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)

1,2-Dihydro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-2-oxo-5-methylpyrazine 4-oxide was synthesized by condensation of the silylated pyrazine base with the blocked chloro sugar, followed by removal of the protecting groups. The compound inhibited the growth of leukemia L1210 cells in vitro by 50% at 2 x 10-7 M. At 400 mg/kg/day x 6 it increased the life-span of leukemia L1210 bearing mice by approximately 55%, without apparent toxicity to the host.
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PMID:Synthesis and antitumor activity of 1,2-dihydro-1-(2-deosy-beta-D-erythro-pentofuranosyl)-2-oxo-5-methylpyrazine 4-oxide, a structural analogue of thymidine. 32 81

5,6-Dihydro-8(7H)-quinolinone was synthesized and converted into thiosemicarbazones which could be considered to be semirigid analogues of the 2-formylpyridine thiosemicarbazone class of antitumor agents. The Z and E isomers were separated and identified by 1H NMR and UV. Although the compounds showed essentially no inhibitory activity against the enzyme alkaline phosphatase, several of these agents had demonstrable anticancer activity in mice bearing the P388 leukemia. The E-configuration analogues in general were slightly more active than their corresponding Z isomers.
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PMID:Synthesis of 5,6-dihydro-8(7H)-quinolinone thiosemicarbazones as potential antitumor agents. 33 14

2.3-Dihydro-1,3-6H-oxazine-dione ("3-oxauracil") was tested against L1210 leukemia. The compound exhibited significant growth-inhibiting effect against this tumor both in vitro and also in vivo following daily intraperitoneal application.
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PMID:Effect of "3-oxauracil" (2,3-dihydro-1,3-6H-oxazine-dione) in L1210 leukemia. 89 36

A series of 1,2-dihydro-1-oxopyrrolo[3,2,1-kl]phenothiazine, 1,2-dihydro-1-oxopyrrolo[3,2,1-kl]phenoxazine, and 1,2-dihydro-1-oxopyrrolo[3,2,1-de]acridine-2-carboxamides were prepared by reaction of 1,2-dihydro-1-oxo-pyrrolo[3,2,1-kl]phenothiazine or other corresponding phenoxazine and acridan ethyl or methyl esters with appropriate amines. Several members of this family were found to be potent, dual inhibitors of cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism and to have in vivo antiinflammatory activity in the rat foot edema assay. Structure-activity relationships within this family of compounds are described. 1,2-Dihydro-N-(2-thiazolyl)-1-oxopyrrolo[3,2,1-kl]phenothiazine-1- carboxamide (34) was found to be one of the best compounds to display potent cyclooxygenase/5-lipoxygenase inhibition of arachidonic acid metabolism. Its IC50s against the enzymes sourced from rat basophillic leukemia-1 (RBL-1) cells were 0.07 and 1.4 microM, respectively. It was active in the rat foot edema test for antiinflammatory effect (48% inhibition at 33 mg/kg po) and in the mouse phenylbenzoquinone induced writhing test for analgesic effect (93% inhibition at 32 mg/kg po).
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PMID:1,2-Dihydro-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamides and congeners, dual cyclooxygenase/5-lipoxygenase inhibitors with antiinflammatory activity. 211 51

The mechanism of action of NSC 368390 (DUP-785, 6-fluoro-2-(2'-fluoro-1, 1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt) was studied using three different approaches. First, we studied growth inhibition by DUP-785 in L1210 leukemia cells and M5 melanoma cells. The concentrations causing 50% growth inhibition after 48 hr of culture were 5.8 and 0.6 microM, respectively. DUP-785 had to be present continuously throughout culture. Growth inhibition by 25 microM DUP-785 could be prevented by addition of 1 mM uridine or orotic acid to cultures of these cell lines; in M5 cells cytidine was also able to prevent growth inhibition. Dihydro-orotic acid (DHO) and carbamyl-aspartate were not able to prevent growth inhibition by DUP-785. Second, we studied accumulation of orotic acid and of orotidine induced by incubation with 1 microM pyrazofurin, an inhibitor of the orotate phosphoribosyl-transferase-orotidine-monophosphate decarboxylase complex. Addition of DUP-785 to the culture medium prevented the orotic acid accumulation. Furthermore, DUP-785 prevented accumulation of H14CO3- into orotic acid of pyrazofurin-treated L1210 cells. Third, we measured the effect of DUP-785 on DHO-dehydrogenase (DHO-DH), since the results indicated that this enzyme was affected by DUP-785. DHO-DH was assayed in isolated rat liver mitochondria. The Km for L-DHO was about 12 microM. DUP-785 appeared to be a potent inhibitor of DHO-DH with an apparent Ki of about 0.1 microM and an apparent Ki' of about 0.8 microM. The mode of inhibition appeared to be linear mixed type. After exposure of L1210 cells to 25 microM DUP-785 for 2 hr DHO-DH was almost completely inhibited. After suspension in fresh medium without drug, DHO-DH activity was recovered to about 60% after 24 hr. In conclusion, DUP-785 is a potent inhibitor of pyrimidine de novo biosynthesis, by inhibition of the mitochondrial enzyme DHO-DH.
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PMID:Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390). 282 96

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) is an inhibitor of ribonucleotide reductase and of DNA synthesis selected for clinical trials because of its activity against L1210 leukemia variants resistant to other inhibitors of this enzyme. A phase I trial designated to allow in-depth pharmacologic evaluation has recently been completed and the clinical results and preliminary pharmacokinetic data are reported here. Each patient received IMPY by three different schedules. A single iv bolus, intermittent 5-day bolus, and 5-day continuous infusion were given at 3-week intervals. The major dose-limiting toxic effects were vomiting, rbc hemolysis, confusion, and somnolence. All toxic effects seemed to be dose- and schedule-dependent and were readily reversible. IMPY enters the cerebrospinal fluid and is highly concentrated in gastric secretions. Clearance of IMPY is impaired in the presence of hepatic insufficiency. Eighteen of 26 patients entered are evaluable for response, including one patient with colon cancer with minimal response and three patients with stable disease.
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PMID:Clinical toxic effects of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) with relevant pharmacokinetic parameters. 740 59