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)

L1210 leukemia was transplanted serially in CDF(1) mice treated with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DIC, NSC 45388). After four different lines (C lines) had been treated for several generations, a marked increase in survival time of untreated mice was observed. In contrast, mice treated with DIC or immunosuppressed with cyclophosphamide succumbed earlier with generalized leukemia. Furthermore, a C line showed unusually high sensitivity to chemotherapeutic treatment with 1,3 bis(2-chloroethyl)-1-nitrosourea. The data suggest that C lines acquired strong antigenicity for CDF(1) and DBA/2 hosts. DIC treatment may have selected highly antigenic variants or induced somatic mutations resulting in the appearance of strong new transplantation antigen(s).
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PMID:Immunological alteration of leukemic cells in vivo after treatment with an antitumor drug. 527 45

Synergistic increases in the survival of mice bearing an L1210 leukemia tumor have been demonstrated previously after treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea together with theophylline over those treated with either agent alone. These results imply that manipulation of cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels in L1210 cells may result in alteration of sensitivity to chemotherapy and alterations in tumor growth. In the present study, we have shown that in vivo treatment of L1210 cells with theophylline results in changes in intracellular cyclic AMP-dependent protein kinase activity levels as well as in an apparent redistribution of both the nuclear and cytoplasmic isozymes. Biochemical events in the tumor cells immediately after administration of theophylline in vivo or a cyclic AMP analog (8-parachlorophenylthio cyclic adenosine 3':5'-monophosphate in vitro were independent of the presence of 1,3-bis(2-chloroethyl)-1-nitrosourea. The changes apparently involve signal transduction via the adenylate cyclase system and manifest as: (a) increased sensitivity of cyclic AMP-dependent protein kinase to activation by cyclic AMP after treatment of L1210 cells with theophylline; (b) decrease in endogenous nuclear protein phosphorylation sites; and (c) protein kinase isozyme redistribution between nuclear and extranuclear compartments, i.e., a relative increase of the type I isozyme activity in the nuclear and of the type II isozyme activity in the 900 x g supernatant fractions after treatment of the mice with theophylline. The relative activity increases are accompanied by a relative decrease of type II activity from the nucleus and type I isozyme activity from the 900 x g extranuclear supernatant fraction. These events appear temporally related to changes in nuclear RNA metabolism as evidenced by altered kinetics of RNA precursor uptake and incorporation into tumor cell RNA after treatment. These results imply that the cyclic AMP-dependent phosphorylative modification of intracellular proteins may play a regulatory role in tumor cell growth and in theophylline-mediated tumor regression.
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PMID:Cyclic adenosine 3':5'-monophosphate-dependent protein phosphorylation and the control of leukemia L1210 cell growth. 628 49

Two nitrosourea compounds--1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)--have been used in the treatment of primary and metastatic brain tumors after operation and/or radiotherapy. Hematological and nonhematological toxicity were recorded in 272 patients treated between May 1973 and June 1978. BCNU was given to 135 patients (80 mg/m2 i.v. daily for 3 days) and CCNU was given to 137 patients (130 mg/m2 orally, single dose) every 8 weeks until progression of the primary disease process or for a total of 12 cycles. Radiation therapy (5500 +/- 500 rads in 6 to 7 weeks) was carried out after the first course of chemotherapy. BCNU and CCNU induced the same hematological and clinical toxicity. The bone marrow toxicity seemed to be dose-related, delayed, and cumulative. One case of acute nonlymphoblastic leukemia arising 2 months after the end of CCNU therapy is reported.
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PMID:Clinical toxicity of combined modality treatment with nitrosourea derivatives for central nervous system tumors. 629 Sep 30

Polyamine depletion by pretreatment with alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, potentiates the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in L1210 leukemia cells grown in a modified soft agar system. The dose enhancement ratio was 1.97 at a control colony formation level of 5%. The basis for this enhancement was investigated at the level of DNA damage using a modified fluorometric assay to quantitate the production of alkaline-labile strand breaks per relative DNA molecular mass. Pretreatment of cultured L1210 cells for 48 hr with 5 mM DFMO depleted intracellular putrescine and spermidine (but not spermine) pools and resulted in a 2.3-fold increase in BCNU-induced (10 micrograms/ml, 2 hr) DNA strand breaks per relative DNA molecular mass. The inclusion of 10 microM spermidine during the DFMO pretreatment fully prevented growth inhibition and enhancement of BCNU-induced DNA damage while maintaining cellular spermidine pools at control levels. The inclusion of 2 microM putrescine or spermidine also prevented growth inhibition and enhancement of DNA damage while maintaining spermidine pools at only 25 to 35% of control. Thus, the portion of spermidine essential for cell growth appears to be associated with DNA. BCNU itself was found to reduce cellular polyamine levels by causing their leakage from cells. In addition, BCNU was found to react directly with spermidine in a cell-free system, resulting in a major reaction product detectable by high-performance liquid chromatography. While decreased interaction of BCNU with polyamines could account, in part, for enhancement effects of DFMO, it is more probable that alterations in DNA structure secondary to polyamine depletion are responsible for these effects.
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PMID:Enhancement of 1,3-bis(2-chloroethyl)-1-nitrosourea-induced cytotoxicity and DNA damage by alpha-difluoromethylornithine in L1210 leukemia cells. 643 May 55

The effects of N,N'-bis(2-chloroethyl)-N-nitrosourea and chlorozotocin upon the proliferation, DNA synthesis, and viability of cultured cells of a sensitive line of L1210 leukemia, a line partially resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea, and a line resistant to cyclophosphamide were determined. The results indicate that neither the effect upon proliferation nor the effect upon DNA synthesis is a good predictor of the extent of cell kill. The similarity of the effects of N,N'-bis(2-chloroethyl)-N-nitrosourea upon these two parameters for the three cell lines indicates that the sensitive and resistant cells are affected to approximately the same extent, but more of the resistant cells survive. Additional studies are required to seek the reasons for this differential survival.
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PMID:Effects of N,N'-bis(2-chloroethyl)-N-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-2-deoxy-D-glucopyranose upon the proliferation, DNA synthesis, and viability of cultured sensitive and resistant L1210 cells. 644 83

Leukemia L1210 cells with acquired resistance to 1-methyl-1-nitrosourea (MNU) (L1210/MNU) and 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (L1210/BCNU) were developed from leukemia L1210 cells sensitive to these drugs (L1210/0). The modal chromosome number of leukemia L1210/MNU and L1210/BCNU cells increases from 40 (L1210/0) to 41. It was shown that in leukemia L1210/MNU cells the inhibition of DNA synthesis after MNU administration in a therapeutic dose (80 mg/kg) is lasted within 24 hours, while that in leukemia L1210/0 cell--within 96 hours. After administration of BCNU (20 mg/kg) inhibition of DNA synthesis in leukemia L1210/BCNU cells reached of 50% of control in comparison with practically complete inhibition of DNA synthesis in leukemia L1210/0 cells. Centrifugation on alkaline sucrose density gradients revealed no differences in the rate of sedimentation of leukemia L1210/0, L1210/MNU and L1210/BCNU cell lysates. After 1 hour treatment with MNU of mice bearing L1210/MNU and L1210/0 leukemia cells single-strand breaks in DNA were determined. After 4 hours these strand-breaks retained in leukemia L1210/0 cells, but were eliminated in leukemia L1210/MNU cells. Administration of BCNU to mice with leukemia L1210/0 and L1210/BCNU cells resulted in both cases in the production of DNA aggregates. There is no complete cross-resistance between MNU and BCNU which allows a substitution of these drugs providing for the increase in their therapeutic efficiency.
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PMID:[Disruption of DNA synthesis and structure of mouse L1210 leukemia cells, sensitive and resistant to 1-methyl-1 nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea in vivo]. 647 85

A new transplantable leukemia (KSL) of unknown etiology that arose in a female Sewall-Wright strain 2 guinea pig is described. KSL cells morphologically resembled medium to large lymphocytes, displayed surface Ia antigen and receptors for complement and for the Fc portion of immunoglobulin, and synthesized surface immunoglobulin (IgM). These characteristics suggest a leukemia of B-lymphocyte origin. KSL cells were shown to be sensitive in vivo to both cyclophosphamide and 1,3-bis(2-chloroethyl)-1-nitrosourea; however, neither drug effectively prevented eventual recurrence of the disease. KSL leukemia was also shown to be distinct from another guinea pig lymphatic leukemia (L2C) with respect to cell morphology, antigenicity, and in vivo growth rate. In this last respect, KSL appeared more closely related to the chronic lymphocytic leukemias. Thus KSL is the first chronic lymphocytic leukemia in the guinea pig to be characterized; it is also the only guinea pig model of lymphatic leukemia that is distinct from L2C leukemia currently available for study.
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PMID:Development of a model of chronic lymphocytic leukemia in inbred strain 2 guinea pigs. 657 84

Tumor cells, treated in vivo with anticancer compounds, may acquire new antigenic specificities in addition to any original antigens associated with parental tumors. Treatment of mice carrying the parental leukemias L1210 Ha or L1210 Cr with leukemia cells antigenically altered by treatment with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (L1210 Ha/DTIC and L1210 Cr/DTIC, respectively) was essentially ineffective in prolonging the life span of the animals. However, synergic therapeutic activity was exhibited by administration of L1210 Ha/DTIC cells plus 1,3-bis(2-chloroethyl)-1-nitrosourea in the treatment of the moderately immunogenic L1210 Ha leukemia and by the combination of L1210 Cr/DTIC cells and lymphocytes immune to L1210 Cr/DTIC administered with 1,3-lymphocytes immune to L1210 Cr/DTIC administered with 1,3-bis(2-chloroethyl)-1-nitrosourea in the treatment of the low immunogenic L1210 Cr leukemia. Early and advanced L1210 Cr-bearing mice showed marked increases in survival time and a significant number of tumor-free survivors on treatment with cyclophosphamide followed by transfer of lymphocytes immune to L1210 Cr/DTIC cells. When parental tumor cells were used as the immunogen, the therapeutic effect was diminished. Thus, in the current investigation, although immunotherapy per se was essentially ineffective, the immunochemotherapeutic modalities used were successful in markedly increasing the survival time of leukemic animals and resulted in an incidence of cures.
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PMID:Chemotherapy and immunotherapy of L1210 leukemic mice with antigenic tumor sublines. 701 35

Strong and heritable increase of immunogenicity of L1210 Ha leukemia has been obtained in vitro following multiple treatments with 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), metabolically activated by mouse liver preparations (MLP) containing liver microsomes. The DTIC-treated leukemia (L1210D line) or the control line treated with MLP alone (L1210N line) showed comparable growth kinetics in vitro. However, progressive increase of immunogenicity occurred in leukemic cells in the course of in vitro treatments with DTIC plus MIP, but not with MLP alone, as evidenced by comparative studies on transplantation immunity elicited in BALB/c x DBA/2 F1 mice by graded inocula of L1210D or L1210N leukemia cells. In vitro experiments confirmed that metabolic transformation of DTIC is required for increasing tumor immunogenicity. In fact, L1210Ha cells became highly immunogenic when treated with DTIC in intact mice but not in animals metabolically depressed by CCl4. Immunochemotherapy experiments based on the antigenic cross-reactivity between the L1210D line and the original L1210Ha leukemia showed that i.p. administration of L1210D cells followed by 1,3-bis(2-chloroethyl)-1-nitrosourea treatment afforded marked protection in mice inoculated intracerebrally with the parental lymphoma. The present findings could provide an adequate in vitro technique for developing further studies on DTIC-mediated immunogenic changes of tumors, including human cancer cells growing in tissue culture.
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PMID:In vitro generation of a highly immunogenic subline of L1210 leukemia following exposure to 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide. 701 15

Nitrosourea derivatives 18-22 which utilize either a piperidine or pyridine ring as a carrier group were synthesized and evaluated for anticancer activity. N'-(1-Benzyl-4-piperidinyl)-N-(2-chloroethyl)-N-nitosourea hydrogen maleate (19) exhibited good activity against intracranial L1210 leukemia as well as the mouse ependymoblastoma brain tumor system. Compound 19 exhibited comparable activity in the Lewis lung carcinoma system to N,N'-bis(2-chloroethyl)-N-nitrosourea. Replacement of the N-benzyl group in both the 3-piperidinyl- and 4-piperidinylnitrosoureas resulted in less active compounds in all tumor systems tested. The 3-pyridylnitrosourea 22 was inactive in the L-1210 leukemia system.
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PMID:Synthesis of nitrosourea derivatives of pyridine and piperidine as potential anticancer agents. 740 Nov 13


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