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)

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.
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PMID:High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse. 352 19

A high dose combination chemotherapy regimen (CBV) consisting of cyclophosphamide (1.5 gm/m2 day 1 to day 4); BCNU (300 mg/m2 day 1) and etoposide (100 mg/m2 every 12 hours for 6 doses), followed by bone marrow transplant from human leukocyte antigen (HLA) identical sibling donors, was evaluated in 29 patients in whom acute leukemia was in relapse or remission. Engraftment of donor cell type occurred in all but one of 21 patients, in whom marker differences between donor and recipient were established. Two of 11 patients transplanted during relapse of the disease, lived beyond 1 year after bone marrow transplantation. One patient died free of leukemia, 41 months after transplantation of meningitis. Two of seven patients transplanted during the second remission of the disease, are alive and free of leukemia at 42+, and 8+ months. All patients transplanted during the third or fourth remission of the disease have died from either a further relapse, or transplant related causes. The low incidence of organ toxicity with CBV allows for further dose escalation of its drug components.
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PMID:High dose cyclophosphamide, BCNU, and VP-16 (CBV) as a conditioning regimen for allogeneic bone marrow transplantation for patients with acute leukemia. 354 28

Alkylating agent-sensitive and -resistant L1210 leukemia cell lines were used to determine the tumor response to dose levels of drugs that exceeded conventional doses up to a factor of 10. Since those dose levels were lethal to the host mice, tumor response was based on the results of in vivo bioassays of spleen and/or tumor from drug-treated and control mice. When mice bearing about 10(8) drug-sensitive leukemic cells were treated with a single, conventional (approximately 10% lethal) dose of cis-diamminedichloroplatinum, L-phenylalanine mustard (melphalan), or 1,3-bis(2-chloroethyl)-1-nitrosourea, 10(1) to 10(4) tumor cells were recovered by bioassay. Treatment at doses that were 2 to 8 times the 10% lethal dose of either of those drugs resulted in no recoverable cells and survival of all bioassay recipient mice. Mice bearing advanced L1210 leukemia resistant to cis-diamminedichloroplatinum (L1210/DDPt), 1,3-bis-(2-chloroethyl)-1-nitrosourea (L1210/BCNU), cyclophosphamide (L1210/CPA), or melphalan(L1210/L-PAM) also were treated with a 10% lethal dose and greater doses of the drug to which the tumor line was resistant. Bioassay results indicated a direct correlation between dose intensity and tumor cell kill, the response being linear. Similarly, when mice with L1210/BCNU were treated with high doses of N-(2-chloroethyl)-N''-(2,6-dioxo-3-piperidinyl)-N-nitrosourea or 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA) and when mice with L1210/DDPt were treated with cyclophosphamide, an increasing, linear cell kill resulted throughout the high-dose range. Overall, these results indicate that resistance to these alkylating agents can be overcome by dose intensification and that the tumor response is linear in relation to increasing dose level.
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PMID:Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy. 356 26

Literature on secondary tumours developing after cancer chemotherapy with nitrosoureas is reviewed. Many case studies show that combination treatments including BCNU and CCNU give rise predominantly to acute leukaemia within an average latent period of about 40 months. However, because other, potentially carcinogenic alkylating agents may be administered during treatment, no direct causal association with nitrosoureas can be made on the basis of these studies. A large case-control study by Boice et al. (1983), however, provides strong evidence of a causal relationship between the induction of acute nonlymphocytic leukaemia (ANLL) and treatment with methyl-CCNU. Among 2067 patients treated with methyl-CCNU and 5-fluorouracil as adjuvant chemotherapy after surgery for gastrointestinal cancers, nine cases of ANLL were observed, whereas 0.71 were expected; the relative risk was 15.9. The results are discussed and are interpreted as providing evidence for the carcinogenicity of methyl-CCNU to humans. They are therefore consistent with other epidemiological data on the carcinogenicity of N-nitroso compounds to man.
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PMID:Carcinogenicity of nitrosoureas in humans. 358 92

The pharmacokinetics of antineoplastic drugs based on compartmental models are combined with deterministic exponential growth models of tumors containing drug-resistant and sensitive cells. Model predictions for single-drug therapy are compared with in vivo data obtained by other investigators for L1210 t-cell leukemia in mice treated with BCNU and Ara-C and for in vitro treatment of L1210 with Ara-C. The model and data compare favorably in terms of rate of tumor growth and duration of drug action for both constant infusion and bolus delivery of the drugs.
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PMID:Multicompartment models of cancer chemotherapy incorporating resistant cell populations. 361 99

DNA damage caused by methazolastone [an analogue of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide which does not require metabolic activation] was investigated in L-1210 leukemia which is sensitive to this drug and in a L-1210 subline [L-1210/N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU)] which is resistant to both chloroethylnitrosoureas and methyltriazenes. Both in vitro and in vivo metazolastone caused formation of DNA alkali-labile sites (assessed by alkaline elution techniques) which were present in similar amounts and repaired at a similar rate in L-1210 and L-1210/BCNU. This suggests that these lesions are not crucial to methyltriazenes activity. DNA alkali-labile sites may be due to the removal of 7-methylguanine by 7-methylguanine-DNA glycosylase which showed the same activity in L-1210 and L-1210/BCNU. Flow cytometry studies revealed that in L-1210 but not in L-1210/BCNU methazolastone induced an arrest of cells in SL-G2-M phases. This blockade was delayed, occurring after at least two cell divisions after drug treatment and therefore appeared temporally unrelated to the presence of DNA alkali-labile sites. There was three times more O6-methylguanine-DNA methyltransferase in L-1210/BCNU than in L-1210 suggesting that methylation of O6-guanine is an important lesion for methyltriazenes activity and resistance to this drug may be linked to its repair.
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PMID:In vitro and in vivo methazolastone-induced DNA damage and repair in L-1210 leukemia sensitive and resistant to chloroethylnitrosoureas. 362 Nov 81

Using centrifugation of the nucleoid in a neutral sucrose gradient, the damages in the secondary structure of DNA and the activity of repair enzymes, such as DNA-polymerases alpha and beta and poly(ADP-riboso) polymerase, induced by 1-methyl-nitrosourea (MNU) and 1.3-bis (2-chloroethyl)-1-nitrosourea (BCNU) injected at maximal nonlethal single doses to mice bearing parent leukemia cells (L1210/0) and resistant to MNU and BCNU leukemia L1210 cells (L1210/MNU and L1210/BCNU), were studied. The MNU-induced production of single-strand breaks in L1210/0 and L1210/MNU cells was more conspicuous in newly replicated DNA than in those in preexisting DNA. A more fast repair of the damages in newly replicated DNA was detected in L1210/BCNU and especially in L1210/MNU leukemia cells as compared with L1210/0 cells. The data obtained suggest that there are prone errors in the repair of DNA template, since most of the single-strand breaks were revealed in the newly replicated DNA synthesized on the repaired DNA. The repair of DNA damages in L1210/BCNU and especially in L1210/MNU cells was accompanied by the activation of DNA-polymerases alpha and beta and poly(ADP-riboso)polymerase. Both DNA-polymerases--alpha and beta--were shown to be involved in repair of DNA damages induced by MNU and only DNA-polymerase beta was involved in the repair of damages induced by BCNU.
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PMID:[The role of N-nitrosourea-induced changes in the nucleoid structure and activity of repair enzymes in the development of drug resistance in mice with leukemia L1210]. 366 67

The damage of DNA structure and synthesis in murine leukemia L1210 cells upon single administration in therapeutic doses of antitumour agents of N-nitrosourea type, such as 1-methyl-1-nitrosourea (MNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was studied. MNU and BCNU were characterized by stronger inhibitory effects on de novo DNA synthesis compared to additional pathway of DNA synthesis in leukemia L1210 cells in vivo. Centrifugation in alkaline sucrose density gradients of L1210 cell lysates has revealed persistent single-strand breaks and alkaline-labile sites in newly replicated DNA. Parental DNA structure was more stable to damaging drug effects than that of newly replicated DNA. The results are consistent with our previous data on the differences in the mechanisms of MNU and BCNU action and the absence of complete cross resistance between the drugs.
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PMID:[Relation between the changes in the structure and synthesis of DNA in the cells of mouse leukemia L1210 induced by 1-methyl-1-nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea]. 394 37

The antitumor action of the 2-chloroethylnitrosocarbamoyl derivatives of peptides related to the 9-13 amino acid residues of alpha-MSH/ACTH and of the C-terminal tetrapeptide analogue of gastrin have been investigated. Series of 2-chloroethylnitrosoureas attached to amino acids, di-, tri-, tetra-, or pentapeptides were examined in a primary screening system. Among these compounds the Pro-Val-, Lys-Pro-Val-, and Trp-Gly-Lys-Pro-Val-containing 2-chloroethylnitrosocarbamoyl groups were the most effective in the L1210 system. The human melanoma xenograft line was also affected by these agents, while colorectal xenografts were insensitive. A combination of tripeptide-2-chloroethyl-nitrosourea with BCNU induced more than additive growth inhibition of L1210 leukemia.
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PMID:Antitumor action of N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of biologically active polypeptide hormone fragments. 394 98

This report demonstrates the synergistic killing of murine L1210 leukemia in vitro by BCNU and theophylline as has previously been reported in vivo. Synergism is also seen with the related nitrosourea CNU plus theophylline. As measured on alkaline sucrose gradients and by pH-step alkaline elution, the nitrosourea-induced inhibition of DNA replicon initiation is completely reversed in the presence of theophylline. DNA interstrand crosslinking, the damage which usually correlates with nitrosourea cytotoxicity, is not increased by the combination of nitrosourea plus theophylline. At high nitrosourea doses, this interstrand crosslinking is reduced in the presence of theophylline. At least part of the mechanism of the two-drug synergism is the theophylline release of nitrosourea-induced DNA initiation inhibition. Some of the results have been presented at the Annual Meeting of the American Association for Cancer Research.
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PMID:Theophylline release of replicon initiation inhibition by nitrosoureas correlates with the synergistic killing in L1210 leukemia in vitro. 400 Jan 48


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