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)

A study was conducted to elucidate functional or chemical parameters that may be useful for in vivo toxicologic and pharmacokinetic analysis of PCNU. The growth-inhibitory and DNA-related parameters of this agent and its serum breakdown products in murine leukemia L1210 cells were carried out in direct comparison with BCNU. In human and dog sera, the T1/2 of intact PCNU (5-12 min) was similar to BCNU (5-16 min). However, much larger T1/2 values for PCNU (140 min) and BCNU (110 min) were determined for drug incubated in dog brain homogenates. Uptake of 14C-labeled PCNU in L1210 cells was rapid, and tenfold higher than in CCRF-CEM, a human leukemia cell line naturally resistant to BCNU and PCNU. BCNU was shown to induce DNA strand damage in L1210 and to inhibit radioactive thymidine incorporation into DNA and cross-link proteins with DNA in L1210. PCNU, by comparison, only weakly inhibited thymidine incorporation and did not induce DNA strand breakage or produce DNA-protein cross-links in L1210 at reasonable concentrations. The compounds are further differentiated in fetal calf serum by the breakdown products derived from initial concentrations of intact drug that are equipotent; those of BCNU inhibit L1210 growth whereas those of PCNU do not. PCNU, which is rapidly broken down into inactive metabolites, may have a selective therapeutic advantage if infused directly to the target site.
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PMID:Functional and chemical markers of PCNU activity. 654 15

The effect of thymosin against tumor progression was examined in mice immunosuppressed by cytostatics or X-ray irradiation. When pretreated with cytostatic agents, such as 5-fluorouracil (5-FU) or BCNU, or by X-ray, and then inoculated with P388 or L1210 leukemias, mice died rapidly within a few days. In these systems, thymosin alpha 1 given concomitantly with the cytostatic agents or after X-irradiation prevented rapid death and extended survival, although the mice eventually died with leukemia like normal mice inoculated with cells of the same tumor. Rapid death in the 5-FU-treated mice was also prevented by adoptive transfer of spleen cells from the donor mice if these had been treated with 5-FU plus thymosin alpha 1, but not if they had received 5-FU alone. However, the restorative activity of the donor spleen cells was abrogated by treatment with anti-asialo GM1, but not by treatment with anti-Thy 1 or anti-mouse Ig serum, suggesting that the effector cells in the spleen are NK cells. In fact, thymosin alpha 1, when given concomitantly with 5-FU or after X-irradiation, maintained the NK activity of spleen, which was damaged by treatment with 5-FU or X-irradiation alone. The present study indicates that thymosin alpha 1 exerts a preventive activity against progression of leukemias at least in part through an effect on NK cells or their progenitor cells.
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PMID:Thymosin alpha 1 restores NK-cell activity and prevents tumor progression in mice immunosuppressed by cytostatics or X-rays. 655 15

Using our new in vitro antitumor sensitivity assay, the basis of which depends on predictive analysis of morphological findings of L1210 leukemia cells under the influence of antitumor agents, 5 kinds of nitrosoureas including MCNU were comparatively tested for antitumor activity. A cell killing effect became apparent very soon under BCNU and CCNU, rather late under Methyl-CCNU and MCNU, and intermediately under ACNU. Various cellular biological effects were apparently induced in L1210 cells by MCNU and its mechanism of action seemed to be broader than that of any other members of the nitrosoureas.
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PMID:[Antitumor activity of a new nitrosourea, MCNU, on a cellular morphological basis evaluated by a new in vitro antitumor sensitivity assay]. 659 74

The M-2 protocol (vincristine, cyclophosphamide, BCNU, melphalan, and prednisone) was administered monthly to 63 evaluable patients with advanced chronic lymphocytic leukemia. Complete remission (absence of all clinical and bone marrow evidence of leukemia) and partial response (greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 x 10(6)/liter) were achieved in 17% and 44%, respectively, for a total response rate of 61%. The median survivals from therapy of patients achieving a CR, RR, or no response were 73+, 40, and 14 mo respectively. The median survival time from onset of treatment for stages II, III, and IV disease were 47, 20 and 19 mo, respectively, which was not statistically different from historical controls. However, when untreated patients are compared to this latter group, a significant survival advantage from diagnosis was found (p = 0.01), stressing the importance of prior therapy as the only unfavorable prognostic factor. Although complete remissions in CLL, as reflected in apparently normal bone marrow B-lymphocyte markers, can be induced wih acceptable morbidity, the majority of patients relapse after cessation of therapy. An alternative approach to the M-2 protocol will be needed to eradicate the disease.
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PMID:Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristine, BCNU, cyclophosphamide, melphalan, and prednisone). 675 36

The combination of high-dose cyclophosphamide, BCNU, and VP-16-213 followed by autologous marrow rescue was evaluated in the treatment of relapsed leukemia refractory to normal-dose chemotherapy. Cyclophosphamide was given at a total dose of 4.5 g/m2, BCNU at a dose of 300 mg/m2, and VP-16-213 at a dose of 600 mg/m2. Seven high-dose treatments followed by marrow rescue were administered to six patients. Two patients achieved complete remissions, three had partial remissions, and one achieved a minimal response. The toxicity of this regimen was moderate.
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PMID:Combination of high-dose cyclophosphamide, BCNU, and VP-16-213 followed by autologous marrow rescue in the treatment of relapsed leukemia. 701 23

The effect of cytotoxic and other drugs on the accumulation of melphalan by L1210 murine leukaemia cells was studied. We have confirmed that uptake is an active process competitively inhibited by L-leucine. In 36 experiments in amino acid-free medium the mean concentration of melphalan taken up was 225 pmoles/10(6) cells. High pressure liquid chromatographic analysis showed that the majority of the drug is present as free native melphalan. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) was the only drug that stimulated accumulation, but without significant effect on influx or efflux rates. Busulphan, chlorambucil, cyclophosphamide, interferon, methotrexate and prednisolone had no effect on accumulation after 30 min melphalan transport. Adriamycin, CCNU, methyl CCNU, mustine and vincristine all impaired melphalan accumulation as did the non-cytotoxic drugs aminophylline, chlorpromazine and ouabain. Adriamycin, aminophylline, chloropromazine, indomethacin and ouabain all reduced melphalan influx.
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PMID:The effect of alkylating agents and other drugs on the accumulation of melphalan by murine L1210 leukaemia cells in vitro. 713 68

The cytotoxicity of the antitumour nitrosoureas BCNU and CCNU and the isocyanates which they liberate (chloroethylisocyanate and cyclohexylisocyanate respectively) has been measured utilising an in vitro-in vivo bioassay. Lines of the TLX5 lymphoma and L1210 leukaemia were used which were either sensitive or resistant to nitrosoureas in vivo. An estimated logarithmic cell kill produced by each compound in vitro (before injecting the cells into animals) was calculated by reference to assays of the survival time of animals given from 2 X 10(5) to 2 X 10(0) cells of each line. Resistance to both BCNU and CCNU was observed in vitro in the cell lines of the TLX5 lymphoma made resistant to either BCNU or a dimethyltriazene in vivo. The latter tumour was cross-resistant in vivo to nitrosoureas. Resistance in vitro to nitrosoureas was also observed in a line of L1210 leukaemia which had had resistance to BCNU induced in vivo. The nitrosourea resistant TLX5 lymphomas were cross-resistant in vitro to both cyclohexylisocyanate and chloroethylisocyanate whereas the nitrosourea resistant L1210 line showed no cross-resistance to cyclohexylisocyanate and marginal cross-resistance to chloroethylisocyanate. The results suggest that the TLX5 lymphoma, which is naturally resistant to alkylating agents of the 2-chloroethylamine type, may be sensitive to in vivo to nitrosoureas as a consequence of the intracellular release of isocyanates. This hypothesis was supported by the finding that the resistant TLX5 lymphoma showed no cross-resistance to other electrophilic agents, for example formaldehyde, monomethyltriazene or HN2. The transport of nitrosoureas into the sensitive and resistant cell lines was similar in profile and there was no difference in the concentration of non-protein thiols.
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PMID:The role of isocyanates in the toxicity of antitumour haloalkylnitrosoureas. 713 75

Chemotherapeutic efficacy is inversely related to pretreatment tumor burden. A possible contributory factor in chemotherapy resistance is the occurrence of decreased red blood cell deformability in mice with advanced tumors. Poorly deformable red blood cells may prevent adequate drug delivery to tumor cells. Two methods for improving red cell deformability were found in this study. The first involved treatment of L1210 leukemia-bearing mice with red cell metabolic substrates, including inosine, adenosine, glucose, sodium pyruvate, and ascorbic acid. The combination of inosine plus sodium pyruvate (3 mg of each drug in 0.5 cm3 phosphate-buffered saline) was most effective in restoring deformability to normal. Administration of an active chemotherapeutic agent (BCNU or cyclophosphamide) also improved red cell deformability, with maximal restoration occurring 4--5 days after drug treatment. Standard and 50% of standard drug doses were equally effective in restoring deformability. The optimal therapy program for day 7 L1210 leukemia utilized inosine plus sodium pyruvate given 10--15 min before BCNU 15 mg/kg on day 7 and before BCNU 30 mg/kg on day 12. This treatment yielded 44% cures, whereas BCNU alone, in identical dose and schedule, gave no cures. Median survival was 50 days for the inosine-pyruvate-treated mice, as against 30 days for BCNU alone. Therefore, treatment with non-toxic doses of red blood cell metabolic substrates plus optimal timing of chemotherapy, two maneuvers that significantly increased red blood cell deformability, resulted in significant therapeutic benefit.
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PMID:Cure of advanced L1210 leukemia after correction of abnormal red blood cell deformability. 729 52

When maximal effective dose (MED) of BCNU is injected together with liposomes to mice with L-1210 leukemia, the effectiveness of the drug is decreased. But when half the MED is injected with liposomes into such mice, survival is increased compared to mice injected with BCNU alone. Study of liposome composition on BCNU anti-leukemic effect revealed that negatively charged liposomes made of dioleylphosphadyl choline plus phosphatidyl serine given with half the MED of BCNU increased both long-term survival and mean survival time. This enhancement was not produced with negatively charged liposomes made of dioleylphosphatidic acid alone or in liposomes in which phosphatidyl serine plus dioleylphosphatidic acid was diluted with the neutral phospholipid, dioleylphosphatidyl choline.
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PMID:Relative enhancement by various liposomes of BCNU effectiveness against L-1210 leukemia in vivo. 743 63

The preterminal intraperitoneal implanted rat leukemia L 5222 was used to test the chemotherapeutic activity of 10 newly synthesized nitrosoureas: ethylmethanesulfonato-CNU, acetamido-CNU, dihydroxypropyl-CNU, carboxyethyl-CNU, cyanoethyl-CNU, morpholino-CNU, piperidino-CNU, methylene-dioxybenzyl-CNU, methylene-3-pyridyl-CNU and methylene-4-pyridyl-CNU; their activity was compared against BCNU, CCNU, MeCCNU and hydroxyethyl-CNU. All compounds tested showed a more or less pronounced chemotherapeutic activity. MeCCNU was superior to all other compounds investigated. The predictive value for human tumors of results obtained from a model which is highly sensitive to nitrosoureas is discussed.
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PMID:Examination of newly synthesized 2-chloroethyl-nitrosoureas on rat leukemia L 5222. 744 75


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