atovaquone. Alternative prophylactic agents must be used in patients developing myelosuppression secondary to TMP-SMZ or dapsone.
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PMID:Management of Pneumocystis jiroveci pneumonia in children receiving chemotherapy. 1792 2

The present study demonstrates photoinduced generation of superoxide radical anion and singlet oxygen upon UVA irradiation of ethyl 1,4-dihydro-8-nitro-4-oxoquinoline-3-carboxylate (DNQC), and its cytotoxic/phototoxic effects on murine leukemia L1210 cells. The formation of reactive oxygen species (ROS) was investigated by EPR spectroscopy using in situ spin trapping technique and 4-hydroxy-2,2,6,6-piperidine (TMP) for singlet oxygen ((1)O(2)) detection. The EPR spectra monitored upon photoexcitation of aerated solutions of DNQC in dimethylsulfoxide evidenced the efficient activation of molecular oxygen via Types I and II mechanisms. The cytotoxic/phototoxic effects of DNQC, analysis of cell cycle, induction of apoptosis/necrosis, DNA damage and molecular mechanism of apoptotic death of L1210 cells in dark and in the presence of UVA irradiation were compared. DNQC induced a different cytotoxic/phototoxic effect, which was concentration- and time-dependent. The four highest tested concentrations of non-photoactivated and photoactivated DNQC induced immediate cytotoxic/phototoxic effect after 24h cultivation of L1210 cells. This effect decreased with the time of treatment. The irradiation increased the sensitivity of leukemia cell line on DNQC, but the cell sensitivity decreased with time of processing. Quinolone derivative DNQC significantly induced direct DNA strand breaks in L1210 cells, which were increased with the irradiation of cells. The DNA damage generated by DNQC alone/with combination of UVA irradiation induced cell arrest in G(0)/G(1) and G(2)/M phases, decrease in the number of L1210 cells in Sphase and apoptotic cell death of certain part of cell population after 24 h of influence. DNQC alone/with combination of UVA irradiation induced apoptosis in L1210 cells through ROS-dependent mitochondrial pathway.
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PMID:Photochemical and phototoxic properties of ethyl 1,4-dihydro-8-nitro-4-oxoquinoline-3-carboxylate, a new quinoline derivative. 2096 43


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