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)

BMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4' of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preclinical antitumor activity of a soluble etoposide analog, BMY-40481-30. 238 14

The in vitro cytotoxicity of etoposide against mouse P388 leukemia cells was kinetically studied and compared with those of podophyllotoxin, the parent compound, and other antitumor agents. When P388 cells were exposed to etoposide, surviving-cell fraction decreased with etoposide concentration and exposure time. Similar results were obtained with doxorubicin, peplomycin and cisplatin. The cytotoxicity of melphalan was dependent on concentration but scarcely on exposure time. From these data, n in Cn X T = K where T, C and K are exposure time, concentration required for killing 90% of P388 cells and a constant, respectively, was calculated. Etoposide gave an n value of 1.16. n values for doxorubicin, peplomycin and cisplatin, all belonging to the Shimoyama type Ib group where the cytotoxicity of the agent depends on both concentration and exposure time, were 1.29, 1.28 and 3.03, respectively. The n value for melphalan, belonging to the type Ia group where cytotoxicity depends only on concentration, was 54.0. From these results, it was concluded that etoposide is of type Ib. The cytotoxicities of podophyllotoxin, 5-fluorouracil, cytarabine and vinblastine were greatly dependent on exposure time. Podophyllotoxin may be an agent of type II whose cytotoxicity depends only on exposure time.
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PMID:[Kinetics of etoposide cytotoxicity against mouse P388 leukemia]. 241 68

An intensive regimen of combined etoposide (VP-16) and 5-azacitidine (5-Az) was used to treat 96 children and adolescents with refractory or relapsed acute nonlymphocytic leukemia (ANLL). Patients were given two sequential five-day courses of VP-16, 250 mg/m2 for three days, followed by 5-Az, 300 mg/m2 for two days. An additional five-day course was administered if marrow aplasia was not evident by day 13. A complete remission rate of 45% was achieved with a median of two courses of VP-16 and 5-Az. The outcome of induction therapy was not influenced by prior treatment, blast cell morphology, or disease status on study entry (refractory or relapsed). Twenty-seven patients have relapsed after remission periods of 35 to 920 days (median, 110 days); seven others are free of leukemia for up to 519 days. The effectiveness of VP-16/5-Az combination therapy in patients refractory to anthracyclines and cytarabine indicates a potential role for these compounds in first-line treatment of patients with ANLL.
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PMID:Combined etoposide and 5-azacitidine in children and adolescents with refractory or relapsed acute nonlymphocytic leukemia: a Pediatric Oncology Group Study. 243 59

We examined the effect of various concentrations of VP 16-213 (25-125 microM/l, 2-h incubation on normal and complete remission bone marrow from patients with acute leukaemia and on leukaemic blasts. The maximal tolerated dose of the drug for normal bone marrow GM-CFC was between 75 and 100 microM/l whereas that for complete remission bone marrow was distinctly lower. More early stem cells measured by aid of LTBMC were more resistant in normal, but not in every remission bone marrow. We have to examine if these LTBMC results are influenced by a damaged microenvironment by using 2 stage LTBMC. Spontaneous leukaemic cells showed a different, sometimes lower sensitivity to VP 16-213 doses maximally tolerated by normal hemopoietic cells so that the VP 16-213 incubation must not be effective for every leukaemia.
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PMID:Growth of hemopoietic cells after incubation with VP 16-213. 248 Mar 14

Our human T-cell leukemia line, CEM/VM-1, selected for resistance to VM-26 (teniposide), is cross-resistant to several drugs that interact with topoisomerase II, including VP-16 (etoposide), 4'-(9-acridinylamino)methanesulphon-m-anisidide, daunorubicin, and mitoxantrone. However, in contrast to cell lines exhibiting multidrug resistance (MDR) associated with overexpression of P-glycoprotein, this line is not cross-resistant to the Vinca alkaloids, is not impaired in drug accumulation, and does not overexpress the mdrl gene (Cancer Res., 47: 1297, 5455, 1987). More recently we found that nuclear extracts of these cells exhibit decreased topoisomerase II catalytic and cleavage activity, compared to the drug-sensitive line (Biochemistry, 1988). These results suggest that an alteration in topoisomerase II or a modulator of this enzyme may be responsible for this altered topoisomerase II-form of multidrug resistance (at-MDR). In the present work, we studied the somatic cell genetics of at-MDR. We produced hybrid cell lines by polyethylene glycol-mediated fusion of the CEM/VM-1 line with a hypoxanthine-guanine phosphoribosyl transferase-deficient, ouabain-resistant CEM line (CEM.AG1.OU1.5) that exhibits VM-26 sensitivity. Ten of the hybrid lines that grew in selective medium were randomly chosen for expansion and four were analyzed for both DNA content by flow cytometry and VM-26 sensitivity in a 72-h growth inhibition assay. The hybrid lines all contained approximately 2x DNA compared to unfused controls, indicating that the fusions were successful. The IC50 for VM-26 in 3 of the 4 lines was the same as that of the sensitive controls, ranging from 4.7 to 7.4 x 10(-8) M, and another was 76 x 10(-8) M. These data indicate that drug sensitivity was reconstituted by the hybridization procedure. By comparison, the VM-26 IC50 values in the CEM/VM-1 cells and CEM/VM-1 x CEM/VM-1 control "fusions" were 360 and 750 x 10(-8) M, respectively. To determine whether a topoisomerase II-mediated function was reconstituted in the hybrids, we measured drug-stimulated DNA cleavage ("cleavable complex formation"). Using 32P-labeled pBR322 DNA as substrate with nuclear extracts from drug sensitive cells, 100 microM VM-26 maximally stimulated DNA cleavage by approximately 11-fold compared to no-drug controls.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetic characterization of the multidrug-resistant phenotype of VM-26-resistant human leukemic cells. 253 2

Two monoclonal antibodies of F (ab')2 form, MRK 16 and MRK 20 that recognize P-glycoprotein and P85 kD protein respectively, were useful to detect multidrug resistant cells in human lymphoma, leukemia and gastrointestinal cancer cell lines. They were classified into 4 groups: Group I (4 cell lines) was insensitive to vinca alkaloids, anthracyclines, etoposide (VP-16) and actinomycin-D (ACT-D), and reactive to MRK 16 and MRL 20. Group II (2 cell lines) was insensitive to vincristine (VCR), but not reactive to both antibodies. Group III (3 cell lines) was insensitive to anthracyclines and VP-16, but sensitive to vinca alkaloids and ACT-D, and reactive to MRK 20 but not to MRK 16. Group IV (all other cell lines) was sensitive to these drugs, and not reactive to both antibodies. MRK 16 detects P-glycoprotein-associated multidrug resistance (MDR), while MRK 20 detects P 85kd-associated novel MDR. These monoclonal antibodies were useful for detection of MDR cells in clinical samples.
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PMID:[Detection of multidrug resistant cells in human malignant diseases by monoclonal antibodies and strategy to eradicate resistant malignant cells]. 256 3

Using flow cytometry and immunocytochemistry, we investigated the reactivities of two different murine monoclonal antibodies (MAbs), MRK 16 and MRK 20, specific to adriamycin-resistant K562 cells (K562/ADM) with peripheral human mononuclear cells (MNC) (mainly blastic cells and lymphocytes) from 31 patients with leukaemia or malignant lymphoma. Reactivity with MRK 16 MAb was observed in five cases and reactivity with MRK 20 MAb in 18 cases. The cases were divided into three groups according to their reactivity patterns: group I, only the proportion of MRK 16-positive cells was increased; group II, only the proportion of MRK 20-positive cells was increased; group III, both MRK 16-and MRK 20-positive cells were increased. Some cases reflected the prior administration of adriamycin, vincristine, vinblastine and VP-16, which are known to induce P-glycoprotein expression. Expression of Mr 85,000 protein was observed more frequently than that of P-glycoprotein in leukaemia and malignant lymphoma, and this was not associated with either the total dose or period of administration of anticancer drugs. The expression of Mr 85,000 protein recognised by MRK 20 was further confirmed by Western blot analysis.
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PMID:High-level expression of MRK 16 and MRK 20 murine monoclonal antibody-define proteins (170,000-180,000 P-glycoprotein and 85,000 protein) in leukaemias and malignant lymphomas. 257 70

Forty cultured human leukemia and lymphoma cell lines never exposed to anticancer agents in culture, apart from doxorubicin (ADM)-resistant K562/ADM, were examined for reactivity with a monoclonal antibody, MRK16 in F(ab')2 form [MRK16-F(ab')2], which recognizes P-glycoprotein (P-gp). The relative resistance index to various drugs was calculated by dividing the 50% growth inhibitory concentration (IC50) of the test cell line by IC50 of K562, which was the negative control in the antibody experiment. MRK16-F(ab')2 reacted with four cell lines, K562/ADM, KYO-1, HEL and CMK, which had relative resistance index values of 2 or more to vincristine (VCR), vindesine, vinblastine, ADM, daunorubicin, mitoxantrone (MIT), etoposide (VP-16) and actinomycin-D (ACT-D). The level of resistance to VCR and ADM in these cell lines decreased significantly in the presence of 10 microM verapamil in vitro. Significant expression of mRNA of P-gp gene was also detected in K562/ADM, KYO-1 and HEL. MRK16-F(ab')2 did not react with 36 other cell lines. Among them, three cell lines, PL-21, P31/FUJ and KOPM-28, had relative resistance index values of 2 or more to anthracyclines, MIT and VP-16, but not to vinca alkaloids or ACT-D. The level of ADM-resistance in these cell lines did not decrease significantly in the presence of 10 microM verapamil. Five cell lines, ATL-1K, HL-60, KMOE-2, ML-1 and U266, had relative resistance index values of 2 or more to some of the drugs, but not to the others, and 19 other cell lines did not. These results indicate that the reactivity of MRK16-F(ab')2 correlates with a relative resistance index of 2 or more to all these drugs in cultured human leukemia and lymphoma cell lines.
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PMID:Multidrug resistance in cultured human leukemia and lymphoma cell lines detected by a monoclonal antibody, MRK16. 257 8

The sequence dependency of the antitumor effect of etoposide and ara-C was investigated against the L1210 ascites tumor in BDF1 mice. Etoposide (7.5 mg/kg or 15 mg/kg) and ara-C (25 mg/kg or 500 mg/kg) were administered intraperitoneally on days 1, 4 and 7 after inoculation of L1210 with or without time interval of 3 or 6 h. Antitumor effect was decided for cure rate and post inoculation survival time of the mice died of tumor. Six hours pretreatment with 15 mg/kg of etoposide followed by 500 mg/kg of ara-C yielded 100% of cure rate, but only 20% of cure rate was obtained with the reverse sequence. Simultaneous administration of etoposide and ara-C produced 70% of cure rate. At every dosage examined, pretreatment with etoposide given 6 hr before ara-C was the most effective antitumor schedule in L1210 leukemia.
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PMID:[Studies on the relationship between therapeutic schedule and antitumor effect of etoposide and cytosine arabinoside in murine L1210 leukemia]. 261 69

Podophyllic acid piperidyl hydrazone nitroxide radical (GP-1) and etoposide (VP-16), derivatives of podophyllotoxin, inhibited DNA, RNA, protein and ATP synthesis of leukemia L7712 cells at a concentration of 5 micrograms/ml. Inhibitory extents were dependent on the exposure time from 3 to 24 h. The inhibitory rates of both drugs were about 15-66%. ID50 of GP-1 and VP-16 on the synthesis of L7712 cells at 24 h were 0.16 and 0.38 micrograms/ml, respectively. The dose-response curve of GP-1 was a parabolic one, while that of VP-16 was a straight line. The inhibition of GP-1 or VP-16 on DNA synthesis existed also after cells washing. It is suggested that the antitumor effects of GP-1 and VP-16 seem to be related to the damage of DNA template.
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PMID:[Podophyllic acid piperidyl hydrazone nitroxide radical and etoposide on nucleic acids and protein metabolism of leukemia L7712 cells in vitro]. 262 25


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