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

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.
 ...
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.
 ...
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.
 ...
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

The etiology and pathogenesis of Hodgkin lymphoma (HL) are not yet known. There are implications of genes involved in programmed cell death (apoptosis), and there have been repeated suggestions of an association with Epstein-Barr virus (EBV). The aim of this study was to investigate the protein expression patterns of key cell cycle-related genes, together with evidence of apoptosis and EBV status, in relation to clinical stage in HLs. A double immunohistochemical and in situ hybridization technique was used to detect the expression of bcl-2, p53, retinoblastoma (Rb), p21, Ki67 (MIB 1), and topoisomerase IIalpha (TopoIIalpha), together with latent membrane protein-1 and EBER for EBV status and TdT-mediated dUTP-FITC nick end-labeling (TUNEL) as a measure of apoptosis, on tissue microarray sections of 62 cases of classic HL (35 NS, 17 MC, 8 LR, and 2 LD). A panel of phenotypic markers was used to facilitate recognition of Hodgkin and Reed-Sternberg (H-RS) cells: CD3, CD20, CD30, CD15, and EMA. The H-RS cells of 62 classic Hodgkin lymphomas were bcl-2-positive in 35 cases (56.45%), p53-positive in 14 (22.58%), and positive for both EBV latent membrane protein-1 and EBER in 37 (59.68%); there was complete concordance of results for EBV by both procedures. No correlation was found between expression of bcl-2, p53, or EBV markers in H-RS cells and clinical stage (P > 0.05). Expression of Rb, Ki67, p21, and TopoIIalpha did, however, show significant differences with clinical stage. Expression of Rb and p21 in CD30-positive H-RS cells decreased with more advanced stage (P < 0.001). In contrast, Ki67 and ToPoIIalpha expression increased with later stage (P < 0.01). No correlation was found between expression of any of these markers in H-RS cells and the subtypes of nodular sclerosis HL, mixed cellularity HL, and LRHL (P > 0.05). TUNEL was found in the nonneoplastic cellular background in all cases and in H-RS cells in only 10 of 62 cases (16.12%) (8 nodular sclerosis HL, 1 mixed cellularity HL, and 1 LRHL). There was a significant correlation between high expression of bcl-2 and a low score by TUNEL (P < 0.05). These data are consistent with the notion that overexpression of bcl-2 may be linked to blockage of apoptosis-mediated death of H-RS cells in classic HL. Abnormal expression of p53-related protein may not play a major role in HL, because it is present in H-RS cells in only a minority of cases. Increased expression of Ki67 and TopoIIalpha by H-RS cells is significantly associated with advanced stage and may indicate aggressive disease. Adverse clinical outcome in HL also is associated with loss of Rb and p21 protein expression, consistent with the possible roles of Rb and p21 in inhibition of the growth of H-RS cells. Within the limitations of the methods used, almost two thirds of cases of HL provide evidence of an association with EBV. The tissue microarray technique is valuable not only for examination of large numbers of cases of a disease by a complex panel of markers but also potentially as a control for staining quality in immunohistochemistry and in situ hybridization.
 ...
PMID:Apoptosis and cell cycle-related genes and proteins in classical Hodgkin lymphoma: application of tissue microarray technique. 1296 46

Etoposide is a derivative of podophyllotoxin widely used in the treatment of several neoplasms, including small cell lung cancer, germ cell tumours and non-Hodgkin's lymphomas. Prolonged administration of etoposide aims for continuous inhibition of topoisomerase II, the intracellular target of etoposide, thus preventing tumour cells from repairing DNA breaks. However, the clinical advantages of extended schedules as compared with conventional short-term infusions remain unclear. Oral administration of etoposide represents the most feasible and economic strategy to maintain effective concentrations of drug for extended times. Nevertheless, the efficacy of oral etoposide therapy is contingent on circumventing pharmacokinetic limitations, mainly low and variable bioavailability. Inhibition of small bowel and hepatic metabolism of etoposide with specific cytochrome P450 inhibitors or inhibition of the intestinal P-glycoprotein efflux pump have been attempted to increase the bioavailability of oral etoposide, but the best results were obtained with daily oral administration of low etoposide doses (50-100 mg/day for 14-21 days). Saturable absorption of etoposide was reported for doses greater than 200 mg/day, whereas lower doses were associated with increased bioavailability, although they were characterised by high inter- and intrapatient variability. Pharmacokinetic parameters such as plasma trough concentration between two oral administrations (C(24,trough)), drug exposure time above a threshold value and area under the plasma concentration-time curve have been correlated with the pharmacodynamic effect of oral etoposide. Pharmacokinetic-pharmacodynamic relationships indicate that severe toxicity is avoided when peak plasma concentrations do not exceed 3-5 mg/L and C(24,trough) is under the threshold limit of 0.3 mg/L. To maintain effective etoposide plasma concentrations during prolonged oral administration, pharmacokinetic variability must be monitored in each patient, taking account of factors from many pharmacokinetic studies of etoposide, including absorption, distribution, protein binding, metabolism and elimination. Dosage reduction is generally useful to avoid haematological toxicity in patients with renal dysfunction (creatinine clearance <50 mL/min). The need for dosage adjustment based on liver function in patients with liver dysfunction is not completely defined, but generally is not indicated in patients with minor liver dysfunction. Adaptive dosage adjustment based on individual pharmacokinetic parameters, estimated using limited sampling strategies and population pharmacokinetic models, is more appropriate. This approach has been used with success in different clinical trials to increase the etoposide dosage, without significantly increasing toxicity. Various pharmacodynamic models have been proposed to guide etoposide oral dosage. However, they lack precision and accuracy and need to be refined by considering other predictor variables in order to extend their application in current clinical practice.
 ...
PMID:Pharmacokinetic optimisation of treatment with oral etoposide. 1513 94

Pixantrone is an anthraquinone-based inhibitor of topoisomerase II. It is similar to both the anthracycline doxorubicin and the anthracenedione mitoxantrone, but lacks the 5,8-dihydroxy substitution pattern of mitoxantrone, and has a tricyclic system unlike the tetracyclic structure seen with anthracyclines. Anthracyclines are the most active drugs in lymphoma therapy, but their use is limited by their cumulative and irreversible cardiotoxicity. Pixantrone was developed to improve the toxicity profile of the current anthracyclines and anthracenediones while maintaining their activity. Interestingly, pixantrone showed no measurable cardiotoxicity compared with its parent compound mitoxantrone or other anthracyclines at equi-effective doses in several animal models. Together with its superior cytotoxic activity in leukaemia and lymphoma models, these features render the drug a promising candidate for clinical development in indolent and aggressive non-Hodgkin's lymphoma. In this review, the latest results of the use of pixantrone in indolen-t and aggressive non-Hodgkin's lymphomas are summarised.
 ...
PMID:The role of pixantrone in the treatment of non-Hodgkin's lymphoma. 1605 Jul 97

Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Sequential administration of a topoisomerase II inhibitor followed by a topoisomerase I inhibitor is potentially synergistic due to increased target enzyme levels. Patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL) were eligible for this phase II study of doxorubicin 25 mg/m2 intravenous (IV) on day 1 and topotecan 1.75 mg/m2/day IV on days 3 - 5, every 21 days. The trial objectives included the overall response rate, progression-free survival, and toxicity. Twenty-six patients were enrolled and 25 patients are assessable for toxicity and response. The median age was 58 (range 23 - 74) years. The patients had received a median of two (range one to five) prior regimens, including five patients with a prior stem cell transplant. Five patients (20%, 95% confidence interval 0.07, 0.42) responded with two (8%) complete remissions and three (12%) partial remissions; an additional four (16%) patients had stable disease. Both patients achieving a complete remission had Burkitt's lymphoma. There were no treatment-related deaths. In conclusion, the combination of doxorubicin and topotecan is well tolerated and has modest activity in relapsed/refractory NHL, with occasional patients having a prolonged remission. The activity in Burkitt's lymphoma should be investigated further.
 ...
PMID:Sequential doxorubicin and topotecan in relapsed/refractory aggressive non-Hodgkin's lymphoma: results of CALGB 59906. 1696 61

Constitutive nuclear factor kappaB (NF-kappaB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kappaB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kappaB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kappaB activation through IkappaB kinase activation in not only H-RS cell lines with wild-type IkappaBalpha, but also in those with IkappaBalpha mutations and lacking wild-type IkappaBalpha. Thus, both constitutive and inducible NF-kappaB are potential targets to treat HL. We also present the data that indicate the involvement of IkappaBbeta in NF-kappaB induction by topoisomerase inhibitors. A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kappaB activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gammac(null) (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NF-kappaB. Results of this study suggest that both constitutive and inducible NF-kappaB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkappaBbeta is involved in NF-kappaB activation in H-RS cells and IkappaBbeta substitutes for IkappaBalpha in H-RS cells lacking wild-type IkappaBalpha.
 ...
PMID:IkappaBalpha independent induction of NF-kappaB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells. 1731 Feb 17

Epidemiological studies show that benzene exposure is associated with an increased incidence of leukemia and perhaps lymphoma. Chromosomal rearrangements are common in these hematopoietic diseases. Translocation t(14;18), the long-arm deletion of chromosome 6 [del(6q)], and trisomy 12 are frequently observed in lymphoma patients. Rearrangements of the MLL gene located on chromosome 11q23, such as t(4;11) and t(6;11), are common in therapy-related leukemias resulting from treatment with topoisomerase II inhibiting drugs. To examine numerical and structural changes in these chromosomes (2, 4, 6, 11, 12, 14, and 18), fluorescence in situ hybridization (FISH) was employed on metaphase spreads from workers exposed to benzene (n = 43) and matched controls (n = 44) from Shanghai, China. Aneuploidy (both monosomy and trisomy) of all seven chromosomes was increased by benzene exposure. Benzene also induced del(6q) in a dose-dependent manner (P(trend) = 0.0002). Interestingly, translocations between chromosomes 14 and 18, t(14;18), known to be associated with follicular non-Hodgkin lymphoma, were increased in the highly exposed workers (P < 0.001). On the other hand, translocations between chromosome 11 and other partner chromosomes that are found in therapy-induced leukemias were not increased. These data add weight to the notion that benzene can induce t(14;18) and del(6q) found in lymphoma, but do not support the idea that benzene induces t(4;11) or t(6;11). However, they do not rule out the possibility that other rearrangements of the MLL gene at chromosome 11q23 may be induced by benzene.
 ...
PMID:Aberrations in chromosomes associated with lymphoma and therapy-related leukemia in benzene-exposed workers. 1758 86

Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is an increasingly recognized treatment complication in patients treated with radiotherapy or chemotherapy for previous hematologic malignancies or solid tumors. Distinct clinical entities have been described according to the primary treatment, corresponding to defined genetic lesions. Chromosome 7 and/or 5 losses or deletions are typical of alkylating agent-induced AML, while development of t-AML with balanced translocations involving chromosome bands 11q23 and 21q22 has been related to previous therapy with drugs targeting DNA-topoisomerase II. In addition, antimetabolites, and in particular the immunosuppressant azathioprine, have been shown to induce defective DNA-mismatch repair. This could promote survival of misrepaired cells giving rise to the leukemic clone. Individual predisposing factors, including polymorphisms in detoxification and DNA repair enzymes have been identified. Their combination may significantly increase the risk of t-MDS/AML. Among patients with hematologic malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased risk of t-MDS/AML, particularly when receiving MOPP-based, and escalated BEACOPP regimens, and when alkylators are combined with radiotherapy. Patients with Hodgkin's and non-Hodgkin's lymphoma are at highest risk when total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation therapy. The addition of granulocyte-colony-stimulating factor and radiotherapy plays a significant role in t-AML following treatment of children with acute lymphoblastic leukemia. In non-hematologic malignancies, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of both lymphoid as well as myeloid leukemia. In all cases the risk of t-MDS/AML drops sharply by 10 years after treatment.
 ...
PMID:Therapy-related leukemia and myelodysplasia: susceptibility and incidence. 1776 13


<< Previous 1 2 3 Next >>