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)

In vivo treatment of leukemic mice with the antitumor agent 5-(3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) results in early increase of tumor-associated immunogenicity which is expected to evoke host-versus-graft responses. However, transplantation immunity is severely impaired in DTIC-treated mice due to the immunodepressant activity of the drug. It follows that the DTIC-mediated increase of tumor immunogenicity effect cannot be of therapeutic value in ordinary conditions. In the present report, we describe the results of studies aimed at restoring immunocompetence of DTIC-treated mice by means of adoptive transfer of syngeneic lymphoid cells. Infusion of spleen cells into DTIC-treated mice failed to restore graft responsiveness even in allogeneic tumor-host combinations. However, when DTIC treatment was followed by administration of cytotoxic alkylating agents such as cyclophosphamide (CY) or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), graft responsiveness was partially restored upon adoptive transfer of syngeneic splenocytes. (BALB/c X DBA/2) F1 (hereafter called CD2F1) mice bearing leukemia L1210 Ha were treated as follows: (a) DTIC for increasing the immunogenicity of the leukemic cells; (b) CY or BCNU; and (c) adoptive transfer of CD2F1 lymphocytes. The results showed that: (a) DTIC alone or DTIC plus spleen cells produced little or no increase in survival times with respect to untreated controls; (b) DTIC plus CY or BCNU increased survival times to a larger extent; and (c) the adoptive transfer of lymphocytes produced marked protection of leukemic mice when the hosts had been pretreated with DTIC plus CY or BCNU but not with CY or BCNU without DTIC. These data may provide a model for exploiting DTIC-induced increase of tumor immunogenicity for immunochemotherapeutic regimens.
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PMID:Drug-mediated increase of tumor immunogenicity in vivo for a new approach to experimental cancer immunotherapy. 744 13

Several bifunctional nitrosoureido sugar alcohol derivatives were synthesized at the Institute for Drug Research in Budapest. For detailed studies two D,L-threitol derivatives have been selected (GYKI 13 324, GYKI 13 485). These compounds were less toxic and more effective than BCNU, the calculated therapeutic index values in a broad scale of transplantable, induced and heterotransplanted tumours were found to be more advantageous than with the referent compound. Both GYKI 13 324 and GYKI 13 485 exert their curative effect when given orally even in leukaemia types of tumours. Their effect on the blood picture of rats is moderate and of short duration.
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PMID:New type bifunctional nitrosoureido derivatives with cytostatic activity. 745 1

The experiments aimed at evaluating the optimal parameters in the chemo-immunotherapeutic treatment of the L1210 lymphoid leukaemia grafted to [female BALB/c (H2d) X male DBA/2 (H2d)]F1 hybrid mice, hereafter referred to as CDF1 mice. In vitro irradiation of leukaemic ascites cells by X- or gamma-rays and subsequent inoculation in mice showed that optimum immunogenicity is radiation dose-dependent. Grafting mice with 10(7) leukaemic ascites cells irradiated at optimum dose (80 GyX- or gamma-rays) delays mortality of the animals when challenged later with untreated L1210 cells, but is unable to cure mice. By contrast, specific immunoprophylaxis induced by Micrococcus, complement-triggering polysaccharides or BCG and irradiated leukaemic cells was able to protect mice against grafts of 10(4) L1210 cells. The i.p. route was notably superior to the i.v. route. When mice bearing advanced L1210 tumour were treated by chemotherapy (12 mg/kg of BCNU) on Day 6.5 after grafting 10(4) L1210 cells and subsequently treated by immunotherapy, a very high percentage (up to 90%) of mice with 10(8) leukaemic cells could be cured by repeated 1mg injections of bacterium or polysaccharide, and challenge with irradiated leukaemic cells was unnecessary. Because of the high cure rate obtained, the very regular response pattern and the non-pathogenicity, the bacterium Micrococcus lysodeikticus would seem a promising new candidate for chemo-immunotherapeutic antitumour strategies.
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PMID:Successful immunotherapy with micrococcus, BCG or related polysaccharides on L1210 leukaemia after BCNU chemotherapy. 747 Mar 82

The in vitro cytotoxicity and differential cellular sensitivity of a series of new N1-methyl, N1-allyl, N1-2-chloroethyl and N1-propargyl nitrosourea derivatives of diamino acids were determined in the National Cancer Institute's primary antitumor drug screen. The compounds tested showed an in vitro anticancer activity similar to commercialized nitrosoureas such as CCNU, BCNU, MeCCNU, chlorozotocin, streptozotocin and PCNU. The alkylating moiety of the nitrosoureas seems to play a role in the general selectivity of our compounds. The N1-methyl and N1-2-chloroethyl nitrosourea derivatives are more selective for central nervous system cell lines, the N1-allyl nitrosourea derivatives are more selective for lung cancer cell lines and the N1-propargyl nitrosoureas are more selective for leukemia cell lines.
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PMID:In vitro cytotoxicity and differential cellular sensitivity of derivatives of diamino acids. II. N1-methyl, N1-allyl, N1-(2-chloroethyl) and N1-propargyl nitrosoureas. 764 70

The increased survival rate of malignant diseases due to more aggressive treatments contributes to the occurrence of drug-induced pulmonary diseases (DIPD). We reviewed, retrospectively over a 10-year period, 15 children (8 girls) who presented a DIPD. Their mean age was 9 years (range, 1 to 17 years), with an underlying malignant disease in 14 (9 leukemias). Three typical patterns have emerged from this analysis: (1) acute hypersensitivity lung disease caused by methotrexate (in 6 patients) or azathioprine (in 1 patient). This acute syndrome consisted of alveolar-interstitial infiltrate with a hypercellularity on bronchoalveolar lavage (BAL) (mean, 714,286 cells/mL; range, 180,000-2,940,000 cells/mL) and an increase of lymphocyte counts (mean, 39%; range 11-64%) with predominantly CD8-suppressor/cytotoxic lymphocytes. Inhibition of leukocyte migration or leukocyte aggregation in the presence of low drug concentrations was positive in the 5 cases tested. Lung function tests showed a restrictive pattern and the outcome of DIPD was always favorable. (2) Chronic pneumonitis/fibrosis was seen in 6 patients who received a variable association of cyclophosphamide (3 patients), bleomycin (2 patients), BCNU (2 patients), and melphalan (1 patient). Symptoms of an alveolar-interstitial pneumonitis developed progressively. BAL showed a moderate increase of total cell numbers (mean, 495,000 cells/mL; range, 150,000-900,000 cells/mL). Lung function tests showed a restrictive pattern. Despite corticosteroid treatment in 4 children, one died after bleomycin lung injury and 2 had functional lung impairment. (3) Noncardiogenic pulmonary edema occurred in 2 patients with leukemia treated with recombinant interleukin II. BAL showed hypercellularity and outcome was rapidly favorable.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytotoxic drug-induced pulmonary disease in infants and children. 789 68

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance has been mostly studied in vitro. In an attempt to better understand BCNU resistance in the in vivo situation, we compared the principal drug-metabolizing enzyme systems in two L1210 leukemia lines, one sensitive and one resistant to BCNU (L1210/BCNU), passaged in vivo in mice. The following enzymes were assayed by immunoblotting: cytochromes P-450 (1A1/1A2, 2B1/2B2, 2C8-10, 2E1, 3A), epoxide hydrolase (EH) and glutathione S-transferase (GST-alpha, -mu and -pi). The following enzymes and cofactors were assayed fluorometrically or spectrophotometrically: 1-chloro-2-4 dinitrobenzene-GST (CDNB-GST), total glutathione (GSH), UDP-glucuronosyltransferase, beta-glucuronidase, sulfatase and sulfotransferase. Results showed that cytochrome P-450 1A1/1A2 was the only isoenzyme detected in both L1210 and L1210/BCNU. CDNB-GST activity was significantly higher in L1210/BCNU compared with L1210. The isoenzyme GST-alpha was more abundant in L1210/BCNU compared with L1210, whereas GST-pi was expressed less in the BCNU-resistant leukemia line. GST-mu was not detected in either L1210 leukemia lines. GSH levels were similar in the two L1210 lines. No significant difference was observed between the two leukemia lines for the conjugative enzymes UDP-glucuronosyltransferase and sulfotransferase, whereas their corresponding hydrolytic enzymes beta-glucuronidase and sulfatase were about two-fold lower in the BCNU-resistant leukemia line. Epoxide hydrolase was 1.3-fold higher in L1210/BCNU compared with L1210 and this level was about three-fold higher than in mouse liver. In conclusion, these studies showed the presence of cytochrome P-450 1A1/1A2 in the two L1210 leukemia lines studied, and indicated noteworthy differences between the two leukemia lines for many enzyme systems such as GST, beta-glucuronidase, sulfatase and epoxide hydrolase. These data are of importance to better understand the mechanisms of drug resistance to nitrosoureas in vivo.
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PMID:Principal drug-metabolizing enzyme systems in L1210 leukemia sensitive or resistant to BCNU in vivo. 796 9

Intoplicine (RP 60475, NSC 645008) is a new 7H-benzo[e]pyrido [4,3-b] indole derivative which interacts with DNA and inhibits both topoisomerases I and II. In vitro it was found cytotoxic against various cell types with greater cytotoxicity towards solid tumor cells. We report here the anticancer activity of RP 60475 against a variety of transplantable tumors of mice, and also its cross-resistance profile in leukemias. The end points used were % T/C (median tumor weight of the Treated over the Control x 100) and logCK (log10 cell kill total). RP 60475 administered i.v. was found schedule-independent with a peak plasma level problem. It had a good therapeutic index and host recovery usually occurred 7.5 days post last treatment. RP 60475 was found to be highly active against early stage colon 38 (T/C = 0%, 2.9 logCK) and could induce 5/5 complete regressions of advanced stage tumor. It was found active against colon adenocarcinoma 51 (T/C = 3.6%, 1.9 logCK) and colon carcinoma 26 (T/C = 11.7%, 1.2 logCK). Most of the mammary adenocarcinomas were found very responsive, MA16/C (T/C = 0%, 2.8 logCK), MA14/A (T/C = 0%, 1.4 logCK), MA13/C (T/C = 0%, 3.1 log CK) and MA44 (T/C = 34%). Excellent activity was also observed against early stage pancreatic ductal adenocarcinoma 03 (T/C = 0%) and RP 60475 could achieve 5/5 complete regressions of upstaged tumor. Activity was also obtained on Glasgow osteogenic sarcoma (T/C = 0%, 3.3 logCK), on B16 melanoma (T/C = 14%, 1.3 logCK) and to a lesser extent on Lewis lung carcinoma (T/C = 33.2%). Evaluation of RP 60475 against leukemia sublines with acquired resistance, revealed that L1210/cisplatin and L1210/BCNU were not cross-resistant to RP 60475 whereas P388/vincristine was partially cross-resistant to RP 60475 and P388/doxorubicin was cross-resistant to RP 60475. Based on RP 60475 broad activity against transplantable tumors of mice, its effectiveness against some resistant sublines, its original mechanism of action and its acceptable toxicological profile, this compound was selected for clinical trials.
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PMID:Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice. 815 69

Stable lipid microspheres (LM) and lipid nanospheres (LN) with average diameters of 200 nm and 50 nm, respectively, were used to encapsulate an lipophilic antitumor agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). LM and LN containing BCNU (lipo BCNU and s-lipo BCNU, respectively) were prepared by homogenizing a soybean oil solution of BCNU with egg yolk lecithin, and their antitumor activity via the intravenous route was tested against L1210 leukemia in mice and compared with that of BCNU dissolved in saline. Both lipo-BCNU and s-lipo BCNU showed significantly enhanced antitumor activity with reduced toxicity, when compared with the corresponding doses of BCNU alone. These results suggest that LM and LN may be suitable carriers for lipophilic antitumor agents and may enhance their efficacy.
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PMID:Enhanced antitumor activity and reduced toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea administered in lipid microspheres to tumor-bearing mice. 822 82

We have pursued our findings of glutathione reductase (GSSG-R) deficiency and disturbed glutathione in cancer patients treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), by investigating how thiol metabolism, cell proliferation, and the nitrosourea interact in human K562 leukemia. Fasting cells arrested in G greatly increased their reduced glutathione (GSH) in response to growth factors. The rise in thiol began after several hours, peaked before DNA synthesis, and resulted from increased production. BCNU inactivated GSSG-R rapidly, and later retarded, doubled, and greatly prolonged GSH formation before stopping DNA synthesis. Pretreatment unlike post treatment with buthionine-S-R-sulfoximine (BSO) diminished BCNU's ability to block GSSG-R. Enzyme inhibition decreased with falling cellular GSH. In the leukemia system as in vivo, sequential BCNU-induced thiol alterations heralded delayed antiproliferative effects. Drug timing markedly affected both thiol and DNA syntheses. By destroying GSSG-R and delaying the upregulation of thiol synthesis while escalating GSH utilization and requirements, the nitrosourea created a striking and previously unrecognized window of vulnerability for GSH-dependent processes. During this period, altered GSH metabolism could contribute indirectly to BCNU's pleiotropic effects by interfering with DNA alkylation repair, glucose decarboxylation, deoxyribose formation, and possibly by influencing other aspects of proliferation. Acquired GSSG-R deficiency was also an early and sensitive marker for prodrug breakdown and activation.
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PMID:Glutathione, cell proliferation, and 1,3-bis-(2-chloroethyl)-1-nitrosourea in K562 leukemia. 825 30

Murine leukemia L1210 cells grown for 5-7 d in the presence of 1% serum without added selenium [Se(-) cells] expressed < 5% of the glutathione peroxidase (GPX) activity of selenium-supplemented controls [Se(+) cells]. Clonogenic survival assays indicated that t-butyl hydroperoxide (t-BuOOH) is much more toxic to Se(-) cells (LC50 approximately 10 microM) than to Se(+) or selenium-repleted [Se(-/+)] cells (LC50 approximately 250 microM). Hypersensitivity of Se(-) cells to t-BuOOH was partially reversed by treating them with Ebselen, a selenoperoxidase mimetic; thus, selenoperoxidase insufficiency was probably the most serious defect of Se deprivation. Cytotoxicity of t-BuOOH was inhibited by desferrioxamine and by alpha-tocopherol, indicating that redox iron and free radical intermediates are involved. Elevated sensitivity of Se(-) cells to t-BuOOH was accompanied by an increased susceptibility to free radical lipid peroxidation, which became even more pronounced in cells that had been grown in arachidonate (20:4, n-6) supplemented media. That glutathione (GSH) is required for cytoprotection was established by showing that Se(+) cells are less resistant to t-BuOOH after exposure to buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. Coupled enzymatic assays indicated that Se(+) or Se(-/+) cells metabolize t-BuOOH 20-25 times more rapidly than Se(-), consistent with the measured difference in GPX activities of these cells. Correspondingly, when challenged with t-BuOOH, Se(+) cells showed an initial loss of GSH and elevation of GSSG that exceeded that of Se(-) cells. It was further shown that like Se(-) cells, BSO- or BCNU-treated Se(+) cells metabolize t-BuOOH more slowly than nontreated controls. These results clearly indicate that selenoperoxidase action in the glutathione cycle is a vital element in cellular defense against toxic hydroperoxides.
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PMID:Selenoperoxidase-mediated cytoprotection against the damaging effects of tert-butyl hydroperoxide on leukemia cells. 845 83


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