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)

Ion channels, activated upon IgE-Fc epsilon receptor aggregation by specific antigen, were studied in micropipet-supported lipid bilayers. These bilayers were reconstituted with purified IgE-Fc epsilon receptor complex and the intact 110-kDa channel-forming protein, both isolated from plasma membranes of rat basophilic leukemia cells (line RBL-2H3). In order to identify the current carrier through these ion channels and to determine their ion selectivity, we investigated the currents flowing through the IgE-Fc epsilon receptor gated channels in the presence of a gradient of Ca2+ ions. Thus, the solution in which the micropipet-supported bilayer was immersed contained 1.8 mM CaCl2, while the interior of the micropipet contained 0.1 microM Ca2+ (buffered with EGTA). Both solutions also contained 150 mM of a monovalent cation chloride salt (either K+ or Na+). The currents induced upon specific aggregation of the IgE (by either antigen or anti-IgE antibodies) were examined over a range of potentials imposed on the bilayer. The type of conductance event most frequently observed under the employed experimental conditions was a channel that has a slope conductance of 3 pS and a reversal potential practically identical with the calculated value for the reversal potential of calcium (134 +/- 11 mV in the presence of sodium, 125 +/- 13 mV in the presence of potassium). These results indicate that this channel is highly selective for calcium against the monovalent cations sodium and potassium. This same channel has a conductance of 4-5 pS in the presence of symmetrical solutions containing only 100 mM CaCl2 and 8 pS in the presence of 0.5 M NaCl with no calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium specificity of the antigen-induced channels in rat basophilic leukemia cells. 284 94

A novel antitumor compound, N-beta-dimethyl-aminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190) was evaluated for its antitumor activity in experimental murine tumor systems. In the initial studies with P388 leukemia (i.p.-i.p.), NC-190 led to an increase of greater than 200% in life span (ILS), and 75% of the mice were alive on day 30, when the optimal dose (50 mg/kg, days 1-5) was given. Additionally, the compound had significant activities against i.p. inoculated mouse L1210 leukemia, B16 melanoma, M5076 reticulum cell sarcoma, sarcoma 180, mouse hepatoma MH134, and rat Yoshida sarcoma and Yoshida ascites hepatoma AH130. The optimal dose resulted in a greater than 280% ILS with a 30-day survival of 50% in mice with L1210 leukemia (100 mg/kg, days 1-5), a 156% ILS in mice with B16 melanoma (50 mg/kg, days 1-5), a 98% ILS with a 90-day survival of 25% in mice with M5076 reticulum cell sarcoma (25 mg/kg, days 1, 5, 9, and 13), a greater than 300% ILS with a 60-day survival of 50% in mice with sarcoma 180 (50 mg/kg, days 3-10), a 148% ILS with a 60-day survival of 25% in mice with MH134 (25 mg/kg, days 1-5), a 129% ILS with a 60-day survival of 12.5% in rats with Yoshida sarcoma (12.5 mg/kg, day 3-10), and a greater than 161% ILS with a 60-day survival of 50% in rats with AH130 (6.3 mg/kg, days 3-10). In the experiments with s.c. inoculated tumors, NC-190 not only inhibited tumor growth, but also increased the life span of mice with Lewis lung carcinoma or B16 melanoma. The 60-day survivors accounted for 60% and 30% in mice with Lewis lung carcinoma and B16 melanoma, respectively. The compound significantly inhibited the spontaneous lung metastasis of Lewis lung carcinoma by more than 90% when eight daily i.v. injections were given. NC-190 was active by the i.p., s.c., and i.v. routes. Five consecutive daily i.p. doses (days 1-5) were more effective than a single dose (day 1), two doses (days 1 and 5), or three doses (days 1, 5, and 9). NC-190 warrants further study as a potential antineoplastic agent against human neoplasms, as it has a broad spectrum of antitumor activity and inhibits metastasis.
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PMID:In vivo activity on murine tumors of a novel antitumor compound, N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]phenazine-6-carboxamide sodium salt (NC-190). 292 70

A number of 6-substituted and 2,6-disubstituted pyrrolo[2,3-d]pyrimidine 2'-deoxyribonucleosides were prepared by the direct stereospecific sodium salt glycosylation procedure. Reaction of the sodium salt of 4-chloro-6-methyl-2-(methylthio)pyrrolo[2,3-d]pyrimidine (6a) or 4,6-dichloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (6b) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranose (9) provided the corresponding N7 2'-deoxy-beta-D-ribofuranosyl blocked derivatives (8a and 8c) which, on ammonolysis, gave 4-amino-6-methyl-2-(methylthio)-7-(2-deoxy-beta-D-erythro-pentofuranosyl )pyrrolo[2,3-d]pyrimidine (11a) and 4-amino-6-chloro-2-(methylthio)-7-(2-deoxy-beta-D-erythro-pentofuranosyl )pyrrolo[2,3-d]pyrimidine (11b), respectively. Dethiation of 11a and 11b afforded 6-methyl-2'-deoxytubercidin (10a) and 6-chloro-2'-deoxytubercidin (10b), respectively. Dehalogenation of 10b provided an alternate route to the reported 2'-deoxytubercidin (3a). Application of this glycosylation procedure to 4,6-dichloro and 4,6-dichloro-2-methyl derivatives of pyrrolo[2,3-d]pyrimidine (15a and 15b) gave the corresponding blocked 2'-deoxyribonucleosides (18a and 18b), which on ammonolysis furnished 10b and 4-amino-6-chloro-2-methyl-7-(2-deoxy-beta-D-erythro- pentofuranosyl)pyrrolo[2,3-d]pyrimidine (17), respectively. This stereospecific attachment of the 2-deoxy-beta-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C1 carbon by the anionic heterocyclic nitrogen. Controlled deacylation of 4-chloro-7-(2-deoxy-3,5-di-O-p-toluoyl-beta-D-erythro-pentofuranosyl) pyrrolo[2,3-d]pyrimidine (20a) gave 4-chloro-7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d] pyrimidine (20b). Dehalogenation of 20b gave the 2'-deoxynebularin analogue 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (19), and reaction of 20b with thiourea gave 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4(3H)- thione (21). All of these compounds were tested in vitro against certain viruses and tumor cells. Only compounds 12a, 20b, and 21 showed significant activity against measles in vitro, and the activity is comparable to that of ribavirin. Although compounds 3a and 12b are slightly more active than ribavirin against HSV-2 in vitro, they are relatively more toxic to Vero cells. Compounds 3a and 20b exhibited moderate cytostatic activity against L1210 and P388 leukemia in vitro but are considerably less active than 2-chloro-2'-deoxyadenosine (1).
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PMID:Synthesis and biological activity of certain 6-substituted and 2,6-disubstituted 2'-deoxytubercidins prepared via the stereospecific sodium salt glycosylation procedure. 299 66

A series of potential prodrug 5-halouridine 3',5'-cyclic monophosphates (5-X-cUMPs, X = F, Cl, Br, I, 1-4) has been prepared and tested for antitumor activity against murine leukemia L1210/0 and human lymphoblast Raji/0 cells and their deoxythymidine kinase deficient (TK-) counterparts, as well as for antiviral activity in primary rabbit kidney cells infected with herpes simplex virus type 1 or 2, vaccinia virus, or vesicular stomatitis virus. The 5-halopyrimidine bases, nucleosides (5-X-U), and 5'-monophosphates (5-X-UMP) were tested for comparison. 5-F-cUMP (1) showed reasonably potent inhibition of tumor cell proliferation (ID50 = 0.33-1.6 micrograms/mL), while the remaining diesters displayed ID50's ranging from 210 to greater than 1000 micrograms/mL. 5-F-cUMP was 70- to 300-fold less active than 5-F-dU in the same systems. With TK- L1210 cells, 5-F-cUMP was as potent as with the normal (L1210/0) line but was about fourfold less active with TK- Raji cells compared to Raji/0 cells. The 5-X-cUMPs showed little potency as antivirals. A single-crystal X-ray analysis of the ammonium salt of 5-I-cUMP confirmed its structure and showed the conformation of the phosphate ring to be the expected chair. The ribose pucker is near 3(4)T, and the torsion angle about the beta-glycosidic N(1)-C(1') bond is in the syn range (-84.8 degrees).
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PMID:Synthesis, structure, and antitumor and antiviral activities of a series of 5-halouridine cyclic 3',5'-monophosphates. 300 59

Exposure of cultured clone A human colon tumor cells to 25 to 75 microM of NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarbox yli c acid sodium salt, DuP 785] for 48 to 72 h resulted in a 99.9% cell kill as determined by clonogenic assay. Cells exposed to NSC 368390 became depleted in intracellular pools of uridine 5'-triphosphate and cytidine 5'-triphosphate. Both uridine 5'-triphosphate and cytidine 5'-triphosphate were decreased to 50% of levels in control cells at 3 h and were undetectable at 15 h after addition of 25 microM of NSC 368390 to the cultures. Similar effects were observed in L1210 leukemia cells. Addition of 0.1 mM of uridine or cytidine restored intracellular pools of uridine 5'-triphosphate and cytidine 5'-triphosphate to control levels and rescued clone A cells from NSC 368390 cytotoxicity. Addition of uridine circumvented NSC 368390 cytotoxicity in L1210 cells, but addition of cytidine did not. This result is consistent with the fact that L1210 cells lack cytidine deaminase and thus cannot form uridine or its anabolites from cytidine. These results indicated that NSC 368390 inhibits a step in the de novo biosynthetic pathway leading to uridine 5'-monophosphate. Therefore, the effects of NSC 368390 on the six enzymes that comprise the de novo pathway leading to the formation of uridine 5'-monophosphate were examined. The results showed that NSC 368390 was a potent inhibitor of dihydroorotate dehydrogenase, the fourth enzyme in the pathway; thus, this study demonstrates that NSC 368390 exerts its tumoricidal effect by inhibiting a step in de novo pyrimidine biosynthesis resulting in the depletion of critical precursors for RNA and DNA synthesis.
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PMID:Mechanism of action of the novel anticancer agent 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarbo xylic acid sodium salt (NSC 368390): inhibition of de novo pyrimidine nucleotide biosynthesis. 301 18

The reduction of the tetrazolium salt MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) to a blue-black formazan product by living but not by dead cells can be used to measure chemosensitivity of tumor cells. The main advantages of the MTT assay are its simplicity, rapidity, and the fact that the results are read automatically with a microplate spectrophotometer. Several reports on the use of the MTT assay in chemosensitivity testing have been published, but all these studies dealt with established cell lines and not with specimens obtained directly from patients. Here we present a study in which the MTT assay has been adapted to assess the effect of antineoplastic drugs on lymphoblasts of children with leukemia.
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PMID:Adaptation of the rapid automated tetrazolium dye based (MTT) assay for chemosensitivity testing in childhood leukemia. 316 5

A microcytotoxicity assay employing a tetrazolium salt has been adapted for testing the response of human leukemic blast cells to a variety of chemotherapeutic agents. After exposure to various concentrations of drugs, the viability of fresh leukemic blast cells was measured using a tetrazolium salt, MTT, which is converted to blue formazan crystals by living cells. The amount of formazan produced was quantitated using a microtitre plate spectrophotometer. In the present study, optimal conditions for chemosensitivity testing of human leukemia samples were determined, and the relative chemosensitivity of five patient samples was tested.
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PMID:Use of the MTT assay for rapid determination of chemosensitivity of human leukemic blast cells. 319 42

The effects of various antileukemic agents on DNA replication associated with the nuclear matrix were investigated in CCRF-CEM leukemia cells. Residual nuclear matrices were prepared by sequential treatment of nuclei with 1.5 M NaCl, DNase I, and Triton X-100 and contained 1-5, 10, and 37% of the total nuclear DNA, protein, and phospholipid, respectively. In control cells pulse-labeled for 45 s with [3H]thymidine, the specific activity of nascent DNA was four-fold greater in the nuclear matrix fraction relative to the specific activity of the high salt-soluble (nonmatrix) DNA fraction. Pulse-labeling and reconstitution experiments indicated that this enrichment of newly replicated DNA on the nuclear matrix did not result from aggregation of nascent DNA with the matrix. A 2-h incubation of tumor cells with either 0.1 microM teniposide (VM-26), 0.2 microM VM-26, or 0.5 microM amsacrine (m-AMSA) reduced the relative specific activity of nascent DNA on the nuclear matrix by 59, 61, and 54%, respectively, compared to control cells. In contrast hydroxyurea and cytosine arabinoside, at concentrations that markedly inhibited total nuclear DNA synthesis, did not decrease the relative specific activity of newly replicated DNA on the matrix. The results provide evidence that the antiproliferative effects of the DNA topoisomerase II inhibitors, VM-26 and m-AMSA, are localized on the nuclear matrix of CCRF-CEM leukemia cells.
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PMID:Effects of antileukemia agents on nuclear matrix-bound DNA replication in CCRF-CEM leukemia cells. 334 63

Gallium nitrate is the anhydrate salt of the naturally occurring heavy metal. It has demonstrated antitumor activity in a variety of murine tumor models, including Walker carcinosarcoma 256, fibrosarcoma M-89, leukemia K-1964, adenocarcinoma 755, mammary carcinoma YMC, reticulum cell sarcoma A-RCS, lymphoma P1798, and osteosarcoma 124F. Preclinical studies performed in rats, rabbits, dogs, and monkeys showed the dose-limiting toxicity to be renal. The hepatic, pulmonary, gastrointestinal, hematologic, and integumentary systems were also involved. The major route of elimination is the kidneys, with 35%-71% of the infused dose excreted within 24 hours. Three phase I studies suggested the following phase II doses: 700-750 mg/m2 by short infusion, once every 2-3 weeks; 300 mg/m2/day by short infusion for 3 consecutive days, to be repeated every 2 weeks; and 300 mg/m2/day by continuous infusion for 7 consecutive days, to be repeated every 3-5 weeks. The major organ toxicity reported was renal; however, this can be adequately controlled either by hydration and osmotic diuresis or by use of continuous schedule. (Either maneuver appears to allow delivery of the recommended phase II dose with a less than 30% risk of change in serum creatinine.) In limited phase II evaluation, the drug has shown antitumor activity in patients with either refractory lymphomas or small cell lung carcinoma, with total objective response rates of 28% and 11%, respectively. In addition, it has been effective in the treatment of patients with cancer-related hypercalcemia by having an inhibitory effect on calcium reabsorption from bone. Single-agent phase II studies are planned in all major tumor types. Some are already ongoing in patients with genitourinary malignancies (renal, bladder, prostate, testicular), small cell lung carcinoma, and multiple myeloma. Metabolic studies are in progress at Memorial Sloan-Kettering Cancer Center to further elucidate the mechanism or mechanisms of the hypocalcemic effects.
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PMID:Gallium nitrate: the second metal with clinical activity. 353 51

The disodium salt of 2,6-dimethyl-1,4-dihydropyridine-3,5-bis-carbonyl hydroxyacetic acid (I) used in the mg/kg dose decreases the cyclophosphane toxicity in mice and potentiates the cytostatic activity of cyclophosphane, 5-fluorouracil and arabinosyl cytosine against leukemia P388, murine sarcoma 37 and Walker's carcinosarcoma. Administered alone I exhibits no antitumour activity. The potentiation of the antitumour effect of drugs appears independent of the administration schedule. Biochemical evidence indicates that I does not block DNA synthesis in leukemic cells in vitro, but significantly enhances the DNA-blocking effect of cyclophosphane in the same cells in vivo.
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PMID:[Potentiating effect of disodium salt of 2,6-dimethyl-1,4-dihydropyridine-3,5-bis-carbonyl hydroxyacetic acid on the activity of various antitumor agents]. 358 40


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