Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Etoposide, a derivative of epipodophyllotoxin, is one of the most important new drugs that was introduced into the management of the malignant lymphomas during the past decade. A growing number of specific protocols include this useful agent in the management of malignant lymphoma, both at the time of primary treatment and at relapse. The broad activity of etoposide across several histologic subtypes of malignant lymphoma and Hodgkin's disease indicates a potential that is only now being fully exploited. Used according to optimal doses and schedules, etoposide has single-agent activity that rivals earlier drugs such as the alkylating agents and doxorubicin. Functioning as a protein synthesis and topoisomerase II inhibitor, it offers the potential for non-cross-resistant cytotoxicity. After a brief comment on the single-agent activity of etoposide, this report will focus on the integration of etoposide into multiagent protocols used in the primary treatment of malignant lymphoma and Hodgkin's disease. The specific findings from protocols such as prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide-cytarabine, bleomycin, vincristine, and methotrexate (Pro-MACE-CytaBOM) (US National Cancer Institute [NCI]) and etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) (Vancouver) for the primary treatment of malignant lymphoma, and vinblastine, etoposide, cyclophosphamide, doxorubicin, bleomycin, vincristine, and prednisone (VECABOP) (Vancouver) for the treatment of previously untreated patients with advanced Hodgkin's disease will be discussed.
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PMID:The evolving role of etoposide in the management of lymphomas and Hodgkin's disease. 198 27

Etoposide has demonstrated highly significant clinical activity against a wide variety of neoplasms, including germ-cell malignancies, small-cell lung cancer, non-Hodgkin's lymphomas, leukemias, Kaposi's sarcoma, neuroblastoma, and soft-tissue sarcomas. It is also one of the important agents in the preparatory regimens given prior to bone marrow and peripheral stem-cell rescue. Despite its high degree of efficacy in a number of malignancies, the optimal dose, schedule, and dosing form remain to be defined. It is possible that continuous or prolonged inhibition of the substrate, i. e., topoisomerase II, may be the key factor for the cytotoxic effects of etoposide. Clinical studies have shown the activity of etoposide to be schedule-dependent, with prolonged dosing, best accomplished by the oral dosing form, offering a therapeutic advantage. This benefit awaits validation by prospective randomized studies, some of which are in progress. Recent clinical investigations have focused on the use of etoposide in combination with (a) cytokines to ameliorate myelosuppression, the dose-limiting toxicity of etoposide; (b) agents such as cyclosporin A and verapamil to alter the p-glycoprotein (mdr1) function; and (c) topoisomerase I inhibitors to modulate the substrate upon which it acts. There is continued interest in the development of etoposide to its maximal clinical dimensions and in the examination of alternative biochemical and mechanistic approaches to further our understanding of this highly active agent.
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PMID:Etoposide: current status and future perspectives in the management of malignant neoplasms. 807 20

A feasibility study was carried out on the treatment for refractory and relapsed non-Hodgkin's lymphomas with a combination of two oral topoisomerase II inhibitors, MST-16 and VP-16. On the basis of the synergistic activity in preclinical studies and the schedule dependency in these drugs, low-dose and long-term administration was planned. For the anticipated myelosuppression, two different regimens were designed as an open label trial in this study. In Regimen I, 400 mg of MST-16 combined with 25 mg of VP-16 was administered daily. With this regimen, the response rate (RR)/median time to tumor progression (TTP) in all evaluable patients was 50% (2/4)8.5 months in low grade (indolent) lymphoma and 60% (6/10)/5.2 months in intermediate/high grade (aggressive) lymphomas. In Regimen II, 400 mg of MST-16 combined with 25 mg of VP-16 was administered intermittently (3 days a week or every other day). With this regimen, there was an RR/median TTP of 60% (3/5)/7.0 months in indolent lymphoma and 33.3% (4/12)/1.1 months in aggressive lymphoma. A major side effect in both of these regimens was myelosuppression, with the incidence of grades 3 and 4 toxicity being higher in Regimen I than in Regimen II. The other side effects were uncommon and not severe. These findings indicated that two regimens were tolerated well and were promising for refractory and relapsed aggressive non-Hodgkin's lymphomas. To define the anti-tumor activity and safety of these regimens precisely, large-scale prospective randomized trials are necessary.
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PMID:Feasibility of salvage chemotherapy for refractory or relapsed non-Hodgkin's lymphoma with two topoisomerase II inhibitors, MST-16 and VP-16. MST-16 Study Group. 892 84

Pulmonary involvement by lymphomatoid granulomatosis (LYG) is characterized by nodules of a polymorphous lymphoreticular infiltrate with necrosis, angioinvasion, and variable numbers of large, atypical cells. Using combined immunohistochemistry, the authors compared the expression of a marker of proliferation (DNA topoisomerase IIalpha) between B cells, T cells, and histiocytes. Sixteen cases of LYG were stained by combined immunohistochemistry for DNA topoisomerase IIalpha and CD-20, CD-3, CD-68, and CD-57. A proliferation index was determined for B cells, T cells, histiocytes, and natural killer cells by dividing the number of cells with coexpression of DNA topoisomerase IIalpha and CD-20, CD-3, CD-68, or CD-57 by the total number of CD-20+, CD-3+, CD-68+, or CD-57+ cells, respectively. A significantly higher proliferation index was present in B cells compared to T cells, histiocytes, or natural killer cells (p < 0.002). The average proliferation index for B cells was 0.25+/-0.24 (range, 0.00-0.76), for T cells was 0.02+/-0.01 (range, 0.00-0.04), for histiocytes was 0.00+/-0.01 (range, 0-0.02), and for natural killer cells was 0.00+/-0.00 (range, 0.0-0.02). The average proliferation index of CD-20+ cells was greater in grade III LYG (0.36) than in grade II LYG (0.17) or the single case of grade I LYG (0.00). The authors conclude that (1) there is a spectrum of B-cell proliferation in LYG that roughly correlates with histologic grade, (2) T cells, histiocytes, and natural killer cells do not proliferate but are recruited, and (3) the average B-cell proliferation index in grade III LYG is similar to that observed in large cell non-Hodgkin's B-cell lymphomas. These observations provide a possible rationale for the use of chemotherapy for grade III LYG and observation or immunologic adjuvants for LYG with grade I or grade II histology.
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PMID:Proliferation and cellular phenotype in lymphomatoid granulomatosis: implications of a higher proliferation index in B cells. 1047 82

Preliminary clinical trials suggest that iodine-131 ((131)I)-labeled anti-CD20 monoclonal antibodies (MAbs) are effective single agents for the treatment of relapsed non-Hodgkin's B-cell lymphomas. However, despite high initial response rates, most patients treated in this manner will eventually relapse. We hypothesized that regimens combining (131)I-anti-CD20 antibodies with standard chemotherapeutic agents may provide synergistic anti-tumor effects, and may improve the durability of responses in patients with lymphoma. To identify promising agents for clinical testing, we assessed the in vitro cytotoxicity of combinations of (131)I-anti-B1 (anti-CD20) antibody and 8 chemotherapeutic agents using 2 human CD20-expressing lymphoma cell lines and 2 corroborative assays, the thiazolyl tetrazolium bromide (MTT) and the Trypan blue dye exclusion assays. ID(50) isobolographic and dose modification factor (DMF) analyses were used to classify interactions between the (131)I-anti-B1 antibody and the chemotherapeutic agents as supra-additive (synergistic), additive or sub-additive. Cytarabine and fludarabine were markedly supra-additive when combined with the radioimmunoconjugate, with the combination enhancing cytotoxicity 3. 5- to 5.2-fold over the level expected by simple addition of the 2 agents (DMFs 3.5-5.2). Etoposide, doxorubicin and SN-38 were moderately supra-additive (DMFs 2.0-2.8). Cisplatin and 4-hydroxycyclophosphamide exhibited merely additive cytotoxicity (DMFs 1.0-1.1). Thus, combination regimens containing (131)I-labeled anti-CD20 antibodies and nucleoside analogs or topoisomerase inhibitors appear particularly attractive for future clinical trials.
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PMID:Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treatment of B-cell lymphomas. 1058 92

First-line chemotherapy and/or radiotherapy can achieve disease-free survival in 30% to 75% of patients with non-Hodgkin's lymphomas (NHL), a diverse group of hematologic malignancies, depending on disease stage. However, as many as 50% of patients with advanced-stage NHL either do not achieve an Initial clinical response or subsequently relapse. Topotecan, a topoisomerase-I inhibitor, is considered a potential treatment for NHL. The efficacy of topotecan, alone and in combination with paclitaxel, in the treatment of patients with relapsed NHL has recently been Investigated. In a clinical study of topotecan as a single agent, patients with aggressive NHL who had received only 1 prior chemotherapy regimen had a 43% response rate, and similar patients with Indolent NHL had a 40% response rate. A combination of paclitaxel and topotecan has been shown to have efficacy in a phase 11 trial, with overall response rates of 27% in patients with primary refractory NHL and 72% in patients with relapsed NHL. Based on these promising early results, further Investigation of topotecan in the treatment of NHL is warranted.
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PMID:The role of topoisomerase-I inhibitors in the treatment of non-Hodgkin's lymphoma. 1062 24

The incidence of secondary myelodysplastic syndromes and acute leukemia (MDS/AL) was reported for 395 patients autografted for Hodgkin's disease (HD) (n = 96) and non-Hodgkin's lymphoma (NHL) (n = 299) between 1987 and 1998. Eleven patients developed secondary MDS/AL (crude rate at 2.8%) including two lymphoblastic AL cases. The mean time of occurrence was at 32 months after autologous stem cell transplantation (ASCT) and 71 months after diagnosis. The estimated actuarial incidence at 10 years was at 6.3% (+/-4%). Karyotyping revealed complex chromosomal aberrations in only one patient, and two translocations [t(8;21) and t(8;16)]. No features of topoisomerase II inhibitor-related leukemia were found. Only one patient had received ASCT in first remission. The remaining 10 patients had received multiple courses of chemotherapy before stem cell collection and four had relapsed after ASCT and before the occurrence of secondary MDS/AL. Five of 11 patients had received localized radiotherapy and five others received TBI in their conditioning regimen. Ten patients died despite chemotherapy and/or supportive care and only one patient is alive and well after genoidentical allogeneic transplantation. We suggest a cumulative leukemogenic role of pre-ASCT radiation and chemotherapy in the occurrence of these secondary MDS/AL more than the high-dose therapy itself.
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PMID:Myelodysplasias and leukemias after autologous stem cell transplantation for lymphoid malignancies. 1096 73

Acute leukemia is the most frequent therapy-related malignancy. Together with the increasing use of chemo- and radiotherapy, individual predisposing factors play a key role. Most of secondary leukemias can be divided in two well-defined groups: those secondary to the use of alkylating agents and those associated to topoisomerase inhibitors. Leukemias induced by alkylating agents usually follow a long period of latency from the primary tumour and present as myelodysplasia with unbalanced chromosomal aberrations. These frequently include deletions of chromosome 13 and loss of the entire or of part of chomosomes 5 or 7. The loss of the coding regions for tumor suppressor genes from hematopoietic progenitor cells is a particularly unfavourable event, since the remaining allele becomes susceptible to inactivating mutations leading to the leukemic transformation. The tumorigenic action of topoisomerase inhibitors is on the other hand due to the formation of multiple DNA strand breaks, resolved by chromosomal translocations. Among these, chromosome 11, band q23, where the myeloid-lymphoid leukemia (MLL) gene is located, is often involved. Frequent partners are chromosomes 9, 19 and 4 in the t(9;11), t(19;11) and t(4;11) translocations. Younger age, a mean period of latency of 2 years and monocytic subtypes are characteristic features of this type of leukemia. Among patients at risk for secondary leukemia, those with Hodgkin's disease are the most extensively studied, with the major impact of alkylating agents included in the chemotherapy schedule. The same is true for non-Hodgkin's lymphoma, while in multiple myeloma and acute lymphoblastic leukemia determinants are the dose of melphalan and of epypodophyllotoxin, respectively. Patients with breast, ovarian and testicular neoplasms are also at risk, in particular if trated with the association of alkylating agents and topoisomerase II inhibitors. According to the EBMT registry, in patients with lymphoma treated with high-dose therapy and autologous stem cell transplantation the cumulative risk of inducing leukemia at 5 years is 2.6%. Among treatment options, supportive therapy is indicated in older patients, while allogeneic stem cell transplantation, related or matched-unrelated, is feasible in younger patients. These data indicate the need for the identification of predisposing factors for secondary leukemia. In particular, frequent follow-up of patients at high-risk should be performed and any peripheral blood cytopenia should be considered suspicious. Whenever possible, the exclusion of drugs known to be leukemogenic from the treatment schedules should be considered, especially in young patients.
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PMID:Therapy related leukemias: susceptibility, prevention and treatment. 1137 39

Seventy-seven patients were identified with Rare recurring (excluding 11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511 patients with treatment-related myelodysplastic syndromes and acute leukemia accepted from centers in the United States, Europe, and Japan. The abnormality subsets included 3q21q26 (17 patients), 11p15 (17 patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients), t(8;16)(p11;p13) (9 patients), and an "other" subset, which included t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3 patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients), t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with additional balanced and unbalanced rearrangements was observed in 70% of cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or 7 abnormalities were observed in 59%. The most frequent primary diseases were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients received alkylating agents plus topoisomerase II inhibitors with or without radiation therapy. The presenting diagnosis was t-AML in 47 cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven cases, five of whom had a t(9;22). The median latency time from initiation of original therapy to therapy-related disease diagnosis was quite long (69 months), and the overall median survival from the date of therapy-related disease diagnosis was very short (7 months). The 1-year survival rate was 34 +/- 7%, with no significant differences among subsets. Comparison with previously reported cases showed increased karyotypic complexity and adult presentation of pediatric-associated chromosome abnormalities.
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PMID:Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. 1192 Dec 74

Between 1972 and 1988, 869 adult patients received MOPP (mechlorethamine, vincristine, procarbazine and prednisone; 462 patients) or ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine; 373 patients) and subsequent high-dose irradiation for Hodgkin's disease. Nine patients developed a leukaemia after MOPP and four after ABVD; 11 patients were diagnosed as acute non-lymphoblastic leukaemia (ANLL) and two as acute lymphoblastic leukaemia (ALL). Both cases of ALL were observed after ABVD and were associated with a 11q23 translocation. The 15-year actuarial risk of secondary leukaemia was 2.4% for the whole group of patients, 3.4% after MOPP and 1.3% after ABVD. For the MOPP subgroup, the risk of leukaemia was significantly associated with the extent of irradiation: 2.4% for limited irradiation and 13.9% for extended irradiation (P < 0.001). For the ABVD subgroup, this risk remained low (1.3%) whatever the type of irradiation. Concerning ANLL, the MOPP regimen was significantly associated with a higher risk: 3.4% versus 0.7% for ABVD (P<or=0.05). The 15-year risk of ALL was 0.6 after ABVD regimen. This study demonstrated that ABVD induced less ANLL than MOPP. However, a low risk of ALL with a 11q23 translocation related to topoisomerase II inhibitors was observed.
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PMID:Fifteen-year secondary leukaemia risk observed in 761 patients with Hodgkin's disease prospectively treated by MOPP or ABVD chemotherapy plus high-dose irradiation. 1210 Jan 47


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