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)

5-Azacytidine is more active when administered parenterally than orally in the treatment of L1210 leukemic mice. Oral coadministration of tetrahydrouridine, a pyrimidine nucleoside deaminase inhibitor with no intrinsic antitumor activity, greatly increases the oral activity of 5-azacytidine. 5-azacytidine (or cytotoxic equivalent) blood levels in BDF mice are much higher after oral administration of the 5-azacytidine-tetrahydrouridine combination than when 5-azacytidine is administered alone by the same route. The therapeutic results (L1210 leukemia) achieved with the oral combination are similar to those observed with parenteral 5-azacytidine alone.
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PMID:Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. 5 11

The pyrimidine analog, 5-azacytidine (NSC 102816), was administered by continuous intravenous infusion in Ringer's lactate in increasing doses to sets of patients with metastatic cancer to establish a dose sufficient to produce mild toxicity. Twenty-one patients (23 trials) were treated with doses of 50-200 mg/sq/m/day for 5 days every 2-4 wk. Nausea and vomiting were moderate and easily preventable. Doses of 100-200 mg/sq/m for 5 days every 14 days produced granulocytopenia, usually after two courses. Less toxicity was observed when courses were given every 21-28 days. Forty-five patients with previously treated and refractory acute myeloblastic leukemia were treated. The majority received doses of 150 mg/sq m for 5 days every 2 wk. Eleven (24%) complete remissions and four partial remissions were observed. The number of courses to achieve remission averaged three and required an average of 59 days. Nine patients with blastic crisis of chronic myeloblastic leukemia and four with refractory acute lymphoblastic leukemia failed to respond. 5-Azacytidine administered by continuous infusion is well tolerated and is an active compound in acute myeloblastic leukemia.
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PMID:5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. 6 Jan 56

1-4-Amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) is a water-soluble nitrosourea that has produced delayed hematological toxicity in man during Phase 1 clinical trials. ACNU has in vitro alkylating activy 40% less than that of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) but shares the property of negligible carbamoylating activity with the latter compounds. ACNU is highly active against murine L1210 leukemia. However, the maximum therapeutic dose, 30 mg/kg (a dose lethal to 10% of the animals), produced a 64% reduction in peripheral WBC and an 85% decrease in circulating neutrophils in normal mice. This was correlated with a 76% inhibition of normal mouse bone marrow DNA synthesis within 24 hr after treatment, followed by full recovery within 48 hr after treatment, followed by full recovery within 48 hr. In contrast, DNA synthesis in L1210 cells was suppressed to less than 10% of control for a minimum of 72 hr. While ACNU, a pyrimidine analog, possesses many of the chemical properties of chlorozotocin, it does not share with the latter compound its reduced myelotoxicity at therapeutic doses. The glucose carrier of the chlorozotocin molecule appears to impart the selective sparing of normal bone marrow.
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PMID:A comparison of the biological and biochemical properties of 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose. 14 14

Several 2,4-diaminopyrimidines which inhibit the enzyme dihydrofolate reductase are quantitated following extraction and separation on silica gel thin-layer chromatographic plates. These compounds are candidates for the treatment of brain tumors and meningeal leukemia, because they have the ability to cross the blood-brain barrier. The ultraviolet absorption of the pyrimidine ring at 275 nm is utilized to quantitate these compounds on thin-layer chromatographic plates with a scanning instrument. This method offers the advantages of speed, specificity, versatility and sensitivity, and has proven to be satisfactory for the measurement of as little as 10 ng/ml of these compounds in biological fluids.
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PMID:Quantitative thin-layer chromatography of pyrimethamine and related diaminopyrimidines in body fluids and tissues. 16 16

Uridine kinase, the rate-limiting enzyme in the activation (phosphorylation) of uridine and the corresponding chemotherapeutic analogues, is present as two isoenzymes localized exclusively in the cytosol of rapidly growing neoplasms, including the S-37 sarcoma, EL-4 leukaemia, HeLa cells (a human carcinoma) and the Novikoff hepatoma. The activities of the isolated isoenzymes are markedly decreased when the concentrations of ATP, phosphate or Mg2+ that are optimum in vitro are replaced by concentrations of ATP, phosphate or Mg2+ that are optimum in vitro are replaced by concentrations approximating to those found in vivo. Further, comparisons of the Km values of isolated uridine kinases with those for cellular uptake of pyrimidine nucleosides and their rate of intracellular phosphorylation suggest that nucleoside-transport systems play a rate-limiting role in nucleoside analogue activation and consequently that it is impossible to estimate the Km of uridine kinase in the intact cell. During the development of tumour-cell resistance to 5-fluorouracil or 5-fluorouridine in vivo there was an early differential increase in the activity of a low-affinity (high-Km) uridine kinase isoenzyme, as measured in cell extracts, and a 7-fold increase in the Km values for the uptake of both uridine and 5-fluorouridine into the intact resistant cells.
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PMID:Uridine kinase activities and pyrimidine nucleoside phosphorylation in fluoropyrimidine-sensitive and -resistant cell lines of the Novikoff hepatoma. 19 85

After nude-mouse-passage, a carcinoma of the nasopharynx was found to contain a few scattered C-type retrovirus particles. Culture of this nude-mouse-grown material over solid agar allowed the human tumour cells to grow as multicellular spheroids which increased in number by budding and could be subcultured for up to 6 months. Within the spheroids the human tumour cells expressed increased retrovirus replication and large numbers of C-type particles were observed. Treatment with a halogenated pyrimidine further enhanced the virus production. This tissue culture system provided sufficient virus production for the identification of the retrovirus as an endogenous xenotropic murine leukaemia virus and not a human agent.
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PMID:Identification of murine endogenous xenotropic retrovirus in cultured multicellular tumour spheroids from nude-mouse-passaged nasopharyngeal carcinoma. 21 58

The effects of two keto-nucleosides on survival time of Mice with i.p. L 1210 leukemia were studied. The purine unsaturated keto-nucleoside was shown to be much more active than the pyrimidine keto-nucleoside.
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PMID:[Antitumor effects of keto-nucleosides. Study of the antitumor activity of y(3'-O-acetyl-4', 6'-dideoxy-beta-L-glycero-hex-3'-eno-pyranosyl) theophylline and 1(4'-keto-2'-3'-O-isopropylidene-alpha-L-''rhamnosyl''O thymine against L 1210 leukemia in mice]. 41 97

Several biochemical parameters were examined relative to the sensitivity or resistance of representative rodent tumors to N-(phosphonacetyl)-L-aspartate (PALA). The activity of the target enzyme, L-aspartate transcarbamylase (ATCase), was evaluated in homogenates of a spectrum of murine neoplasms. ATCase activity was significantly lower in PALA-sensitive as opposed to PALA-refractory tumors. However, among tumors sensitive to PALA, there was no clearcut relationship between ATCase activity and degree of sensitivity to PALA. Thus, a number of hypotheses were proposed to explain differential sensitivity to PALA in vivo. Enzyme activities in the salvage pathway which phosphorylate pyrimidine nucleosides and deoxynucleosides were found to be greater in refractory tumors. The uptake of PALA, in vitro, though quite slow, was found to be two to eight times greater in two sensitive tumors as compared to the refractory L1210 leukemia. However, in vivo, 24 hours following graduated doses of PALA, nearly identical intratumoral drug concentrations were observed in representative sensitive and refractory tumors. Thus, ultimately, PALA transport would not appear to correlate with differences in drug sensitivity. A number of other biochemical parameters were also found to have no association with sensitivity to PALA in vivo. These included: kinetics of inhibition of ATCase, capacity for restitution of ATCase activity after a dose of PALA, degree of inhibition of ATCase at various doses of PALA, detoxification of PALA by tumor cells, kinetics of uptake of uridine, or catabolism of pyrimidines or pyrimidine nucleosides.
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PMID:Mechanisms of sensitivity or resistance of murine tumors to N-(phosphonacetyl)-L-aspartate (PALA). 47 6

In view of the tumor inhibitory activity of various pyrimidine derivatives, investigations aimed at the structure modification of barbituric acids were performed. In accordance with the aminomethinylation principle, barbituric acids (2) are converted into 5-formimidoylbarbituric acids (4) by s-triazine (1). Aside from the free barbituric acid (2a), both 1-substituted (2b, d, and f) and 1,3-di-substituted (2c, e, and g) barbituric acids are amenable to this reaction. After introduction of the formimidoyl group into 5-position of the barbituric acid ring system, marked tumor inhibitory effects against lymphoma, lymphocytical leukemia, and luekemia L-1210, are ascertainable.
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PMID:[Tumor-inhibiting agents. 8. 5-Aminomethylated barbituric acid derivatives]. 58 70

The amount of free purine and pyrimidine ribonucleotides in the spleens of mice (C57Bl and DBA/2) and in lympholeukemia cells (La and L1210), sensitive and with induced resistance to 5-fluorouracil, was determined by chromatography on a column with DEAE-cellulose. It was found that the cytidine ribonucleotide pool in the spleens of DBA/2 mice is 2 times lower as compared to C57Bl mice. The lympholeukemia cells (La and L1210) isolated from the animals also differed in their uridine nucleotide pools. The development of leukemia was accompanied by a decrease in ATP and GTP. No significant changes in the total amount of pyrimidine nucleotides under developing resistance to 5-fluororuacil were observed.
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PMID:[Comparison of free ribonucleotide pool in the spleens of C57BL and DBA/2 mice and in leukemia cells sensitive and resistant to 5-fluorouracil]. 62 43


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