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)

The new semisynthetic epipodophyllotoxin VP 16-213 has been tested for antitumor activity and toxicity in a non-randomized phase II trial. The study included 33 patients with solid tumors and acute leukemias. The drug was given in 5-day courses every 3 weeks, parenterally for the first 2 courses and thereafter orally. Subjectively VP 16-213 was well tolerated in both i.v. and oral administration, but almost universally induced leukothrombopenia and hair loss. The best results were achieved in 12 patients with oat cell carcinoma of the lung (4 good and 4 less good responses). Remissions of lesser quality were also observed in anaplastic lung cancer, ovarian carcinoma and acute myelomonocytic leukemia. VP 16-213 possesses proven, clinically valuable cytostatic activity against various human neoplasms. Complementary studies to establish its optimum dosage and administration, and its place in combination chemotherapy, are in progress.
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PMID:[Therapeutic experiences using the new podophyllotoxin derivative VP 16-213 in malignant human tumors]. 17 37

Two children with leukemia are presented, each demonstrating an unusual aspect of anthracycline-induced cardiomyopathy. In the first patient (a 7-month-old female with acute monocytic leukemia) extremely young age and previous chemotherapy with a podophyllotoxin derivative, VP-16, may have prediposed the patient to fatal congestive heart failure at a total Daunorubicin dose of only 225 mg/m2. In the second patient, a delay of 4 1/2 years was not sufficient in preventing congestive heart failure resulting from the administration of additional anthracycline chemotherapy. We conclude that extremely young age and, possibly, prior therapy with VP-16 may be addition risk factors in the development of anthracycline cardiomyopathy. Also, we suggest that once an anthracycline agent has reached a toxic threshold for the myocardium, the heart may always be at risk to injury from additional Adriamycin or Daunorubicin therapy.
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PMID:Anthracycline cardiomyopathy in children: report of two cases. 29 72

cis-Dichlorodiammineplatinum(II) (cis-platinum) has no more than additive, and often much less than additive, lethal toxicity for mice when given in combination with other anticancer agents representing several of the major functional classes of clinically useful anticancer drugs. The previously reported broad spectrum of anticancer activity of cis-platinum against tumors in laboratory animals has now been extended to promisingly useful therapeutic synergism in combination with other active anticancer drugs, including advanced-staged tumors in mice; eg, cis-platinum plus cyclophosphamide against advanced Ridgway osteogenic sarcoma and advanced P388 leukemia, and as surgical adjuvant chemotherapy against advanced colon tumor 26; cis-platinum plus Adriamycin against advanced P388; and cis-platinum plus VP-16-213 against advanced P388. Therapeutic synergism was also seen with cis-platinum plus carminomycin (an Adriamycin analog) against early colon tumor 26. Resistance and cross-resistance studies using sublines of L1210 and P388 selected for resistance to various alkylating agents (cyclophosphamide, melphalan, BCNU, or cis-platinum) indicate a variety of resistance and cross-resistance patterns which further support the growing body of evidence that wide differences in mechanism of cytotoxic activity exist among alkylating agents having experimentally and clinically useful anticancer activity. These data support the observed therapeutic synergisms with combinations of alkylating agents seen against a broad spectrum of murine tumors, and they suggest other drug combinations that might be considered for experimental and clinical trial based on a growing number of logical differences in biochemical mechanism of action of alkylating agent anticancer drugs that have been reported.
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PMID:cis-Dichlorodiammineplatinum(II): combination chemotherapy and cross-resistance studies with tumors of mice. 29 80

VP-16-213, a semisynthetic podophyliotoxin, was tested for antitumor and clinical toxicity in 126 children. The drug was administered iv daily x 5 days every 2 weeks at a starting dose of 75 mg/m2/day. The dose was increased by 25 mg/m2/day/course until clinical response or significant toxicity occurred. The only major toxicity was hematologic, with neutropenia as the most predominant feature. There was one local allergic reaction at the site of injection. No systemic allergic responses were reported. The drug demonstrated significant activity in acute myelomonocytic leukemia with four responses among 19 patients, less activity in acute myelocytic leukemia with two responses among 44 patients, and little activity in acute lymphocytic leukemia with only one partial response among 12 patients. Objective partial responses occurred in ten of 48 patients with solid tumors: two each with Wilms' tumor, lymphoma, and histiocytosis X, and one each with rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, and undifferentiated carcinoma. The inclusion of VP-16-213 in combination chemotherapy for childhood acute myelomonocytic leukemia and acute myelocytic leukemia appears indicated in patients relapsing after initial therapy. For solid tumors this is an interim report, with further patient accrual required before specific comments can be made.
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PMID:Phase II study of VP-16-213 in childhood malignant disease: a Children's Cancer Study Group Report. 29 6

VP 16-213, a derivative of podophyllotoxin, is currently entering phase-III studies. Its mode of action is incompletely understood, but differs markedly from that of its parent compound. The greatest lethal damage is experienced by cells in the late S and G2 phases. In the L 1210 system the drug shows marked schedule dependency: prolonged administration may be more effective than single bolus administration. As a single agent, VP 16-213 is the most active compound yet tested against small-cell bronchial carcinoma. It may also prove to be a useful agent in patients with other types of lung tumour, testicular teratomas, and some types of leukaemia. No long-term or cumulative toxicity has been reported. Most side effects are predictable and reproducible.
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PMID:Podophyllotoxin derivative VP 16-213. 38 78

The in vivo effects of VM-26 and VP-16-213 upon hematopoietic stem cells and L1210 leukemia cells were quantitated using the spleen-colony assay technique. The effect of VM-26 on leukemia cells was further quantitated using an endpoint dilution assay. The dose-response curves for leukemic clonogenic cells for both agents when given by iv injection were exponential and biphasic, indicating the existence of two populations. The survival of leukemia cells when VM-26 was administered as a 24-hour infusion was less than that found for equivalent doses administered as single injections. The survival kinetics with respect to time for a low dose (0.02 mg/mouse) and a high dose (0.15 mg/mouse) of VM-26 were similar in that the decrease in survival was rapid, reaching a maximum effect within 4 hours after administration. With the low dose, repopulation of the femoral marrow started immediately, whereas with the high dose, there was a 20-hour delay in repopulation. The data from the increase in lifespan studies were in excellent agreement with the quantitative assays. The dose-response curves for the normal hematopoietic clonogenic cells were also exponential, but these cells were much less sensitive to the agents than were the leukemia cells.
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PMID:Kinetics of cytotoxicity of VM-26 and VP-16-213 on L1210 leukemia and hematopoietic stem cells. 68 75

Fifteen patients with acute myeloic leukemia in the first relapse following initial therapy were treated with a combination of adriamycin, vincristine, 6-thioguanine and the new podophyllotoxin derivative VP 16-213. Complete remission was obtained in 3 cases and partial remission in 3 further patients. The combination was generally well tolerated. These preliminary results are compared with those available in the relatively meagre literature. The study is being continued.
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PMID:[The treatment of acute myelocytic leukemia during the first recurrence by means of a new cytostatic combination]. 107 Jan 54

A group of chrysophanol and emodin derivatives with DNA-intercalating capability and with or without alkylating potential have been synthesized and shown to have antitumor activity in vitro. The topoisomerase II (Topo II)-mediated DNA cleavage activities induced by representative compounds 3-(2-chloroethylamino) methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31690), 3-bis [(2-chloroethyl)amino]methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31662), and 3-(2-hydroxyethylamino)methy-1,8-dihydroxy-9,10-anthraquinon e (SK-31694), and their cytotoxicities, have been investigated. All three compounds inhibited the kinetoplast DNA decatenation catalyzed by DNA Topo II. These compounds inhibited leukemia cell growth and stimulated, in a dose-dependent manner from 0.5 to 60 microM, the formation of Topo II-DNA cleavable complexes, when 3'-32P-labeled DNA was used. The mapping of Topo II-mediated DNA cleavage sites using HindIII-digested 3'-32P-labeled DNA showed that, at 10 microM, these compounds induced protein-linked DNA breaks that correlated with cytotoxicity, with respect to their maximal efficacy or the reciprocal concentration for the half-maximal effect. The reversibility study showed that the amounts of protein-linked DNA cleavage induced by 4'-(9-acridinylamino)methanesulfon-m-anisidide and VP-16 as well as SK-31694, which lacks alkylating potential, were markedly decreased during 30-sec exposure to 65 degrees or 0.5 M NaCl. In contrast, protein-linked DNA cleavages induced by SK-31662, which has two alkylating functionalities, and by SK-31690, which has one alkylating functionality in its structure, cannot be reversed during the 15-min exposure to 65 degrees or 0.5 M NaCl. These data suggest that Topo II is a major cellular target for cytotoxicity of these compounds. Furthermore, DNA intercalators with alkylating potential interact with Topo II-DNA cleavable complexes in an irreversible manner, with enhanced toxicity.
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PMID:Topoisomerase II-mediated DNA cleavage activity and irreversibility of cleavable complex formation induced by DNA intercalator with alkylating capability. 131 6

A novobiocin-resistant subline of WEHI-3B D+ murine monomyelocytic leukemia cells was developed by the continuous exposure of cells to this agent in vitro. Sensitive (WEHI-3B/S) and novobiocin-resistant (WEHI-3B/NOVO) sublines were cloned in vitro. WEHI-3B/NOVO cells were stable in the absence of novobiocin for more than 3 months, and the sensitive and resistant clones displayed the same growth rate, cell cycle distribution, cell size, DNA and protein content, and cloning efficiency. Novobiocin has been shown to compete with ATP for the ATP-binding site of topoisomerase II; therefore, intracellular ATP levels can influence the cellular sensitivity to novobiocin. High-performance liquid chromatographic analysis of total cell extracts demonstrated that no difference exists between WEHI-3B/S and WEHI-3B/NOVO cells in the content of ATP. Furthermore, exposure of both cell lines to novobiocin did not affect intracellular ATP levels. In addition to an approximately 2-fold level of resistance to novobiocin, the WEHI-3B/NOVO subline was also 7- and 11-fold cross-resistant to the topoisomerase II-targeted drugs, teniposide and etoposide (VP-16), respectively. A lower level of cross-resistance, comparable to that of novobiocin, was observed in WEHI-3B/NOVO cells for the intercalating topoisomerase II-reactive drugs, doxorubicin, 4'-(9-acridinylamino)methanesulfon-m-anisidide and aclacinomycin A, while the sensitivity to the cytotoxic action of the non-topoisomerase II-acting agents, camptothecin and vincristine, was not altered. After 3-6 h of exposure to 1 microM VP-16, WEHI-3B/S cells accumulated in the S and G2 + M phases of the cell cycle. Similar changes were detected in WEHI-3B/NOVO cells only after exposure to a 10-fold higher concentration of VP-16. Exposure to 150 microM novobiocin caused an accumulation of WEHI-3B/S cells in the G0-G1 phase of the cell cycle but did not affect the cell cycle distribution of WEHI-3B/NOVO cells, while camptothecin induced the same type and extent of changes in the cell cycle distribution of both cell lines. Although the WEHI-3B/NOVO subline appeared to be less responsive to the differentiation-inducing activity of novobiocin and teniposide, the capacity of WEHI-3B/NOVO cells to respond to the differentiation-inducing agent 13-cis-retinoic acid was not significantly different from that of WEHI-3B/S cells. A slight decrease in the accumulation of VP-16 occurred in the resistant cell line, which did not appear to be of sufficient magnitude to account for the 11-fold increase in the degree of resistance to this agent.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development and characterization of a WEHI-3B D+ monomyelocytic leukemia cell line resistant to novobiocin and cross-resistant to other topoisomerase II-targeted drugs. 131 27

Treatment of human K-562-J leukemia cells for 1 h with the topoisomerase II-reactive drugs VP-16, VM-26, or mAMSA resulted in a dose-dependent inhibition of proliferation and in an increase in the percentage of cells staining positive for hemoglobin, a marker of erythroid differentiation. Staining for hemoglobin of up to about 60% of the cells was observed at 20 microM VP-16, 1 microM VM-26, and 8 microM mAMSA. Such treatment also caused a G2/M arrest in the cell cycle. Incubation of the cells with radiolabeled VP-16 indicated that the induced erythroid differentiation was not due to continuous cell exposure to a residual amount of the drug. VP-16-induced erythroid differentiation was also not affected by DNA, RNA, or protein synthesis inhibitors. Differentiation induction and the G2/M arrest evoked by VP-16, VM-26, and mAMSA were, however, reduced in the presence of novobiocin. Our results indicate that topo-reactive drugs that cause G2/M arrest in the K-562-J cell cycle can induce in these cells erythroid differentiation after a short and irreversible interaction with their target molecule(s).
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PMID:The effect of topoisomerase inhibitors on the expression of differentiation markers and cell cycle progression in human K-562 leukemia cells. 133 Jun 53


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